I’m thrilled to welcome
you to the last Longwood Seminar of 2018. Thank you for being
with us tonight. I’m Gina Vild. I’m the Associate Dean for
Communications and External Relations at Harvard
Medical School. We have been offering this
mini med school for 18 years, and it’s a success because
of your continued interest and enthusiasm. There are so many people
who have been attending year after year. You are familiar faces, and a
Longwood Seminar family to us. So I want to thank you for
your engagement, for attending, for joining our discussion
on social media, and from tuning in from
locations all over the world, because I’m really thrilled to
also welcome our live stream viewers tonight. I’d like to share with you
that this year, the first three seminars were viewed by
more than 60,000 people from all over the world,
including countries Brazil, Japan, Australia,
South Korea, Morocco, and the United Kingdom. So, thank you. We’re thrilled to have
you be a part of this. And I invite you, if you missed
any of this year’s seminars, or would like to view any of
our past seminars, many of them are Evergreen, please look
at the Harvard Medical School website. I also invite you to access
additional Harvard Medical School resources by visiting
Harvard Health Publishing website,
www.health.harvard.edu, where you will find extensive
health-related information, including tonight’s topic
of obesity and nutrition. We ask that you help us
keep our future Longwood Seminars fresh and topical
by responding to a survey that we’re going to be sending
you within a few weeks. We use these surveys to evaluate
the success of our seminars and to help us plan future
seminars, including topics. We do tend to
crowdsource our topics, so your ideas are
valued and appreciated. Now, a couple final
announcements. More than 160 of
our attendees have earned certificates
of completion by attending three or
more seminars this year. And, that number, I’m told, may
be as high as 200 individuals. So we’re thrilled. We’re awed by your commitment,
and we honor your achievement, so please join me in
congratulating all of you. [APPLAUSE] Thank you. If you’ve already
qualified, you will be able to pick up your
certificate in the lobby after the seminar, or, we
will mail it to your home. We also will be mailing our
professional development point certificates for teachers. Those will be coming to you in
the mail in the coming weeks. Our speakers will
be taking questions at the end of the talk, so
please write your questions on a card that you
will see our staff passing up and down the aisle. Just hand them your questions. If you’re watching
from the live stream, please write your
question in the Facebook Live or the YouTube
comments section, and we will try to get to as
many of those as possible. Now, please silence your
phone, but don’t turn it off, because we invite you to join
our Twitter conversation using #hmsminimed. Before we formally
begin the program, I just want to take
a moment to introduce two members of our
team who, and really to express my gratitude
to them for all their extraordinary work. They’re good listeners. They’ve listened to
everything you’ve told them. They’ve tried to really
orchestrate a perfect seminar season for you, and they have
tremendous attention to detail. So please join me in thanking
Barbara Berlin and Elsa Fong. [APPLAUSE] Thank you. Thank you so much. Thank you. Thank you. OK, for this evening’s program,
Weighing the Facts of Obesity. Obesity tops the list of acute
health challenges in the US. Here are just a few statistics
from the National Institutes of Health. Did you know that more
than two in three adults are considered to be
overweight or obese? More than one in three adults
are considered to be obese. About one in 13
adults are considered to be extremely obese. Particularly worrisome as this,
the statistics for children, about one in six children
and adolescents ages 2 to 19, are considered obese. But what’s the root cause, and
why is it affecting children as young as two years of age? Former First Lady Michelle
Obama worked for eight years to raise awareness for obesity. In launching her
initiative, Let’s Move, she said the physical
and emotional health of an entire
generation is at stake. You may already know that
obesity is not simply the result of too much food
and too little activity, but what are the
contributing factors? Is there a connection
between obesity and genetics? Does being overweight put
you at risk of developing chronic medical conditions? And, what positive steps
can both children and adults take to shed the extra
pounds, and to begin to rebuild their physical
and mental health? We don’t yet have
all the answers, but we do have is a panel of
experts from Harvard Medical School. They’re here with us to share
their research expertise on the causes of obesity, and
possible treatments that could help combat this epidemic. Dr. Frank Scheer is
an associate professor of medicine at Harvard
Medical School, and Director of the
Medical Chronobiology Program at Brigham
and Women’s Hospital. Dr. Christos Mantzoros
is a professor of medicine at Harvard
Medical School, and the Director
of Human Nutrition Unit in the Division of
Endocrinology Diabetes and Metabolism at Beth Israel
Deaconess Medical Center, and the Joslin Diabetes Center. And first you’ll hear from
our moderator, Fatima Cody Stanford. Dr. Stanford is an instructor
of medicine at Harvard Medical School, and an obesity medicine
physician at Massachusetts General Hospital. A nationally recognized expert
on obesity, Dr. Stanford has recently been
exploring the impact of behavioral environmental
factors in the complex process of weight regulation. Thank you for attending,
and please join me in welcoming our guest speakers. [APPLAUSE] Good evening, everyone. Let’s try that again. Good evening. Good evening. Excellent. Today we’re going to learn
about weight bias and stigma. We’re going to spend some
time learning about obesity and its pathophysiology,
and as soon as my slides appear there,
because they are here, we will move forward. So I’m Dr. Fatima Cody
Stanford, and we’re going to spend time talking
about weight bias and stigma, and its impact on care. So what we’re going
to do, is we’re going to discern how weight
bias and stigma contribute to energy storage. We’ll learn about how early
life interactions influence weight bias. Then, we’ll determine the
deleterious impact of weight bias on health
outcomes, ascertain how health professionals
harbor both implicit, which is bias that is inside of
us that we’re not aware of, and explicit, which is
bias that we are aware of. And then I’m going to explain
how organized medicine organizations have
sought to tackle the issue of weight bias. So, we’re going to start
talking about my childhood. So, I am in this orange here. So, that’s me, and
this is my sister. So I thought– I
wanted to make sure that we were both included. And the reason why I’m starting
here is because I was humbled, and then actually a
little bit perturbed when a colleague of
mine came up to me and told me that
at the age of five, I came up to her in
dance class, which is why you see these
dance pictures, and said to her
that she was fat. Now, she just told me
this about a year ago. She actually is an
obesity medicine physician practicing currently,
but she said that that influenced her life. And she said that
if anyone was– if I was capable of
change with regard to this issue of weight
bias, then anyone was capable of change. So that was quite
humbling, that someone that dedicates my life
to the care of patients that have obesity– you will notice I will state
the words “have obesity” because this is a condition
that people aren’t defined by. They have the
disease of obesity. So we’re not going to refer
to patients as obese patients throughout the course
of this presentation. Rather, these are patients
that have obesity. But you can imagine,
that if someone that is committed to
this disease process, that it was quite startling
that at the age of five I went to a colleague of mine,
I guess our childhood friend, and called her something that
had a major impact on her life. It could have been
a negative impact. Thankfully, it was
a positive impact. But let’s think about how,
starting at this very young age, this causes major issues. Now, we’ve learned
about energy balance, and we’ve learned that
it’s about just calories in and calories out, the food
and beverages that we take in, and the bodily functions,
and physical activity. We have stool output, et cetera. But if it were really the
simple, I wouldn’t have a job. I would not be an obesity
medicine physician scientist. So we’re going to learn about
why this is indeed incorrect. It’s not a lifestyle choice. It is a disease process. And yes, we are interacting
with our environment, which is an obesogenic environment. But we’re going to learn about
why this is indeed false. So, obesity is a
multi-factorial disorder where genetics, environment,
development and behavior all play a role in a person’s
likelihood of having obesity. Now, we’re going to start
with some really complex information, but
this will explain why obesity is a disease process. So what really regulates
our weight is the brain, OK? So the brain is very
important in all of this. It helps define our set point,
or set range, for our weight. The hypothalamus,
which is located here, gets signals from our fat
tissue, our large intestine, our small intestine, our
pancreas and our stomach, and then sends
signals to your brain to tell us not only
how much to eat, but it also tells us
how much to store. So let’s look at the brain. The brain is getting signals
about our diet quality. So I will always ask my
patients not about the number of calories they’re eating. I’m asking them about the
quality of their diet. Their energy density
is important. It’s getting information
about physical activity. Now, the important thing for us
to know about physical activity and the role it plays
in regulating weight, is that it helps to
create weight stability. However, in January of every
year, in the United States and across the world, we go
and join gyms to lose weight. When our gym enthusiasm doesn’t
lead to weight loss, many of us leave the gym. That’s important to
not do, because we know that physical
activity is one of the best things
that contributes to weight maintenance. Not often weight loss. On average, people lose no
more than about to two pounds if they’re dedicated to
their physical activity, but it does have a lot of
other positive impacts. Now sleep. Sleep quality and duration
plays a large role in how the body
regulates weight, and we’ll hear about
that a little bit later from one of
the other speakers. Medications that we
prescribe, as physicians, can lead to weight gain. I go through a laundry list
with patients, of medicines that can lead to weight gain. I’ll go through
that now with you. Lithium, Depakote Tegretol,
Celexa, Cymbalta, Effexor, Paxil, Prozac, Ambien,
trazodone, Lunesta, Gabapentin, gliperide, glipizide,
glimepiride, atinalum, Toprolol, propanalol,
long-term insulin, and long-term
prednisone, just a few of the drugs that can
cause weight gain. And I do do that
with every patient. [APPLAUSE] Patients that have circadian
rhythm disturbances can have issues with
regards to rate. So those pathways that we
looked at in the brain are affected by circadian rhythm. And then, finally,
thermogenesis, which is just how much we burn
with activity and with rest. A lot of that is
genetically determined. So these things play a role
in how the body is regulating your weight, and
whether or not you have a propensity
to having obesity. Now, this is a very busy
