UCSF CME Course, Feb. 26, Calories In. Calories Out. Calories In

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1 The First Law of Thermodynamics Childhood Obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics Robert H. Lustig, M.D. Division of Endocrinology Department of ediatrics University of California, San Francisco UCSF CME Course, Feb. 26, 2010 The First Law of Thermodynamics The First Law of Thermodynamics Calories In Calories Out Calories In 1

2 The First Law of Thermodynamics Weight Gain Calories Out Calories In What happened to willpower? I love fat people. Every fat person says it s not their fault, that they have gland trouble. ou know which gland? The saliva gland. They can t push away from the table. Jesse Ventura (I), Former Governor of Minnesota. layboy,, November 1999;46:55. Behavior? ersonal responsibility? Behavior? ersonal responsibility? Three reasons to doubt this formulation: 1. No child chooses to obese. The quality of life of an obese child is equivalent to those on cancer chemotherapy. (Schwimmer et al. JAMA 289: , 1819, 2003) 2

3 2. Does diet and exercise work? 2. Summary of meta-analyses analyses results of randomized trials of treatments for pediatric obesity ADULTS Wadden et al. Int J Obes. 13(suppl 2):39, 1989 Schwartz, Arterioscler Thromb Vasc Biol 17:233, 1997 CONCLUSIO: Limited evidence supports the short-term efficacy of medications and lifestyle interventions. The long-term efficacy and safety of pediatric obesity treatments remain unclear. McGovern et al. J Clin Endocrinol Metab 93::4600, Exercise for treatment of obesity 2. Summary of meta-analyses analyses results of randomized trials of preventions for pediatric obesity Main results: The 43 studies included 3476 participants. When compared with no treatment, exercise resulted in small weight losses across studies. Exercise combined with diet resulted in a greater weight reduction than diet alone (WMD kg; 95% confidence interval (CI) -1.3 to -0.7). Increasing exercise intensity increased the magnitude of weight loss (WMD kg; 95% CI -2.3 to -0.7). Shaw et al. Cochrane Reviews 2006, Issue 4: CD DOI: / CD pub3. CONCLUSION: ediatric obesity prevention programs caused small changes in target behaviors and no significant effect on BMI compared with control. Trials evaluating promising interventions applied over a long period, using responsive outcomes, with longer measurement timeframes are urgently needed. Kamath et al. J Clin Endocrinol Metab 93:4606,

4 3. We even have an epidemic of obese 6-month olds They don t exhibit any of these behaviors (Kim et al, Obesity 15:1107, 2006) Behavior Stedman s Medical Dictionary Def. A stereotyped motor response to a physiological stimulus So any hypothesis that attempts to explain the obesity epidemic, must be able to explain this as well Behavior Behavior Stedman s Medical Dictionary Def. A stereotyped motor response to a physiological stimulus Corollary: Behavior has a biochemical basis Stedman s Medical Dictionary Def. A stereotyped motor response to a physiological stimulus Corollary: Behavior has a biochemical basis What are the biochemical underpinnings of gluttony and sloth? 4

5 Why do people eat? The homeostatic (hunger) pathway: The homeostatic (hunger) pathway The hedonic (reward) pathway (won t discuss) The stress pathway (won t discuss) Leptin resistance and the role of insulin Controlled by the hypothalamus The neuroendocrinology of energy balance Dexfenfluramine 5

6 Weight loss lowers REE/FFM by 20% Why the negative plateau with weight loss? Because of decreased energy expenditure, to offset the decreased caloric intake Decreased non-exercise associated thermogenesis (NEAT) Decreased resting energy expenditure Decreased thermic effect of food mitochondrial adaptation (UC's?) This is a manifestation of leptin resistance! Leibel et al. N Engl J Med 332:621,

