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 1 Key Questions Does the majority of the U.S. lack willpower? Is obesity a disease that keeps on giving even after it has supposedly been cured by weight loss? 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: They need to maintain dietary restriction (eat less than matched individuals at usual weight). 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) 2 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 3 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 4 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 Autonomics: Decreased SNS and Increased PNS tone z Effects: Decreased energy expenditure, decreased thyroid hormones, and increased muscle efficiency Neuroendocrine: Decreased bioactive thyroid hormones and decreased leptin z Effects: Decreased energy expenditure and increased muscle efficiency. Increased muscle efficiency z Decreased energy expenditure 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. 5 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 Leptin signaling pathway affecting both energy output and intake Exercise type (affecting muscle) Other hormones (thyroid) 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] 6 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 In vivo increased skeletal muscle efficiency after weight loss is symptomatic of a shift to more efficient type 1 muscle. This will be seen biochemically (decreased glycolytic/oxidative enzyme ratio) and in expression of relevant genes (increased MHCI, SERCA2, etc.,.) Some or all of these changes in muscle after dietary weight loss will be reversed by leptin repletion. 7 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 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). 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). 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 8 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. 9