chart, and this is something that you can access by
looking at the obesity society infographics. But what I love
about this chart, is that it explains the
potential contributors to obesity that we know of. What you can see
there are things that happen inside of the person. There are things that happen
outside of the person, that– and they’re contributors
or influencers to obesity. These things here at the top
increase how much you take in. These things here
at bottom decrease how much you’re able to
burn, and these things here in the middle affect
either how much you’re eating, or how much you’re burning, or
notice there’s an unknown here. We just haven’t figured it out. But this is how complex it is. Now, we’re not going to go
through each of these factors here, but we are going to
touch on a few of them, just to give you an idea of
looking at these contributors or influencers. Now when we look at contributors
or influencers to obesity, they fall within
these broad categories of biological or medical. Food and beverage
behavior and environment, maternal and developmental,
social, psychological, economic, and then environmental
pressures on physical activity. Now let’s look at some of these
contributors that happen inside of the individual, things that
might create, then increase intake or hyper-reaactivity
to environmental food cues, delay to tidy, so this delayed
idea of how long it takes you to feel full. Disordered eating, we can have
decreased expenditure explained by the gut microbiota,
meaning the bacteria in the gut of individuals
that has obesity is different than the bacteria
of those that are lean. Thermogenesis, we talked about. Physical disabilities,
things that might affect your intake
and your expenditure may be genetics and
epigenetics, age-related changes or mood disturbances. Things that may happen
outside of you that contribute to your intake are environmental
or chemical toxins, pervasive food advertising,
or large portion sizes, things that might
decrease your expenditure or our built environment,
how our environment allows us to be active, sedentary
time, labor-saving devices, and things that might
affect our increased intake or expenditure may be weight
bias and stigma, which is the focus of my
segment, weight cycling, and/or maternal or
paternal obesity. Now when we look at
the bias, you know, the other thing that we
really pay attention to, especially here in the
United States, is race bias. Now race bias– I specifically
put up this post here, is that if you did
a Google search and typed in the term black
teenagers, or black teen men, you got mug shots,
unfortunately, so nothing positive. If you typed in a white
or Caucasian teen, you got these kind of
nice, smiling pictures that was featured in
The Washington Post. So this is pervasive, even
in our search engines, unfortunately. Google has tried to change
their algorithm to combat this. Now when we look
at weight bias, we do have these kind of adjectives
that are demonstrated here. So you have this
very lean individual, and so there are
adjectives that might be used to describe her as
vain, superficial, ambitious or conceited. For this woman that has
obesity on the right, she might be
considered to be lazy, insecure, given,
undisciplined, or passive. So just by looking
at them, we’ve made judgments on what
their qualities are without learning anything about
them and their experience. Now, let’s look at when do we
really start to exhibit bias? When does this happen? So there was this
study that was done, looking at mothers and children,
and they looked at children across an age spectrum. And they found that older
infants, about 11 months of age, tended to view,
or have a preference for, a heavier body type, so a
body type that had obesity. Now, as they got a
little bit older, older toddlers, so
around 32 months of age, instead pervert looking
at average-size or leaner individuals. And this was strongly influenced
by the mother’s prejudice against those that had obesity. So just as early as
32 months of age, children begin to
demonstrate bias. Now, let’s look at how
parents can influence weight bias in children. This was a big
study that was done, exploring the role of
parents in the transmission of the stereotype about
body size and attitudes. They looked at 279
three-year-old children and their parents, and
they asked the parents to complete self-reported
body size attitude and dieting measures, and
interviewed the children. Over time, negative attitudes
towards large bodies and awareness of weight
loss strategies are merged, but there was a really
strong preference, such that fathers that
had this significant bias were more likely
to convey it upon– amongst their sons. For daughters, there
wasn’t specifically that the fathers or mothers
had a preference in terms of conveying that information. So, we have to pay attention
to what’s happening, and our biases, as people
that are parents, and how they affect our children. Now this was a great city. This was actually
done in Germany, so for my German audience
there, this study was looking at weight
teasing and weight bias internalization, and
psychological functioning, and they looked at close
to 1,100 male children between the ages of
7 and 11 in Germany. They completed surveys on
weight teasing, weight bias internalization, restrained
eating behaviors, and emotional conduct program– problems. And here, you can
see that BMI is the thing that they looked at. BMI stands for
body mass index, is what the World
Health Organization uses to define
someone’s weight status. And if someone had
issues with their BMI, they were predisposed
to weight teasing and predisposed to weight
bias internalization. They also decided to
restrain their eating. Now, weight teasing
was specifically associated with emotional
problems and conduct problems in these individuals that
struggled with obesity, and then internalizing
the bias they experienced also affected both restrained
eating and emotional problems. So here we are seeing
that in these young boys, this is affecting their
medical health and also their psychological functioning. So does this really
mean anything? Does this translate
to outcomes later on? Absolutely. So, this particular
study looked to identify whether weight-based
teasing in adolescents predicted adverse eating,
or weight-related outcomes 15 years later. What they did, was they
collected information from Project EAT-IV, which
was almost 2000 individuals. And they did a cohort study,
meaning, they started in 1999, and went over all
the way to 2015, to see what the impact
was of this weight teasing in adolescence was
on individuals. So what you found here is
that weight-based teasing in adolescence predicted
a higher body mass index, and obesity, 15 years later. So people that had
a high BMI, then led them to have binge eating,
dieting and unhealthy weight control, and affected
their body image. Now for the females that
were studied, what we saw was that both peer and
family-based teasing caused issues, whereas for
the males in the study, peer-based teasing specifically
appear to have the highest impact on their BMI long-term. So, let’s look at weight
bias internalization and metabolic syndrome,
and metabolic syndrome is this likelihood of
developing obesity. They looked at blood pressure,
waist circumference, glucose, which is blood sugar,
triglycerides, which is a type of
cholesterol, and HDL, which is a good
cholesterol measure, and adults with obesity
in a weight loss trial. In this trial, you
can see that this was predominantly
African-American and 88% female, which is pretty
indicative of what we see in weight management. And 51 adults, or about
a third of the adults met criteria for
metabolic syndrome. And they’re higher weight
bias internalization, so we’re really feeling the
impact of the weight bias they experience,
predicting greater odds of metabolic syndrome
and high triglycerides. And high triglycerides is one
of these bad cholesterols. So, the mental health
of persons with obesity who experience bias, it
causes physiologic stress. It leads to weight gain. It leads to disordered eating,
and then maladaptive behaviors, which we see in adult life. So, this particular study looked
at about 20 to 2,400 adults that completed questionnaires
about weight stigma, bias internalization and
coping strategies. Women, overall, reported higher
weight-based internalization compared to males. Black men and women, however,
reported less weight bias internalization than
white men and women, and black women were less
likely and Hispanic women were more likely to cope with
stigma using disordered eating. Black men, however,
surprisingly, were more likely
to cope with stigma using disordered
eating, which was a bit surprising
in their findings. So, what happens
with medical students who become your physician? So they did a study
at Wake Forest, and they looked at 310
third-year medical students between 2008 and 2011. They took a test called the
Weight Implicit Association Test, and in this
particular test, they found that a third
of the individuals exhibited moderate or
strong explicit bias. Explicit bias is
this bias that we know that we have to individuals
that struggle with weight. But what was more surprising
is that 2/3 were unaware of their implicit anti-fat bias,
so that they didn’t realize that they had this prejudice
towards individuals that struggled with their weight. This is a really great study. This is the Medical Student
Bias in CHANGES study. And this was a study
that looked at students for 49 US medical schools
throughout the country. These were public
and private schools, and they made sure that
they covered all regions within the United States. They looked at about
1,800 medical students at the beginning of
their first year, and at the end of
their fourth year, which is the conclusion
of medical school. They used web-based
surveys to include measures on weight bias,
and their medical school experience, and climate. So, in the implicit bias,
remember, implicit bias is this bias that you’re
unaware that you had. They also compared
this to the public. So they looked at about
398,000 persons in the public. And you can see that the weight
bias measures in the public are here, and the
CHANGES study, which were the medical students,
is here in this line. So over the course of that
four years of medical school, you saw a decrease
in implicit bias within the medical students,
compared to the general public. But, let’s not be so
excited about that, because explicit bias,
which is that bias that we know that we
have to individuals that struggle with
weight, you can see that over the
course of those four– those same four years, we saw
an increase in both the public and within the medical
students in terms of their explicit bias towards
that persons that struggle with weight. So what did they learn? That medical
students may reduce– or medical schools
may reduce weight bias by increasing positive contact
between students and patients with obesity, eliminating
unprofessional role modeling by faculty members
and residents, and altering the
curricula to focus on treating difficult patients. So, they did a big
systematic review, which means they looked
at all of the literature, looking at weight bias
in health professionals, and they found 15 studies with
health professional students, and two studies with
health professionals. So these are people that are
no longer students, people that have finished their training. What they found was that
the studies reported changes in health professionals’ beliefs
and knowledge about obesity and its ideology. However, the evidence of
effectiveness is poor, and we don’t know much about
how long-term effects are, because the studies
