Document 6520835

Why Our Physiology Makes It
So Hard To Keep Pounds Off
Michael Rosenbaum, M.D.
Professor, Clinical Pediatrics and Clinical Medicine
Associate Program Director, Clinical Research Center
Columbia University College of Physicians & Surgeons
Collaborators: All our volunteers and...
Columbia University Rockefeller University
UC Irvine
Rudolph L. Leibel
Dympna Gallagher
Ellen Murphy
Elisabeth Shamoon
Katherine Pavlovich
Yomery Espinal
Elinor Naor
Rochelle Goldsmith
Judy Korner
Sharon Wardlaw
Harry Kissileff
Joy Hirsch
Steve Heymsfield
Louis Weimer
Fernando Arias-Mendoza
Richard Smiley
Martica Heaner
ICCR Nurses and
Nutrition Staff
Kenneth M. Baldwin
Fadia Haddad
Shlomit Aizik
Jules Hirsch
Louis Aronne
Cindy Seidman
David Markel
Rachel Kolb
Elio Presta
Karen Segal
University of Pennsylvania
Krista Vandenborne
Marty Eastlack
Jack Leigh
Most
Important
Slide
Laval University
Denis Joanisse
Jean-Aimé Simoneau
Disclosures
Relevant Funding:
• NIH DK30583
• NIH DK64773
• NIH UL1 TR00040
• MH095982
• DK63068
• The Starr Foundation
• Nutritional Science Initiative
Perceptions of Obesity
•Most people that the following are true:
• 68% of U.S. population overweight (34%) or obese (34%).
• African, Latino, Asian, Native Americans more affected
• Parallel increases in adiposity-related co-morbidities.
• Weight loss is hard – most treatments (behavior, surgery,
pharmacology) promote weight loss for 6-8 months.
• It is harder to sustain weight loss (>80% recidivism rate).
•Most people think that the following are true:
• Obesity/difficulty in sustaining weight loss are products of
lack of will power coupled with sloth and gluttony.
• Difficulties for lean people to keep off a few pounds are
biological.
Flegal et al, JAMA, 303:235, 2010; Kraschnewski et al, Int J Obes, 34:1644, 2010; Puhl et
al, Heal Educ Res, 23:347, 2008; Foster et al, Obes Res, 11:1168, 2003
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Key Questions
ƒ Does the majority of the U.S. lack
willpower?
ƒ Is obesity a disease that keeps on
giving even after it has supposedly been
cured by weight loss?
ƒ If body weight regulation is biological
then is it operant in lean individuals as
well?
Evidence that body weight is regulated
• Heritability of body fatness equals that of height.
• ~75%-85% of those who are successful at losing
weight will regain it within 2 years.
• Those successful at keeping weight off report:
ƒ They need to maintain dietary restriction (eat
less than matched individuals at usual weight).
ƒ They need to maintain regular exercise
(exercise more than matched individuals at
usual weight)
• There is a remarkable long term constancy of
body weight in adults
Willer CJ, et al. Nature Genetics. 2009, 41:25; Stunkard et al, JAMA,256:1, 1986 ; Foster et al, J Consult
Clin Psychol 65:79, 1997 Wing et al, 2005, AJCN, 82:222S
Heritability Estimates Based on Studies of Body
Fatness Versus Other Medical Conditions*
Condition
Heritability (G±SEM)
Childhood Body Fatness (age 7)
0.77± 0.17
Adult Body Fatness (age 45)
0.64 ±0.13
Schizophrenia
0.68 ±0.14
Hypertension
Epilepsy
0.57 ±0.25
0.50 ±0.33
Coronary Artery Disease
0.49 ±0.30
Breast Cancer
0.45 ±0.30
*Heritability refers to the proportion of the variance in a trait
in the population that can be attributed to genes. Calculations
are based on Stunkard et al, JAMA,256:1, 1986
Definition and likelihood of successful weight
loss maintenance in adults
• Successful weight loss maintenance is “individuals who
have intentionally lost at least 10% of their body weight and
kept it off at least one year”
(Wing and Hill, Annu. Rev. Nutr., 23:323, 2001)
• “One out of every 6 adults who has ever been overweight
or obese has accomplished LTWLM of at least 10%”
(Kraschnewski et al, Int. J. Obes., 34:1644, 2010)
(LTWLM – Long-term weight loss maintenance)
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Study of Successful Weight Loss Maintainers:
The National Weight Control Registry
• Subjects: Caucasian women with BMI of 24.0 kg/m2 and
average weight loss of ~33kg sustained for about 6 years.
• Diet: 1800 kcal/day (corrected for under-reporting and
ongoing weight loss, 250 kcal below expected for weight).
Low fat is better. Eat breakfast every day.
• Exercise: 400 kcal/day or roughly 200 kcal/day more than
the average person at usual weight.
• TV: Average <10 hrs/week versus 28 hours average
• Eat breakfast every day
• Most successful subjects had low dietary disinhibition.
• Best reason for losing weight is a medical trigger.