7 Autonomic Function during the Starvation Response In response to declining leptin: Reduced sympathetic activity decreased lipolysis decreased gluconeogenesis decreased energy expenditure Increased vagal activity reduced myocardial oxygen consumption increased adipocyte insulin sensitivity increased insulin secretion increased energy storage Aronne et al. Am J hys 269:R222, 1995 Rosenbaum et al. JCEM 87:2391, 2002 Knockout studies of leptin resistance: leptin pathway Leptin and Leptin Resistance Insulin Leptin Leptin levels are a function of adipocyte energy stores Leptin tells your brain how thin you are, not how fat you are Leptin deficiency causes energy expenditure to decrease, and tdins-4- tdins-3,4-2 The brain perceives leptin deficiency as a state of starvation TEN K+ channel X I 3-kinase tdins-3,4,5- tdins-3,4,5-33 tdins-4,5-2 tp1b I 3-kinase thyroid levels to decline, while leptin repletion corrects them Caloric restriction leads leptin decline before weight loss, and JAK2 S T tp1b A T 3 SOCS3 SH2-B promotes drive to resume caloric intake IRS2 Leptin resistance Obese subjects are hyperleptinemic and "leptin resistant" If we could fix leptin resistance, there wouldn't be obesity Insulin-induced Gene Transcription Leptin-induced Gene Transcription Lustig, Nature Clin ract Endo Metab 2:447,

8 Knockout studies of leptin resistance: insulin pathway Insulin tdins-4- tdins-3,4-2 TEN K+ channel X I 3-kinase tdins-3,4,5- tdins-3,4,5-33 tdins-4,5-2 Insulin Leptin Knockout studies of leptin resistance: insulin pathway tp1b IRS2 I 3-kinase tdins-4- tdins-3,4-2 TEN K+ channel X I 3-kinase tdins-3,4,5- tdins-3,4,5-33 tdins-4,5-2 I 3-kinase JAK2 S T A T 3 SOCS3 SH2-B Leptin tp1b IRS2 Leptin resistance JAK2 S T A T 3 SOCS3 SH2-B tp1b tp1b Leptin resistance Leptin sensitivity Insulin-induced Gene Transcription Leptin-induced Gene Transcription Lustig, Nature Clin ract Endo Metab 2:447, 2006 Insulin tdins-4- tdins-3,4-2 K+ channel The neuroendocrinology of energy balance tdins-4,5-2 Leptin I 3-kinase tdins-3,4,5-3 Leptin-induced Gene Transcription Lustig, Nature Clin ract Endo Metab 2:447, 2006 Genetic studies of leptin resistance: hyperinsulinemia? TEN Insulin-induced Gene Transcription I 3-kinase tp1b IRS JAK2 S T A tp1b T 3 SOCS3 SH2-B Leptin resistance Leptin sensitivity Insulin-induced Gene Transcription Leptin-induced Gene Transcription Lustig, Nature Clin ract Endo Metab 2:447,

9 Effects of Insulin on the Adipocyte Stimulates Glut4 mrna and protein Stimulates Acetyl-CoA Carboxylase Stimulates Fatty Acid Synthase Stimulates Lipoprotein Lipase 9

10 Hypothalamic Obesity Models/Hypotheses of Hypothalamic Obesity Damaged Ventromedial Nucleus Hyperphagia Obesity Insulin Secretion IGF-I Receptor Growth Adapted from Sklar. ediatr Neurosurg. 1994;21: Damaged Ventromedial Nucleus Vagal Firing Rate Insulin Secretion Glucose Utilization Hyperphagia Obesity Adapted from Bray and Gallagher. Medicine. 1975;54: Regulation of β-cell Insulin Secretion 10

11 Hypothalamic Obesity ilot Study urpose Hypothalamic Obesity ilot Study Weight and BMI Change 1. To assess the insulin secretory dynamics of patients with hypothalamic obesity 2. To assess the efficacy of octreotide in reducing basal and glucose-stimulated stimulated insulin release in patients with hypothalamic obesity 3. To assess the efficacy of octreotide in promoting weight loss in patients with hypothalamic obesity Lustig et al. J ediatr 138:162, 1999 Hypothalamic Obesity ilot Study Effects on Glucose and Insulin Responses Hypothalamic Obesity ilot Study Weight Loss Versus: Lustig et al. J ediatr 138:162, 1999 Lustig et al. J ediatr 138:162,