have really not studied the long-term impact
of any of these issues. So, when we’re looking at
weight stigma and the treatment of obesity, it’s
important for us to recognize that weight
stigma leads to stress. It affects eating and
physical activity behaviors, so we see binge eating,
increased caloric consumption, maladaptive weight control,
which we’ve talked about, disordered eating,
lower motivation for physical activity. We also see
physiologic reactions. So, we see increased
levels of stress hormones, like cortisol or
c-reactive protein, increase in our blood sugar, and
increase in our blood pressure. When patients experience
weight stigma, they have poor treatment
adherence, less trust of health care providers. They avoid follow-up care. They delay in preventing–
getting preventive health screenings, and they
have poor communication with their providers because
they really don’t respect them. This also leads to weight
gain and physiologic distress with depression, anxiety,
low self-esteem and poor body image, and it can lead
to poor glycemic control and advanced chronic disease,
which is very important. And then we also see lower
health-related quality of life. Now when we look
at ethnic identity and how it affects
implicit bias, there are similarities
and differences between African-American
and Caucasian women. Overall, African-American women
have less explicit weight bias, meaning, we don’t
specifically go to people and give them information that
tells us we have weight bias, but when they use the Implicit
Association Test, which is a pervasive
implicit anti-fat bias, African-American as well
as non-Hispanic women were found to have
implicit weight bias. African-American women that
had a lower ethnic identity, so maybe did not
as much identify with being African-American,
were negatively biased. And non-Hispanic white women
who had higher ethnic identity were more likely to
be negatively biased. So that ethnic
identity and how people relate to their race and
ethnicity plays a large role. Now, what– how
does this translate to what happens in
daily life in terms of things like graduate
school admissions? They did a study,
and they looked at all of these
schools, which I’ve heard is not in the live
stream, but the higher BMI significantly predicted
fewer post-interview offers of admission into
psychology graduate programs throughout the United States. This was specifically worse
for female applicants. And, BMI was not related
to the overall quality of the applicants, but it
did relate specifically to the number of weight– stereotypically weight-related
adjectives in the letters of recommendation. Higher BMI was related to
more positive adjectives in the letters,
but overall, they were not being accepted as
much into these schools. And then, there’s a lot
of bias in employability. So they specifically
did a study. They gave kind of
pictures of this woman, and they explained– they rated their impression
of her overweight image after learning
that she previously gained and lost weight. So people were really happy
that this patient lost weight, but when they found out that
this patient had undergone weight loss surgery, they
experienced significant bias compared to whether or not– comparing that to
someone that potentially could have lost weight
through diet and exercise. When I think about
weight loss surgery, I think it’s important
for us to recognize that it’s a tool in the spectrum
of treatments for persons that have severe obesity. So, we should not
judge negatively for the people that need
to utilize that tool, but just recognize that it’s a
tool that someone like myself might not need to utilize
to achieve and maintain a healthy weight. So, people have heard of
this show, The Biggest Loser, and so, how does this
affect our weight bias? People might say, “Oh, it
improves our weight bias,” but they did a study
where they looked at people that looked at an
episode of The Biggest Loser and compared those
to a control group, which was just a nature show. And what they found,
was pretty quickly, that persons that watch
this particular show, just one episode, exhibited
higher levels of weight bias because it showed the
controllability of obesity. Now what most of you
guys are unaware of, is that 96% of the patients
that go on The Biggest Loser regain all of their weight,
because there is the set point that we
talked about, which is why we start off
looking at the hypothalamus and how it regulates weight. There is a decrease in
resting energy expenditure, and so, when you decrease your
resting energy expenditure, which is how many
calories you have to have on board above something
like 600 calories, which is where theirs gets
dropped to after their very intense exercise
and eating programs, they eat 601
calories, their bodies do whatever it can to
compensate and come back to where it was previously. So they looked at
levels way by using the IAT, the Implicit
Association Test that we talked about, the Obese Person Trait
Survey which is the OPTS test, and the Anti-Fat Attitude Scale
at baseline and one week later, and you can see that
they felt as though this was more controllable
in these individuals, so significant higher bias
after looking at the show. So what are we doing here? So as an officer of the
Massachusetts Medical Society, I helped write the legislation
that recently passed last year, looking at discrimination
against persons with obesity. And it states the following:
“The Massachusetts Medical Society recognizes that weight
stigma in the health care setting leads to a disparity of
care and poor health outcomes in patients with obesity,
that the Massachusetts Medical Society will develop and
promote educational information to physicians, and physicians in
training, about weight stigma, and that the Mass Medical
Society will advocate for legislative policies
and institutional practices to prevent weight stigma.” I also helped draft
the language that passed the American
Medical Association right before it passed,
and actually the year after, the Mass Medical Society. So this just passed last annual
meeting, which was last June. And it is as follows. It says that, “Our AMA,”
which is the American Medical Association, “encourages the
use of people first language, meaning that we say
patients with obesity, patients affected by obesity,
in all discussions, resolutions or reports, regarding obesity. That we encourage the use of
preferred terms in discussions, resolutions and
reports regarding patients affected by
obesity, including weight and unhealthy weight,
and discouraging the use of stigmatizing terms, including
obese, morbidly obese, and fat. And, to educate
health care providers in the importance of
people first language for treating patients
with obesity, equipping their health care
facilities with proper size furniture, medical equipment,
and gowns for patients with obesity, and
having patients weighed in a
respectful fashion.” So, in summary, weight
stigma has a negative impact on the health and psychological
health of patients who struggle with obesity. It’s seen as early as infancy,
and maternal and paternal anti-fat bias
influences children. Weight bias may be mitigated
by proper training in health professionals, and that is all. So I want to thank
you for your time. I’m going to shift over
to Dr. Frank Scheer who will take over from here. [APPLAUSE] Thank you, Fatima,
for the introduction. I would like to thank the
organizers for inviting me to speak here,
and I’m very excited, seeing all you here attending. And, I’m a little bit
nervous, because I hear this is attended by
maybe 60 or 100,000 people. But, I will be talking
to you about kind of another side that
links to obesity and metabolic and
cardiovascular disease, which is sleep and the circadian system. And I’m dedicating this
lecture to my lovely wife, and my two fantastic sons
Bart and Toby, my wife Linda. And, as you’ve heard,
obesity is an epidemic currently in the United
States and in many developed countries. This is an image from just
about 20 years ago or so. So, the rates back then
were about 10% to 20% of the population in the
United States had obesity. But then just in a
short amount of time, just 20 years, this doubled
to about 20% to 40%, depending on the states
you are looking at. So a very rapid increase. And you can see
that it’s especially true in the southeastern
parts of the United States, and I’ll ask you to
just keep that in mind. So, we heard a lot about
the causes of obesity, if you think about
an individual level. And so, what are
the primary factors, from a biological
individual point of view? Well, these are genetics. So, each person is
different, but also your diet and your physical activity. And, of course,
they’re connected, because your genetics
may drive your diet, and may drive and influence
your physical activity. But if we ask what of– which
of these factors that really changed a great
deal in our recent– in the recent years which
is causing the rapid rise in the obesity epidemic? Well, it’s not going to
be genetics, of course. Because human species
hasn’t changed much in the last 20 years. So the focus has been,
for many decades, on diet and physical activity. And this is also why behavioral
approaches to prevent or treat obesity have been
focused on what we eat and how much we eat, and
how much we exercise, and how much we limit
sedentary activity. But might there be
other lifestyle factors that we can think
of that may help us? Because, the truth is, we
need all the help we can get, because diet and
exercise aren’t enough, as is clear from the obesity
rates and in the country today. So, one of these
factors might be sleep, which is what I’m going
to try to convince you of, and so Toby, my
youngest son, actually made me aware of insight by
a famous actor who actually recognized that sleep is– might actually be a super power. So Bill Murray wrote this. He said, “I love sleep, because
it’s like a time machine to breakfast.” OK, so there’s
already a clear link between sleep and metabolism
there, right, and nutrition. But on a more
serious note, sleep is a behavior that is really
representing one-third of our life, especially, of
course, when we are babies and toddlers, we sleep a lot. But even though we sleep
less and less as we age, it represents about
a third of our life. And so, that factor
by itself has really– intrigues many investigators
and clinicians. And it was actually
Alan Rechtschaffen who is one of the pioneers
in the sleep field who actually was– co-invented the
Sleep Scoring System, who very eloquently
indicated that, “If sleep does not serve an
absolutely vital function, then it’s the worst
mistake in evolution.” So, now this picture of– the same kind of picture as I
showed you before, of obesity, now for short sleep. And, what you can see is that
the rates of short sleep, and here defined as less than
seven hours of sleep per night, are between about 25 or
50% of the population. You’ll notice, again, that it’s
especially this same region here that is mostly affected. Now, this is, of course,
no evidence at all. And so, now we
have to really look at the scientific evidence. And, the scientific evidence,
based on epidemiological data, have shown, indeed,
that individuals who have either short
sleep or disturbed sleep have an increased risk
of being obese, having diabetes, or having
cardiovascular disease. And this is one example. Here, you can see short sleep,
as assessed by actigraphy. So, this is a wrist-worn
device, motion detector, that can objectively estimate sleep. And, of course, you’ve
all heard of many of these commercial devices,
but there are better scientific devices as well. And, in this study, it was