AJCN, 82:222S, 2005; Ann. Behav. Med., 38:94, 2009; Obesity, 14:1816, 2006;
IJO, 33:173, 2009; AJCN, 66: 239, 1997; Prev. Med.39:612, 2004
Is there a physiological basis for what you need to
do to keep weight off or is it just willpower?
• Exercise: Why do successful long-term weight-reduced
subjects need to exercise more?
• Diet: Why do successful long-term weight-reduced
subjects need to eat less than controls, despite
increased exercise, to keep weight off and why is
compliance so poor?
• Obese versus lean: Overall, both obese and neverobese people do a remarkably good job of maintaining
their usual weight – why not a reduced weight?
Study Design Issues in examining the effects of
weight loss on human physiology
• Subject population
• Weight Loss vs. Reduced Weight Maintenance (not
the same processes)
• Weight stability
• Quantifying energy intake and expenditure
• Controlling and measuring physical activity
• Compliance
Systems that need to be tested:
• Body composition
• Fat vs. muscle
• Energy expenditure:
• Total energy expenditure
• Resting energy expenditure
• Activity
• Energy Intake:
• Hunger and Satiety
• Autonomic nervous system
• Sympathetic and Parasympathetic
• Neuroendocrine function
• Thyroid function and leptin
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The hypometabolic state in individuals maintaining
a reduced weight does not abate with time
Rosenbaum et al, AJCN, 88:906, 2008 .
24 hour EE (kcal/day)
How many calories needed to maintain weight
5000
4000
*
3000
*
2000
1000
0
Thin
Weight
Loss
Average
50
Heavy
60
70
Weight
Loss
Obese
80
FFM (kg)
Lei bel et al, 199 5, NEJ M 3 32:5 21
Wi ng and Hil l, 20 01, Amu Rev Nu tr, 21:323)
% of Wtinitial
Adaptations During Maintenance of
Reduced Weight: Schematic of Protocol
•Each weight plateau or loss
period takes 6-8 weeks.
•Testing includes: feeding and
energy expenditure; body
composition; skeletal muscle
physiology; neuroendocrine axis
function; and ANS physiology
110
100
90
TEST
Wtinitial
TEST
Wt-10%
TEST
80
Wt-20%
Time
Predominance of NREE changes after weight loss
suggests skeletal muscle is the primary effector organ.
†P<0.001 compared to Wtinitial
*P<0.05 compared to Wtinitial
†
†
*
*
Kulkarni and Shetty, Ann. Hum. Biol., 19:421, 1992; Leibel et al, NEJM 332:521, 1995; Kern et al,
JCEM, 84:4185, 1999; Rosenbaum et al, AJP, 285:5183, 2003
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Increased muscle efficiency and utilization of FFA as fuel
after weight loss, opposite after weight gain
20
*
*
% Change from Wtinitial
*
10
0
-10
*
Wt-10%
Wt+10%
*
-20
*
-30
Efficiency
RQ
(Work/EE)
(10W)
Ergometry
Pi
(rest)
kPCr
Pi/PCr
(41.4kPa)
MRS
Rosenbaum, M. et al, AJP285: R183-R192 2003;
Autonomics and Neuroendocrine
†
*
†
*
*p<0.05 compared to zero
†p<0.01 compared to zero
T3
*
T4
rT3
*
TSH
Adaptive thermogenesis after weight loss
ƒ Autonomics: Decreased SNS and Increased PNS tone
z Effects: Decreased energy expenditure, decreased thyroid
hormones, and increased muscle efficiency
ƒ Neuroendocrine: Decreased bioactive thyroid hormones and
decreased leptin
z Effects: Decreased energy expenditure and increased
muscle efficiency.
ƒ Increased muscle efficiency
z Decreased energy expenditure
ƒ NET EFFECT: 300-400 kcal/day decreased weight
maintenance caloric requirements compared to someone of
the same body composition but not weight reduced.
Energy Intake
• At usual body weight, energy intake and
output are coupled to maintain weight.
• If this coupling persisted after weight
loss, it would be easy to keep it off.
• Behavioral and fMRI studies indicate
that this is not the case.
• At reduced weight energy intake and
output are “uncoupled” to favor weight
regain.
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Energy Intake: Decreased perception of fullness and
amount eaten after weight loss favor weight regain
*
*
*
Before Meal
After Meal
Kissileff et al, AJCN, 95:309-17, 2012
Battle Plan: Possible interventions to reverse
the opposition to sustained weight loss
ƒ Leptin signaling pathway affecting both
energy output and intake
ƒ Exercise type (affecting muscle)
ƒ Other hormones (thyroid)
ƒ Predictive testing
F (Ideal - Actual
energy store)
CNS:
Definition of
‘ideal’ energy
store
F (Ideal - Actual
energy store)
Energy Intake
‘Signal’ of Energy Stored
Partitioning of
Energy Stores
Energy
Output
Protein and
Carbohydrate
Adipose Tissue
obese
lean ANABOLIC RESPONSE
SYMMETRIC AND ASYMMETRIC ENDOCRINE PHYSIOLOGY
THRESHOLDS
[TESTOSTERONE]
[LEPTIN]
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Schematic of Protocol
Hypothesis:
Though leptin administration has little effect on
subjects at usual weight, it will reverse aspects of the
weight-reduced phenotype if given after weight loss.