12 Octreotide treatment of hypothalamic obesity Demographics Octreotide treatment of hypothalamic obesity 1st Window (6 Months) Double-blinded, 6 month placebo-controlled trial of octreotide 20 subjects with pediatric hypothalamic obesity ages 8-18; 11M, 9F 2 from St. Jude 18 from other institutions 13 with craniopharyngioma 4 with hypothalamic astrocytoma, optic pathway glioma 1 with suprasellar germinoma 2 with ALL, S/ cranial XRT and chemotherapy Weight 96.8 ± 5.7 kg, BMI 36.3 ± 1.3 kg/m2, annualized weight gain 15.9 ± 2.9 kg weight (kg) Weight BMI = = Octreotide (n = 9) lacebo (n= 9) BMI Octreotide (n = 9) lacebo (n = 9) Lustig et al. JCEM 88:2586, 2003 Lustig et al. JCEM 88:2586, 2003 Insulin (µu/ml) Octreotide treatment of hypothalamic obesity Insulin dynamics during OGTT (1st Window) Lustig et al. JCEM 88:2586, 2003 Drug n = 9 0 months 6 months Minutes lacebo n = Minutes ediatric Cancer Quality of Life CQL-32, Version 1 32-item proctored questionnaire atient and parent reports on: Cognitive functioning hysical functioning sychological functioning Social functioning Validated for ages 8-18 yr 12

13 Octreotide Treatment of Hypothalamic Obesity CQL-32 (6 months 0 months) Functioning lacebo Octreotide Intergroup Cognitive 0.33 hysical 0.33 sychological 0.11 Social 0.22 Lustig et al. JCEM 88:2586, 2003 Child arent Child arent Child arent = =0.09 = =0.09 = = Quality of Life CQL-32 arent Report Correlation between Quality of Life and Insulin Response (6 Months 0 Months) Lustig et al. JCEM 88:2586, 2003 = = 0.77 lacebo Octreotide Insulin Response 13

14 Octreotide x 1 yr ostulated scheme of hypothalamic obesity VAGUS OCTREOTIDE FOOD GLUCOSE IULIN OU OUR FAT ilot Study of Octreotide for Adult Obesity Hypotheses: Insulin hypersecretion occurs in a subset of obese adults Octreotide-LAR 40 mg IM q 28d Effects on Weight and BMI Stratified By Response atients who completed 24 weeks (n=44) Insulin suppression using octreotide will Slow or reverse adipogenesis romote weight loss Velasquez-Mieyer et al. Int J Obesity 27:216, 2003 < ANOVA with repeated measures 14

15 Octreotide-LAR 40 mg IM q28d Effects on Specific Nutrient Daily Intake Octreotide-LAR 40 mg IM q 28d Insulin Dynamics During OGTT de ( 0.001) Velasquez-Mieyer et al. Int J Obesity 27:216, 2003 Velasquez-Mieyer et al. Int J Obesity 27:216, 2003 Octreotide-LAR 40 mg IM q 28d Changes in lasma Leptin Octreotide-LAR 40 mg IM q28d Changes in Resting Energy Expenditure (REE) d epti Lustig et al. Int J Obesity 28:1342, 2004 Lustig et al. Int J Obesity 28:1342,