shown that as sleep duration decreases, the odds of
being obese goes up. And so, for example, here,
less than five hours of sleep, it’s doubling or quadrupling
of the odds of being obese. Now, of course, this
is an association. And, we all know that
association is not causation. So unfortunately,
epidemiological studies by themselves cannot
make that case. So we need to ask
the question, what is the causal evidence for the
link between sleep and obesity, and is it actually
sleep disturbances that cause obesity? Or, might it be that
if people have obesity, that this perturbs their sleep? And, there’s good
evidence for that as well. As you will probably know,
the chance for sleep apnea is greatly dependent on
one’s body mass index. And so, because sleep apnea
influences your sleep, that is a very reasonable
reverse causality right there. But there is actually a very
strong experimental data to make the case
to link, actually causally, decreased or impaired
sleep with adverse health consequences. So, highly controlled
in-laboratory studies, experimental within subject,
randomized controlled trials, have shown that disturbed
sleep or shortened sleep leads to disturbances of those
factors involved in glucose control, such as decreases
in the release of insulin, or decreased sensitivity
to the insulin, which are both risk factors for the
development of Type 2 diabetes. Similarly, although the
picture is a little bit more complicated, there
is also good evidence for changes in hunger
and appetite hormones, also hunger and, if people
are allowed how much they eat of experimentally
manipulating sleep duration, and finding that people
actually will crave to eat more. And, there’s also
some preliminary data that when you are not sleeping
as well, that you will not exercise as much, which is not
hard to understand when you’re feeling exhausted and tired
after a bad night of sleep. So this provides
experimental data to show that, indeed, short
sleep or disturbed sleep can lead to increased risk
for developing obesity. And similarly, for
cardiovascular disease, or changes in inflammation,
or changes in blood pressure, an autonomic nervous
system regulation is also tied together,
disturbed sleep to increased risk for
cardiovascular disease. Now the image
actually gets worse, because, as I just mentioned,
if you have an increased risk for obesity, and this
obesity may disturb your sleep through sleep apnea,
perpetuating and aggravating your disturbed sleep altogether. And, so, yes. So, poor sleep–
there’s real evidence that this leads to poor health. And so, this is one of
these experimental studies. This is work by Karine
Spiegel and Eve Van Couter and colleagues in Chicago,
a very nice study showing, in early days, and replicated
by many various studies that already two days of short
sleep, four hours time in bed, results in changes
in physiology, so an appetite hormone. So, ghrelin is a hunger hormone. Leptin is a tidy hormone
that will actually stop you from eating. And as you can see,
this balance is such that these people
will experience an increase in
hunger and appetite throughout their whole
wake up as shown. And so, this provides this
experimental evidence bit by bit, that, yes. Short sleep can result
in increased risk for developing obesity. Now, sleep, for
the longest time, has been viewed as something
that is by the brain and for the brain. And so, the initial
studies really have focused on the
cognitive consequences of impaired sleep,
such as impaired memory and poor cognitive function. And, of course, this is
very important, you know, for your school grades,
for example, or for traffic accidents, crashes on the
road, many severe consequences. But it doesn’t stop
there, because short sleep has many various effects,
also, on the rest of the body. So, I’ve already been talking
about blood sugar control, hunger, and especially,
high-density foods if sleep is disturbed, and
decreased physical activity. Of interest, if you are
dieting, and you are restricting your sleep, you
actually are impairing the fat loss, and actually
stimulating muscle loss, as compared to when
you’re well-rested. Increases in blood
pressure, and even vaccinations against, for
example, the flu vaccine, aren’t as effective
when you have been exposed to short sleep. So, conclusion is that sleep
is not just for the brain, but it’s also for the body. And I think that the
National Sleep Foundation put this very nicely,
saying, that “Sleep is as important as diet and
exercise, only maybe, easier.” OK, so I think we
should add sleep here to the list of behavioral– considerations for
behavioral approaches, where we can tackle
obesity and other metabolic and cardiovascular
diseases given the existing literature out there. Now sleep is something you
typically do at night, and not during the day. And sleep is, thereby,
also one of the factors that is controlled by
the circadian system that you may have heard of. And so, the question
is, is there something specific about the
circadian system that has changed over the recent years? And, of course, you get– you
will have heard about many of these examples where
the use of electronics, handheld electronics, iPads, or
telephones or computer screens may interfere with your
sleep, or people are exposed during the night to
external light pollution, or, they may be doing
nighttime snacking. So there are many
behavioral factors that have changed since the
invention of the light bulb and beyond that
have really impacted on how we schedule our day. We’re no longer purely
a diurnal species. And so, what does the
circadian system influence? Well, it’s not just
sleep that it influences, that you will have heard of. It affects basically
most, if not all, of our physiology
and our behavior. So, for example, cardiovascular
control, immune function, endocrine system, the
autonomic nervous system. And, with the knowledge that
the circadian system influences these many aspects
of physiology, the question
immediately comes up, how might this be involved
and also disease states? So pathology. And, of course, we can
think about prevention, behavioral lifestyle
modification. We can think of diagnostics. If your metabolite
or your hormone or your measure of interest
varies by time of day, one has to keep that into
mind treatment approaches. For example, in
the cancer field, the use of
chrono-chemotherapy is something that really has
grabbed the attention, also, of the NIH. And we can also think about
genetics and personalized medicine, where knowing the
interindividual differences between one’s chronotype that
might be based on clock gene differences may help us
in viewing and treating the disease. So, I’m going to take
you back in time. We spoke about a
time machine before, but now I’m going to
really take you back in time, so 3.5 billion years
ago, that’s a lot of zeros right there. Since when life on Earth has
been exposed to the day-night cycle, of course, due to
the rotation of the Earth– of the rotation of the
Earth around its axis. And life has found
ways to adapt to this. Because, of course,
these are very dramatic changes in the environment,
light-dark cycles, radiation, temperature cycles,
predation, et cetera. And so, that’s illustrated
here by this heliotrope plant that opens its leaves during the
day and closes them at night. And so, you may wonder,
why does this leaf open– this plant opens its
leaves during the day? Might this just be the
exposure to sunlight, and then when that is
absent it closes them again? Or might it be an internal
clock in the plant? And this very question
was a question that was asked 300 years ago by
a French astrophysicist Jacques Dortous de Mairin. And what he did, is he
stopped the rotation of the Earth, at least from
the point of view of the plant, of course. Because he placed the
plant in continuous dim light conditions. And, to his amazement,
when he very carefully looked at the plant, he found
that the plant was still opening and closing its leaves. It was a rhythm
of about 24 hours. So really, the first
piece of evidence that there is such a
thing as a circadian clock in living organisms. And, so then, it was quite, for
a long time in the circadian field. But then, the next question was,
OK, we have an internal clock, and there was more
evidence coming after that. But where is this located? And so, the first
question that was asked was, to us in the
mammalian system. And the approach
that was taken was to look at different
brain areas. If you would remove
those brain areas, if the animal would
become arrhythmic, if it lost its
circadian rhythmicity. And it was found that there
is one particular area, very small in the
hypothalamus, called the suprachiasmatic
nucleus, that if you remove that specific area,
the animal becomes arrhythmic, but no other areas. So that indicated,
well maybe, this is a key area that
is the master clock. But there was not enough,
because maybe it’s just a path through,
something is passing through the
suprachiasmatic nucleus. Maybe that’s not the real clock. So the next question
was, if you now move this superchiasmatic
nucleus in a Petri dish, can it still be rhythmic? And this was done, of
course, much later. But it was shown that
even in a Petri dish, this tiny structure,
a cubic millimeter, is able to generate this
beautiful 24-hour rhythm in a dish when it’s completely
separated from the rest of the body. So it’s not only
necessary, it’s also sufficient for circadian
rhythm generation. So for the next 20 years or so,
that was the overarching model, that we have one
clock in our brain, and this dictates all
our 24-hour rhythms. But then, about 20
years later after this, it was recognized that the same
property is true for virtually every single cell in your body. So if you take a heart cell,
a liver cell, a fat cell, even a skin cell, you put
it in a Petri dish, it will cycle with
a 24-hour rhythm. And so, the whole model
changed, where we now have a master
pacemaker in the brain, but that is like a conductor
of an orchestra, that synchronizes all the rhythm, all
the clocks throughout our body. So then the question
was, well how on Earth can a single cell
generate a 24-hour rhythm if there is no neural network? And so, the quest for
this molecular machinery actually resulted just
last year in a Nobel Prize in physiology and medicine by
Jeffrey Hall, Mike Rosbash, and Mike Young, who
discovered using the fruit fly, the underlying
molecular machinery, which was a transcription
translation feedback loop, so circadian clock genes,
of which the protein products inhibit their own production. And the Nobel Prize committee
recognized this contribution as a fundamental
discovery in biology. But, in addition, they also
recognized the implications for health and disease. And so, for example, this is
a quote from the Nobel Prize committee that, “Our
wellbeing is affected by the temporal mismatch
between this internal timing system and our environment.” And, the most famous example
is, of course, jet lag if you travel to Europe or
to Asia, or for listeners there, to the United States. You will experience what the
powers of the circadian system. But a more dramatic
example is shift work, where people are chronically
exposed to the back and forth of the behavioral
cycle that is working against their
internal body clock. It has been associated
with a variety of diseases. And so, examples of
circadian disruption include genetic
mutations that can disturb the clock,
anatomical, as I mentioned to you, lesion studies. Behavioral, if you miss
time, either the environment or behavior, such as the
sleep-wake cycle, feeding, or the light-dark cycle. And shift workers,
as I’ve mentioned, and also under highly-controlled
laboratory studies that we’ve been