% of
Wtinitial
110
Randomized single blind
100
Wtinitial
90
Wt-10%
placebo
80
Wt-10%LEP
(5 weeks)
Time
Leptin-reversible changes in energy expenditure, muscle
efficiency, and fuel use following weight loss
Net Mechanical
Efficiency at
Rosenbaum, M. et al. J. Clin. Invest. 2005;115:3579-3586
Autonomic and Neuroendocrine Weight Loss and Leptin Effects
¦ Wt-10%placebo
? Wt-10%lep
*P < 0.05 versus zero
†P < 0.05 versus Wt–10%placebo
Rosenbau m, M. et al. J. Clin. Invest. 2005;115:3579-3586
Muscle Hypotheses
ƒ In vivo increased skeletal muscle efficiency after weight
loss is symptomatic of a shift to more efficient type 1
muscle.
ƒ This will be seen biochemically (decreased
glycolytic/oxidative enzyme ratio) and in expression of
relevant genes (increased MHCI, SERCA2, etc.,.)
ƒ Some or all of these changes in muscle after dietary weight
loss will be reversed by leptin repletion.
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Leptin-reversible changes in muscle enzymes
20
PFK
COX
HADH
PFK/COX PFK/HADH
% Change fromWtinitial
10
0
Wt-10%placebo
Wt-10%lep
-10
-20
*
-30
*
*
Baldwin et al, AJP, 301:R1259-66, 2011
Leptin, MHC and SERCA isoforms
* P<0.05 compared to 0
† P<0.05 compared to 0 and to Wt-10%placebo
*
40
30
%ChangefromWtinitial
20
10
*
0
-10
-20
SERCA SERCA SERCA
1
2a
1/2a
-30
-40
†
MHC
I
MHC
IIa
MHC
IIx
MHC
I/II
MHC
IIa/IIX
? Wt-10%placebo
¦ Wt-10%leptin
Baldwin et al, AJP, 301:R1259-66, 2011
Energy Intake Hypotheses
ƒ After weight loss – subjects are hungrier despite having
ingested the same 300 kcal of food 2 hours prior to testing.
z Hypothesis 1: Reduced weight maintenance is
associated with increased activity in response to food in
brain areas related to reward (orbitofrontal cortext).
ƒ After weight loss – subjects have delayed satiation and less
awareness of how much they have eaten.
z Hypothesis 2: Reduced weight maintenance is
associated with decreased activity in response to food
in brain areas related to restraint (prefrontal cortex).
ƒ Energy output changes are largely leptin-mediated.
z Hypothesis 3: So are energy intake changes.
Hunger and
Satiety
*
*P<0.05 vs. both reduced weight conditions
†P<005 vs. both leptin-sufficient conditions
Kissileff et al, AJCN, 95:309-17, 2012
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Weight reduced (leptin-deficient) vs. Initial weight and weight
reduced but leptin repleted (both leptin-sufficient states)
Wt-10%place bo>Wtinitial and Wt-10 %leptin
Wtinitia l and Wt-10%lept in > Wt-10%placebo
Structure
Net Function (effect)
Structure
Net Function (effect)
Brainstem
↑signal processing (food recognition)
Hypothalamus
Globus pallidus
↑reward from food (how good it tastes)
? integration of leptin/humoral signaling (satiety recognition)
Insula
↑reward expectation (how good you expect it to taste)
Amygdala
Ventral striatum
↑ Reward and motivation (how good it tastes + how hard you’ll work for it)
? response to sensory cues (feelings of fullness)
Cingulate
Lingual and superior temporal gyri
↑ affective response to high (lingual G) and low caloric density foods (Sup. Temp. G) (emotional and cognitive response to food) ? self‐control and error recognition (dietary restraint)
Inferior parietal lobule
? response based on past experience (action based on previous food knowledge)
Summary
• Maintenance of reduced weight invokes
metabolic, autonomic, and endocrine changes
that act coordinately to favor weight regain.
• Most of these changes are alleviated by shortterm ‘replacement’ leptin administration –
longer studies are needed.
• The actions of leptin in weight-reduced
subject are consistent with known leptin
physiological effects.
• The weight-reduced state may be viewed as a
state of relative leptin deficiency.
• Obesity, and the inability to sustain weight
loss, are usually biological diseases, not
psychological weaknesses.
Why this biology is not so bad
• I would rather be told that it is hard to keep weight off
because of my biology than because I have no will power.
• Public labeling of individuals who have trouble sustaining
weight loss as weak, rather than acknowledging and
supporting their accomplishments, worsens the problem.
What Next?
• More and more individuals are recognizing that weight loss
(negative energy balance) and reduced weight
maintenance (energy balance) require different therapies.
• Weight loss maintenance therapy should focus on undoing
the changes that weight loss induced.
• Should be possible to identify the best type of therapy
based on genotypes and/or pre- or post- weight loss
phenotypes.
• Should be possible to derive pharmacotherapy to get our
bodies to work with us after weight loss.
• More early intervention work on prevention.
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