focusing on primarily. And all of these
point to increases in the risk of
obesity, diabetes, cardiovascular disease, and
World Health Organization has recognized shift work
as a probable carcinogenic. So this is work by Christopher
Morris, a very talented post-doc in my lab, who
has shown that circadian misalignment has adverse
effects for glucose control, so blood sugar control, as
a risk factor for Type 2 diabetes, for increases
in inflammatory markers, and increases in blood
pressure, both risk markers for cardiovascular disease. And these studies were
done in healthy controls, raising the question
among critics, well, maybe this is not
true in real shift workers because maybe they’re adapted,
or maybe they’re selected, and they are not affected. Also here,
unfortunately, we found that chronic shift
workers are not immune against the adverse
health effects of circadian misalignment. We also found that it’s
not just the impaired sleep during the
day that contributes to this adverse effect. So circadian
alignment, I think, is a second behavioral
component we should consider, and the forefront of new
discoveries to help with diet and exercise to improve
cardiometabolic health. And then finally, I want
to talk about meal timing, which, of course, meal timing
is one of these elements, one of these behaviors that may
be aligned or misaligned relative to your
circadian system. And so, in 2009, work by
Deanna Arble and colleagues show that eating
during the time window where the animals would
normally be sleeping, but the animals
then become obese. And so, then the question
was, what about humans? And so, this led to a very
fruitful collaboration with Marta Garaulet, whom I
met about six years ago, who– with whom I was discussing this
common interest in food timing and obesity, where she had
this beautiful population of patients who are
either obese, or were overweight, who she then had
undergo a 20-week-long weight loss intervention
where the question was, does the timing of
their main meal, in this case, lunch
in Spain, whether this was predictive of the
success of their weight loss. And, to our surprise, we found
that the effect was actually quite large, and that the
early eaters lost about 25% more than the late eaters. We didn’t find differences
in energy intake or physical activity,
and we’re now studying whether
energy expenditure, that the previous speaker
also commented on, might be a key
mechanism that links meal timing to differences
in weight regulation. But, there are many
other pieces of evidence that have now– are now
showing to you– starting to show that meal timing,
either lunch timing, both with behavioral
interventions, or bariatric surgery,
or– and even timing relative to the circadian
cycle, that actually is important for adiposity,
that the distribution between big dinner and small
breakfast, or vice versa, is a key player,
that glucose control that is known in normal
glycemic individuals to decrease from
morning to evening is an important circadian
control, and that late dinner eating, when your melatonin
levels are already elevated, that this leads to impairment
of glucose tolerance. And this is especially true if
you are one of the about half of the population who is a
carrier of this melatonin receptor snip. So, yes. Mealtime, I think, is a
potential third behavioral component that we
may add– want to add to those promising
new approaches, and the battle against obesity. And so, the take-home
messages are that, in addition
to physical activity and what we eat, we may want to
start considering the quantity and quality of sleep,
and also, when we eat, and also circadian
disturbances including shift work, social jet
lag, that I can talk about if there is interest, night
eating and lights at night. And, in more general
terms, circadian time, so far, has received
very little attention in the prevention, treatment
and diagnosis of disease. And so, if any of you
are interested in helping us uncover these new
mechanisms and possible uses for future treatment,
then we have a number of studies that are
ongoing that are listed on clinical
trials of partners.org. And, with that, I would like
to thank all my colleagues, and I would like to thank
you for your attention. Thanks. [APPLAUSE] And so, with this, I would like
to invite Christos Mantzoros to speak, and Chris just
told me that this year was a good year for him. This year he received
no less than four national and
international awards, including on obesity,
endocrinology, nutrition, et cetera. So, over to you, Chris. [APPLAUSE] Thank you. Thank you, Frank. Good evening, good
morning, good afternoon, depending on where
in the world you are. I have only limited time to
talk about a really big problem, obesity, and put
everything together. So what I’m planning to
do in the next 20 minutes is try to address
three questions. How does our genetic makeup
interact with the environment, nutrition and exercise to
regulate our body weight? For some of us,
keeping it normal, for others, failing and creating
obesity, or extreme leanness, like anorexia nervosa or
hypothalamic amenorrhea. Number two, what can we do? What is our current
understanding of the mechanisms? And, what can we do to
prevent this from happening? And, number three, how are we
learning from these mechanisms, and we can treat the problem? So these are my
conflicts of interest, and this is the problem. The problem is that
over the past 40 years, here in the United States, the
rates of obesity are going up. One third of the
population is overweight. One third of the population
is obese, and only one third is lean. And if these trends continue
for another 10 years, most of us are going to be
obese and it will be the exception to be lean. Well, there’s also the problem. The problem is that each and
every nation in the world follows the United
States, in part a little, and there is only a lag
phase of a few years, which corresponds to the
degree of Westernization of their societies. So everybody’s
following us, maybe not good in this case, right? And why do we care? Do we care whether we have
a few extra pounds or not? Some of us who are really
lucky, they don’t really care from the health
aspect point of view, and let me explain,
but most of us do, because it causes
health problems. So if we are one of
those people, about 20% of the population who are born
with a genetically-endowed large storage space
for fat, where they can store all their fat,
there is no health problems with obesity. And this is CAT scans
of one of these people. So the fact remains in
the subcutaneous tissue. This is the abdomen. These are the extremities. But what happens to most of us? To most of us, especially
those who are Orientals, they don’t have a
lot of storage space, or, in the Western
population, when we exceed the storage space
for fat, the fat we eat, the energy, has to
be stored somewhere. And if it cannot be stored
in the adipose tissue, it will go in the liver and
cause fatty liver disease, or will go to the muscle,
and cause ectopic deposition in muscle, or will
go intra-abdominal. And this is what our
bodies do not like. So they send macrophages,
immune cells, to try to clean the fat
from areas that it’s not supposed to be, from
muscle, or the liver. And this creates inflammation,
and the intra-abdominal fat creates low levels
of a hormone called Adiponectin, which is a
protective insulin sensitizer. And this leads to metabolic
syndrome, inflammation, and if this continues for years,
will lead to disease states like diabetes,
disease, and cancers. So also, the obesity
becomes more and more frequent in the United States. The rate of diabetes
goes up, the rate of cancers, non-alcoholic
fatty liver disease, which is the more frequent cause
of liver failure, cirrhosis, and transplants than
hepatitis C, B, and alcohol together today. We did not know of
this 30 years ago. Many cancers are
caused by this problem. So, if an angel would
come to our world to make obesity disappear,
about 2/3 of endometrial cancer would disappear, 1/3
of breast cancer, gastric, esophageal cancer,
liver cancers, would go away. So why is that, and what
can we do to prevent this from happening,
and what can we do to save billions,
hundreds of billions of dollars we all pay for
our insurance premiums every year for this problem? What is our current
understanding? When I started studying this as
a young trainee 20 years ago, two decades ago, the classical
textbooks of physiology, here guidance on the left, had
only a brief two paragraphs about the adipose tissue,
that fat is a depot storage organ where we dump all
the calories we’re not going to use. We knew nothing about it. But since the
problem was going, it was becoming more and more
frequent and significant, we started studying this. And we know now, that there
is a complex mechanism in our brains, hypothalamus, the
reward system, and the cortex. In bisons, only
the hypothalamus. But in our brains, are
much more complicated. It’s the reward system that
plays a role, and the cortex. That coordinates,
gets information from genes, hormones in the
periphery, the environment, and integrates this information. And in people who keep
their body weight normal, it normalizes food intake
and energy expenditure. In others, it fails. Let’s see this in detail. So how important are our genes? The previous speaker said that
our genetic makeup has not changed once. We had the opportunity over
the past five, six years to check the entire genome
of thousands, of hundreds of thousands of human beings. And we found that
genes play a role, like one gene leading to
obesity in a very, very distinct minority of people. So very few people, one
in hundreds of thousands, would have a mutation
in the molecule that is secreted from adipose
tissue called leptin, or molecules that are downstream
of leptin, melanocortins, for example. And because of this single gene
mutation, or gene variance, they develop obesity,
very, very small minority. But, these are the lucky ones. Because, if we find it
through genetic testing, and we use a medication
that attacks downstream of this mutation, we can treat
this obesity very easily. So this is a child, you
know, animals and humans, a child with leptin deficiency. We gave him leptin
and he’s normal. Melanocortin deficiency,
give melanocortins, normal. This is beautiful,
emphasizes the biology of the mechanisms underlying
the pathophysiology of obesity, but does not apply
to most of us. Most of us, there are many, many
genes that play a minor role, and they interact
with the environment. They interact with
the environment even before we are born. Why? As I’m going to show you
later, how our mothers and fathers live causes
epigenetic changes in our genome. Also, it’s very important
what happens early in life. Most of us don’t remember that
from the very first cell that creates us to the neonate,
there are 45 divisions, and there is only 55
up to the adult life. So a lot of changes
during our in utero life. So, as I told you,
it’s very important how the mother sleeps, whether
she has sufficient quantity, a good-quality diet, and
whether where she lives, there is pollution or not. That’s what our
studies have shown. It’s very important. It’s also very important,
what happens during pregnancy. So if the mother smokes
or drinks alcohol, if she does not sleep
well, if she does not follow a healthy diet, this
has an impact on the baby. Change is the epigenetic
modifications in the brain. Immediately after pregnancy,
it’s very important the duration of
lactation, and also, whether the babies sleep
well and whether they have the right Mediterranean diet. And I’ll come back to
this in a few minutes to tell you what we think
the right diet is today. And this is also important
as we grow older, to sleep we’ll, avoid
smoking and too much alcohol, and have the right
diet and exercise. We’ll put this together. So, studies have shown
that if one follows a low-calorie, low-fat
diet, and exercise is about 30 minutes
every day, this is better than medications in
terms of preventing diabetes, in terms of avoiding
diabetes late in life. And if someone has a
heart problem, following the right Mediterranean type
of diet here in these studies delays significantly years
the next heart attack. This is also important, not
only for secondary prevention, but also primary prevention. So if someone is healthy
and wants to remain healthy, what are the most things
that we need to do? Just a few simple things. No smoking, alcohol
in moderation, this means for women
up to one drink a day, and, for men, up to
two drinks a day, exercising at least
30 minutes per day, replacing red meat with
fish or white meat, and replacing saturated
animal fat with olive oil or nuts, very simple
things, difficult to follow. Animal fat? With olive oil. so cardiologists have
stents to open the arteries. You know, this could
be a bare metal stent in your kitchen, which would
have exactly the same magnitude of an effect. Right? To prevent cardiovascular
disease, cancers, arrythmias. And if my cardiology
colleagues tell you that they have
drug-diluting metal stents, you also have a drug-diluting
metal stent in your kitchen, right? You load your mental stent
with fish and vegetables and olive oil and nuts. So, how do we put
everything together, trying to associate
this with numbers? So if you are a
middle-aged man or a woman, say 50 years old, what
is important to make you live a longer, healthier life? These are five things it was
just published in circulation from our community, nurses
and health professionals helps them. Five factors. One, following the
diet I told you about. Number two, not smoking. Number three, physical activity. Number four, alcohol. Number five, keeping
s normal body weight. If someone has all five,
a woman who is now 50 is going to live
up to 93 years old. If none of the five, 73. So it is a big difference
in terms of years lost or years gained if we
follow this advice. But most of us say, “Well,
I’m trying to lose weight, and my body goes back
to the set point” that the first speaker
told you about. So I tried to lose weight,
and then I exercise less, and something else happens
also, that earlier in life, we have a lean set point. We try to lose weight. This brings us back. But as we grow older,
our set point moves up, and we gain weight
as we grow older. So, we did not know
what this meant, and what caused this
a few years ago. But, since the discovery of
leptin a couple of decades ago, we started learning
more about it. And this is an active
area of research. We cannot– we don’t
know everything, but we know a lot at this point. So we know that in normal
people, as we limit our energy intake, and this is our claim
to fame, leptin levels go down. This is leptin, is an adipose
site, secreted hormone, which is a thermostat. It tells the brain how much
fat we have in our body. So as we try to decrease
our body weight, this thermostat goes down, tells
the brain, “Do something else. Eat more, exercise less.” Why? Because our brain has
the same mechanisms that we had thousands
or millions of years ago when we were starving. Not in societies of affluence,
but in societies of starvation. And we need it to survive. So, the low leptin
levels make us survive by regulating
all these hormones here. If someone tries hard,
one can train the system and remain in low body
weight, or something goes wrong in these
hormones, and it will remain in low body weight. This is anorexia nervosa,
or female triad in exercise, right? Strenuously exercising athletes. Just the opposite happens, and
we can utilize this medication now, to treat these
women who have exercise-induced amenorrhea. or anorexia nervosa. We can normalize all their
neuroendocrine abnormalities. So we leverage this knowledge. So what happens if we overeat? Thanksgiving,
Christmas, we overeat. For most of us, there
are other hormones that are going to be activated,
like DLP1s and incretins. And, for most of us, without
even understanding it, a few days later,
our body weight will come back to normal. And if we exceed this
for a long period of time and we also have diabetes,
there is another set of molecules called
glucose receptors, and they help us excrete
calories in the urine. And we leverage this now
to create medications. If our own bodies cannot
bring us back to normal, we can use these medications
to help our bodies lose weight. And these medications, most
of them, act in the brain. So you will hear from
a lot of speakers talking about the hypothalamus. This is what we had learned
a few years ago from mouse studies. The hypothalamus is
responsible for our survival. So in mice, and
lower like animals, it is important to
regulate food intake. But, in humans, we have
a much bigger brain, and much more complex brain. So it’s the reward
system, which is also activated, or inactivated,
by these hormones. A lot of people
will tell you, “I eat because I want
to be rewarded, or because I feel sad.” And it– also, our
cortex, which is responsible for our
executive functions. For some of us, we will
just eat when we go out, outside from this conference,
just because there is food. And we’ll be talking to people. We’ll be distracted. Our cortex will not
regulate what we eat. These medications make us
more aware of what we eat. This is just the
beginning, but we are learning how to control
now, appetite in humans. So as I told you, we
are also leveraging this to treat women or men who
have either extreme leanness, in this case, anorexia nervosa,
hypothalamic amenorrhea, strenuously exercising
women athletes. 5% of our college-age
young girls, or 5% of our medical students
where women who exercise a lot have the female triad,
hypothalamic amenhorrea. And they suffer from
stress fractures. They don’t realize why. You know, they say
we exercise a lot. But their hormones are abnormal. If we give them
back leptin, which is the hormone that is
missing, as I told you earlier, we fully normalize
all their hormones, and we can treat their bone
density and avoid fractures. So we’ve shown this
a few years ago. We also leverage now, GLP-1. We create medications. I don’t want to
give names, which decrease body weight by
10%, new medications 15%, when combined with
the right diet. They are not as good
as surgery, which decreases body weight by about
30%, but we are getting there. We are also learning
from surgery, and this is one of
our studies where we study why people
who undergo surgery, they keep their
body weight down. So we study the hormones
that are secreted, and these are some
of the hormones, the pre-Progluamune-derived
hormones like GLP-1, oxyntomodulin,
glicentin that go up. And these will be medications
in the next few years. So the goal will be
not to have surgeries, but to have 30%, 40%
weight loss by giving back to people the hormones
that change after surgery. Now why are we doing this? Are we so smart
to think about it? Not really. You know, this is
exactly the same way that people who treated
hypertension 50 years ago were moving in science. So 60, 70 years ago, people
would measure blood pressure and would say it’s a normal
variant, even for very famous and beloved people. One of them, whom I
always keep in mind, is President Roosevelt.
President Roosevelt had high blood pressure. No one was treating it. He suffered strokes
and he died from it. And then people
started realizing there is a problem we need to treat. So obesity, people were
not paying attention to it, right, a few years ago. Now, then what
did the people do? What did people– how did people
treat high blood pressure? Crude [INAUDIBLE] surgeries. Now the most effective
way today is surgeries. And through these
surgeries, people learn how to create hormones
and medications to treat. And that’s what
we are doing now. So if we treat people with
these medications, or surgery, we can improve their
diabetes with surgery about 80% of people, with
medications most of them. And now, I told you about
cancers when I started. If you do surgeries
for obesity, you decrease cancers by about 35%
over a period of 20 years. And we just submitted a paper,
that with a toolbox approach for treating obesity,
medical treatment, we decreased cancers
by about 25%. So one in four people
would not have cancers if we treat their risk. So what if we cannot
treat obesity, or if cannot remove it? So people are
learning now what are the molecules downstream of the
obese cells, the adipocytes? What are the hormones
that are going down, and why these are
causing diseases. So this is from our work. Adiponectin is an endogenous
insulin sensitizer, the levels of
which go down if we have intra-abdominal obesity. And when we have low levels
of this protective hormone, we develop diabetes,
pro-inflammatory state, you know, adipokine
changes, and this leads to non-alcoholic fatty
liver disease, diabetes, or cancers. So can we make adiponectin
and give it to people? Adiponectin is a
complex molecule, but we are learning
about the receptors. So people now are developing
either medications that bind to the
adiponectin receptor to treat these
conditions, or medications that can stimulate fat. And when the fight
is decreasing, the production of this
hormone, this goes up. And, we have that these
medications, and we are testing these medications. This is for diabetes, and
works better than medications that we know of today. And now this molecule is being
tried for other disease states like non-alcoholic fatty liver
disease or other disease states we have no treatment for. Great. So, I gave you a lot
of information today. But going back to
the essentials, what I would like you to
remember is that there are some people who are
lucky, and they have a lot of storage space in their fat. They can eat more than
others, be overweight, and have no problems. Others, if they exceed the
storage space in their fat, adipose fat will go to ectopic
positions: liver, muscle, intra-abdominally, and
create medical problems. We are learning how
to leverage biology to create new medications,
but for all of us, I think prevention is
better than treatment. So how do we prevent obesity? By exercising, alcohol in
moderation, nuts and olive oil, fish instead of meat,
fruits and vegetables. So, in essence, a
Mediterranean-type diet. Exercise, so walking up
these hills to go home. Or cultivating the fields,
or, even moving, right, to a Mediterranean nation
to adopt the lifestyle, if we can not bring it here. In fact, that’s my
secret, and that’s where I spend a couple
of months every year. This is an Nafplio, in Greece,
a small town on the water, and I recharge my
batteries there. I follow the
Mediterranean diet, and I get inspired before I come
back, because on this hill here overlooking the
port, was working the very first scientist
in the human history, the written history,
Palamedis, as he was mentioned in Iliad and Odyssey. So having said that, I
would like to thank you for your attention. I hope you get some
information in your mind. [APPLAUSE] Right, right on time. One word only. So everyone, I know
that a lot of people have to leave the
actual audience. We’re going to answer questions,
both from the audience and from the live stream. So if you have to leave,
you can feel free to leave. We will stay and devote at
least 15 minutes to questions. I’m going to pose the question. If I can answer, then
I’ll try to answer, but there are several
questions that are specific to Dr.
Scheer or Dr. Mantzoros. So one of the key things that
we didn’t do, and I apologize. I guess none of us
really did it, really, give just a slide of this,
was one of the questions was, define the word obesity. So when I talked
earlier about obesity, we use body mass index
to define obesity, and a patient has
obesity if they have a BMI that’s greater
than or equal to 30, if they’re an adult patient. I won’t specifically talk
about pediatric patients because their BMI criteria
is somewhat different. A person has mild
obesity if their BMI is between 30 and 34.9. They have moderate obesity if
they have a BMI of 35 to 39.9, and they have severe
obesity if their BMI is greater than or equal to 40. Now, the BMI in and
of itself is just a measure that looks
at height and weight, and there are
calculators online. One of the ones that people use
most frequently here in the US is the NHLBI, which is
the National Heart, Lung, and Blood Institute
calculator from the NIH where you put in your
height and your weight and it calculates a BMI to
determine where you fall. So that is the terminology
that we’re using. We did not focus on
pediatric obesity. That is done by growth
chart measurements. Persons that have a
percentile and that’s physically from the age of
two and 20 years of age, if your BMI percentile is
less than the 84th percentile, that’s considered of
normal weight status. If it’s between
85th and the 95th, that’s considered
to have overweight, and then obesity
defined by someone that has a BMI of greater
than the 95th percentile. And then, we can get
into mild, moderate, and severe beyond
the 95th percentile for pediatric patients. So it’s important to
recognize that BMI by itself, because pediatric
patients are growing, it’s not utilized in the same
way we look at it for adults. Can I take it to the
next level, if I may? Because I see that– He wants to take it
to the next level. I’d love that. Our audience is sophisticated. Yes, I like that. So a few weeks ago, a body
builder came into my clinic. A bodybuilder, OK. And his BMI was 27, and he said,
am I now obese or overweight? He wanted the challenge. Well, BMI is convenient from
the population point of view. But in essence, obesity
is excess adipose fat. So BMI applies to most
people, but not all. And if we want to take
it one step further, what is significant obesity
is too much fat that causes health issues,
metabolic syndrome, or insulin resistance. So, if we could, and
we had an inexpensive, a convenient measurement
like the BMI in the clinic, like if we could measure
fat mass in a cheaper and faster way, we could be
using different criteria. But for convenience, we use BMI. Absolutely. In addition to that, for every
single patient that comes in to see me at MGH, I do
measure waist circumference, which does give us a
bit more information. For females, having
a circumference of less than or equal to
35 inches is our target. For men, having a circumference
less than or equal to 40 inches is our target. We can utilize
that in conjunction with height and weight to
view very quick measures. But as he’s stated, using more
physiologic measures really gets us down to the personalized
or precision medicine that is becoming commonplace. Now, the next question was,
are there mental health issues tied to obesity, and do those
issues get treated along with the disease? I’m going to take
a stab at this. Every single person
that I see, we do screen for issues that are
related to their mental health. As you saw in my slides,
there is a correlation with persons that have obesity
and have mental health issues, such as anxiety, depression,
bipolar disorder. Approximately a third of
our patients at the weight center at MGH do have
concurrent issues with these, I guess, psychological
issues that are being concurrently treated. And what I also
mentioned to you earlier is that many of the
medications that we utilize to treat
these conditions then cause weight gain. So we have to figure
out ways to medicate the weight gain associated
with the use of these agents. And we are able to mitigate that
with the use of pharmacotherapy such as metformin, which is
in front that usually used to treat diabetes, or for
persons that have PCOS or polycystic ovarian syndrome. So that’s interesting. Does anyone want to weigh
in on that question? There’s a lot of specific
questions to you guys. So this is a question, I
think, that was answered, but the question was,
do people who are obese, and we’re changing that,
people that have obesity, have a greater risk
for pancreatic cancer and how does this
differ by gender? Do you want to take this? I know that– do you
want to talk to this? Yeah, it is a
complex relationship. And this is more
complex and difficult to study because pancreatic
cancer evolves so fast. But, obesity does have an
effect on pancreatic cancer [INAUDIBLE]. When people develop
pancreatic cancer, they start losing weight,
and they get emaciated. But for each and
every GI cancer, esophageal cancer, pancreatic,
stomach, liver, colon cancer, obesity is contributing to a
great percentage of people. We cannot say for everyone. Absolutely. This is specifically
for Dr. Scheer. It says, “How does
less sleep cause people to decrease
tolerance of glucose, if the body relies on it
for cellular respiration?” Right, so the interesting
thing about reduced sleep, and it’s linked
to glucose control, is that, in essence,
we are still in a very early stage
in understanding the molecular machinery
of what overlies that. So hypotheses exist to look
at autonomic nervous system. So since the vagal
balance changes, that may make tissues
less sensitive to insulin, or may even reduce the
release of insulin. Other hypotheses are that
increases in cortisol might be involved
that would decrease the sensitivity to insulin. But really, the whole
field is still looking for, kind of the explanation. One interesting point is that
the phenotype, however, is even located in the
fat tissue itself, so very nice work by
Joseph Broussard’s is showing that if you
sleep deprive people, you do a biopsy of their
subcutaneous adipose tissue, and you look at the
sensitivity to insulin of the adipose tissue,
that is affected. So it’s really, even
so that suggests that at least acutely, even
without the autonomic nervous system or hormonal systems, it
is a property in the fat issue itself, which may, of
course, be an after effect of those factors. That’s excellent. Hopefully you guys got some
great information there. One of the questions,
and the next question, is what about surgical
procedures to correct obesity? Are those usually effective? I’ll take a stab at this. So there are several
surgical procedures, what we call bariatric
surgery, that are utilized both here in the
US and throughout the world to treat persons that have
moderate to severe obesity. They are effective. They’re the most effective
tool that we have for treatment for those patients, and
what was mentioned earlier is that we see
significant reduction in those co-morbid conditions
associated with obesity including cancers,
including things like sleep apnea, hypertension,
and things of this sort. Now, I think it’s important
for us to recognize, when we look at the two
primary procedures done throughout the world, the
number one procedure now has become the vertical
sleeve gastrectomy, and the second most
common procedure now is the Roux-en-Y gastric bypass. That was kind of the
leader for many years. Overall, it leads to
significant weight loss. So, on average, if we
have excess body weight, let’s say, 100 pounds in
excess, a sleeve, on average, will lead to 50% to 60% of that
excess body weight being lost, so an average 50 to 60
pounds at the low point. And then, a Roux-en-Y
gastric bypass, about 60 to 70
pounds, which means that these patients will still
likely have obesity, right? Just the degree of the
obesity has improved, and it requires
quite a bit of work on the part of the patient,
and we see significant changes in hormones, as was
mentioned earlier, that vary from patient
to patient that determines their degree
of relative success with these procedures. Would you like to
also comment, or is– Yeah, no. Bariatric surgery is by
far the most effective way of reducing body weight today. These are the two
mostly used surgeries. There are less effective
treatments that are also better to tolerate. Most people are, if they’re
going to go through surgery, they don’t prefer
to have a lap band, or they don’t prefer
to have balloons in their stomach,
which is another way to limit food intake. But I think the most
exciting aspect of it is that we are understanding
now why surgeries work. Now, this is the glass is
half full or half empty. We understand the
hormones that are responsible for 50% of the
weight loss and maintaining, there is another 50% that
we haven’t discovered. So we are half
way at this point. Now this is a question
for each of us, and the question is, how do
we pick this as a specialty? How do we choose to specialize
and focus our life on these, and this complex
issue of obesity? And I’ll talk first, and then
I guess we’ll go down the– get down the pathway here. So as an
African-American woman, I became particularly intrigued
of the racial and ethnic disparities in obesity. We did not focus on
that today, but what I do know about here
in the United States is that 60% of all
African-American women here in the US have obesity. Another 20% have, or
are as overweight, which means that 80% of all
African-American women here in the United States have
overweight or obesity. I found this to be particularly
disturbing as someone that comes from that background
to understand why this is and what are the nuances
that really explain that. And that really is what
led me to this work, back about 15 plus years ago. So that’s my story. But I’m going to let
Frank tell his story. Yeah, so, that’s interesting,
because I was, for a long time, interested in the
regulation of leptin from a circadian point of view,
because colleagues were already in Amsterdam who had been
looking at this, and colleagues in Boston. And then, actually,
by serendipitous luck, really, we stumbled upon
the effects of circadian misalignments, or what happens
when people who are actually changing their sleep/wake
cycle, their feeding/fasting cycle by 12 hours. And so, initially,
we were struggling with understanding the
regulation of leptin as a hormone until we
realized that it wasn’t just the circadian system
influencing it. It wasn’t just the sleep-wake
cycle influencing it. It was the interaction when
these two didn’t line up correctly that we saw
some of the leptin levels were dropping. And so, that really was the
initiation of this interest, and it’s important in obesity. For me, I think,
I think that this was because of two
influential people in my life. If I look back. As a student in
training here, I had– I attended the lecture by
the late Judah Folkman, who was a very great scientist
of Children’s Hospital, who was teaching medical
students and young doctors about research. And he said, you have
to decide in life, so he started like
your question. He says, you know, there
are 33,000 diseases in medicine today. Only for 6,000 of those we
have effective treatments. If you want to be an effective
doctor, you need to decide. Focus on one, do good
work, and it’s up to you whether you are going to
focus on a rare disease and try to create a big
difference, or a very common disease, and
have a small difference. I said, I would like to
have a common disease, maybe make some difference. And then I started
talking to people, and I went to talk
to Jeffrey Flier, who he was our former dean. And at that time, Jeff
was about to discover, and closing, narrowing down, to
the gene which was responsible for obesity in an animal model. And he said, this
is a risky project. So he talked to
me about projects, and he wrote on the
blackboard like 10 projects, from the easiest to
the most difficult one. And the 10th and most difficult
and most risky one would be, well, we may have
a gene for obesity. And if this works, this
may be the beginning of trying to make a difference
in a big disease problem. I said, OK. This is my lab. This is my career. I’ll take number one, which
is the easiest, and number 10, because this was the riskiest. So two, to split the difference. And split difference,
hedge my bets, right. So number one, the
easiest, never worked out. But number 10, the most
difficult, was leptin, and this defined my career. That’s amazing. So obviously, different things
that brought us to this fill. This question is
not quite clear, but I’ll try to
make it cohesive. I think what the
question is, is it says, sometimes even with
good diet, exercise, Weight Watchers’ group,
you can still have obesity. What can really being done
to help those people that are motivated to treat
this serious condition when they’ve really tried
everything, and, I think, this is kind of
why I have devoted my life to obesity
medicine, so I only care for patients that
have a history of obesity, both pediatric and
adult patients. You come to me when
you’ve tried the things that we’ve talked about. We’ve tried modifying
our diet, looking at lean proteins, whole
grains, fruits, and vegetables. We’ve tried physical activity. We try modifying our sleep
and things of that sort. And when you’ve done
all of these things and you’re still
struggling, you need to go to someone that
specializes in what we can do to treat your obesity. And maybe just modify
your behavior further. Maybe we use pharmacotherapy
agents, which are medications used to treat obesity. Maybe we utilize
surgery, or maybe we come across the next
frontier of things that we just have yet to
discover because I think that’s what excites
us about this work is that there’s so much that
is yet to be discovered. Our ability to collaborate
across disciplines, really, is when we uncover
the best possible strategies of approaching this
multi-factorial, multi-disciplinary disease. So that’s my response to that. And I’m going to
shift over a bit, because this question is
more specific to Frank, here. And this is, as we age, do we
require more or less sleep, especially as it’s related
to weight management? Actually, let me– there’s
a Facebook current question that I tried to organize these. Then, the question is
from Facebook, what is the ideal duration of sleep? So duration, and then
more or less as we age, and how that relates to weight. Right. So the question whether we
need less sleep as we age is a very challenging question. Of course we see that as people
in general, when they age, the amount of sleep
obtained teens becomes less. Then the question is,
well, if you give people maximum amount of sleep
opportunity in a lab, let’s say you them 16 hours
of sleep, 24 hours a day, for a week or so. And people asymptote at a
particular level of sleep. And so, older
people, in general, will asymptote to a
shorter amount of sleep. Now the question is, is that
because they don’t need it, or because they
can’t achieve it? And there’s really two camps
in the field, two– yeah, in the field of sleep medicine. However, there is clear evidence
that with aging, especially animal experimental and data,
but also human data, that are changes in the
hypothalamic structures, such as the ventral, lateral,
pre-optic area involved in sleep regulation, where the
number of neurons decreases, such that the ability to obtain
a particular amount of sleep is decreasing. So even though
people get less sleep doesn’t mean they
need less sleep. The key question
then becomes, OK, how can you then achieve
a higher amount of sleep with the change biology? So I think that’s a challenging
question that people are, of course, working on. How much sleep do we need? So, also, there–
the field, well I think the field has settled
on kind of an ideal sleep duration. So I think for adults, the
common duration of sleep that is recommended is at
least seven hours of sleep. Now, recognizing that there are
individual differences in sleep amount that we need, the
simplest question you can ask– well, there’s two
questions you can ask to see if you have
obtained enough sleep. One, is, do you feel sleepy? Sounds too simple to
be true, but that’s a very strong indicator. The second question
you can ask, is, do you need an alarm clock in
the morning to wake up? If the answer is yes, you’re
not getting enough sleep. And then, I was just
reminded of– so I’m organizing of the National
Sleep Meeting this year, a very exciting lunch debate
between Shawn Youngstedt and Charles Czeisler who will
be discussing whether sleeping too long can be bad for you. And I think this is another
really interesting point of view, that a small group
of sleep investigators think that, well,
if you sleep longer than a particular
amount, whether this can carry adverse health. I think, personally, that
there is no evidence for that. The idea comes from
epidemiological work where people have found a
new shaped curve with people who have increased risk
for Type 2 diabetes or cardiovascular disease. You can also see
this association with very long sleep, which
I think is probably primarily reverse causality,
where disease leads to lengthy periods
of time in bed. All right, so this
would be for Christos. This is coming from Nigeria. It says, “The middle age
spread type of obesity would be an interesting
group to focus on. Are there currently any
studies targeting individuals between the ages of 40 and 60?” I am not certain
what is happening in Africa, but I would say– I think they’re asking,
they’re just from Nigeria. Right. I think they’re asking– But I would say that here in
the United States of America, or in Europe, or from the
scientific point of view, we should not be focusing
on specific age ranges because this is a spectrum,
starts very early in our lives, and does not end. You remember in my
slide, the effect of nutrition and
the years gained by following the right nutrition
and exercise persist up to the age of 90, and maybe
after we are 95 or 100. The effect is like very small. But, yes, we should focus on
everybody who has a problem. Absolutely. Now this is also from Facebook. It doesn’t tell me the country. But this is more of a
policy-based question. It says, “Could policies aimed
at reducing the growing wealth and wage disparity
have any effect on rising rates of obesity
and mental health disorders?” So I’m a policy
person also, and I think it’s hard to just
pinpoint one policy and say that that leads
to significant change. I think that we need
multi-sector, multifactorial approaches to this
issue, but I would love to hear from our
additional speakers to see if they would like to
weigh in on this question. Do you want to? You may not want to. No. I mean, there is a lot that
has been proposed in terms of making one small change. I think it’s so
multi-factorial, and people don’t realize that if we change
one thing in our nutrition, for example, or the way we,
you know, we live and behave, people will eat something else. And these experiments
have happened in the past with very limited
success, very limited success. So it’s a
multi-factorial approach starting from how we live
our lives as individuals, but also how we live our lives
as members of our society. And we forget this
in Western societies who are more individualistic. It depends on how we build
our cities, whether we walk, whether we exercise,
how we commute to work, how we build our systems, or
for feeding the population, what we tax in terms of
nutrients and food items, how we train our students
and our children, and so on and so forth. OK, so I would have to
tie up our questions here, so I’m going to ask
one last question which I think it’s a two-parter. And the question is
as follows: “Is there legitimate science behind
this, and this is what this is. Every person has a fixed
number of fat cells, you can’t lose them. They just shrink
when you lose weight, and grow when you gain weight. And if this is indeed true,
how does someone use that to maintain a healthy weight?” So they’re talking about
adipocytes or fat tissue, fat cells, and
whether or not there’s this fixed number of cells
that you’re born with, and it adjusts based
upon weight loss. So does anyone
want to take this? Yes and no. Yes, in the past, we
thought that there is a fixed number of adipocytes. Now we think that there are
certain periods in our life that the number of
adipocytes may change. But it is true that
obesity, to a large extent, does not depend of the
number of adipocytes. It depends on how full
these adipocytes are or not. So given this, we don’t know all
the signals in endocrinology. We think about
hormones as signals. The adipocyte communicates to
the other organs, information, constantly, to our brain,
to the other organs, and this is what happens. If, say, hormone is
low or high, right? The message goes to the
pancreas to create diabetes, or another organ
to create cancers. This is the idea of one. Or to of the brain, leptin,
right, to change our appetite. Now we need to find all
these signals, hormones, and I hope I’m not
oversimplifying. If a signal is low, missing,
like adiponectin, or leptin, we give it back. If a signal is high, we try
to block the communication by decreasing the levels. That’s what we’re going
to do in the future. Absolutely. So I want to thank everyone
here in the live audience and from around the world
for tuning in to Weighing the Facts of Obesity. We will stay around and answer
some additional questions here live, but thank you
so much for your time. [APPLAUSE] Very nice. Thank you.