16 Octreotide-LAR 40 mg IM q 21d: 6 month extension Effects on Weight and BMI stratified by initial response Randomized dose-finding trial of octreotide-lar in adult obesity due to insulin hypersecretion o ee Randomized, double-blind, placebo-controlled, dose-finding trial of octreotide-lar in adult obesity due to insulin hypersecretion (as measured by baseline CIR > 1.0) 19 centers nationwide Inclusion criteria: Age BMI > 30 CIR > 1.0 on screening OGTT Exclusion criteria: Diabetes mellitus revious voluntary weight loss Use of weight loss medications Use of any autonomically active or psychoactive medications Gallstones, hepatic disease, renal disease Lustig et al. Int J Obesity 30:331, 2006 Role of Race and CIR in rediction of Response to Octreotide-LAR Octreotide-LAR x 6 months percent body weight lacebo Non<1.43 Cauc<1.43 Cauc>1.43 Non>1.43 percent body weight mg, = Non>1.43 Non<1.43 Cauc<1.43 Cauc>1.43 percent body weight mg, = mg, =0.02 Non<1.43 Cauc<1.43 Non>1.43 Cauc>1.43 percent body weight Non>1.43 Cauc<1.43 Non<1.43 Cauc>1.43 Caucasians, CIR > 1.43Ñ Treatment Group Comparison, =0.046 Lustig et al. Int J Obesity 30:331,

17 Improvement of leptin sensitivity Improvement of leptin sensitivity Forced weight loss (Rosenbaum) Forced weight loss (Rosenbaum) Drug-induced reduction in insulin (Lustig) Drug-induced reduction in insulin (Lustig) What s the similarity? The drop in insulin Measuring Leptin Sensitivity Octreotide-LAR 40 mg IM q28d Changes in the REE:Leptin Ratio Lustig et al. Int J Obesity 28:1342,

18 Overlap between hypothalamic insulin and leptin signaling Insulin tdins-4- tdins-3,4-2 I 3-kinase TEN tdins-3,4,5-3 tdins-4,5-2 DK1 mtor kcζ ζ Akt p70s6k 4E-B-1 GSK3B Tsc1/2 S6 eif4e Leptin I 3-kinase Insulin is an endogenous leptin antagonist (?) H tp1b TB IRS2 JAK2 tp1b S T A T 3 Grb2/SOS Foxo Gene Transcription MAK MEK raf ras Gene Transcription Isganaitis and Lustig, Arterioscl Thromb Vasc. Biol. 25:2451, 2005 Insulin is an endogenous leptin antagonist (?) Insulin is an endogenous leptin antagonist (?) Does this make sense teleologically? Does this make sense teleologically? Insulin gives the human the ability to modulate weight gain acutely, by allowing insulin resistance to induce leptin resistance: 1. uberty 2. regnancy 18

19 Restating The First Law of Thermodynamics Restating The First Law of Thermodynamics Obligate weight gain (insulin) Weight Gain Restating The First Law of Thermodynamics Obligate weight gain (insulin) Restating The First Law of Thermodynamics Obligate weight gain (insulin) Weight Gain Calories Out Weight Gain Calories Out Calories In 19

20 The limbic triangle Childhood Obesity Behavior or Biochemistry? Reinterpreting the First Law of Thermodynamics Childhood obesity is on the rise Hyperinsulinemia and leptin resistance are both hallmarks of obesity Energy expenditure decreases in response to declining leptin, invoking the starvation response, and causing weight plateaus or reversals Reduction in insulin improves leptin resistance and promotes weight loss Insulin appears to be an endogenous leptin antagonist Our diet is insulinogenic; we have to get the insulin down Our food alters our hormones which alter our food Mietus-Snyder and Lustig, Ann Rev Med 59:147, 2008 Behavior really is biochemistry St. Jude Children's Research Hospital Melissa Hudson, M.D. Heme/Onc Kleebsabai Srivanaboon, M.D. am Hinds, h.d. Nursing Robbin Christensen, D.h. Richard Heideman, M.D. Larry Kun, M.D. Rad/Onc Tom Merchant, D.O., h.d. Collaborators Heme/Onc harmacy Neuro/Onc Rad/Onc Susan ost, MSII, Chicago Medical School Sue Kaste, D.O. Diagnostic Imaging Karen Smith, R.D. Clinical Nutrition Bill Mackert ulmonary hysiology Xiaoping Xiong, h.d. Shesh Rai, h.d. Biostatistics Biostatistics Dana Jones-Wallace, M.S. Shelly Lensing, M.S. Biostatistics Biostatistics Shengjie Wu, M.S. Biostatistics St. Jude Clinic Nurses and Staff U.T. Memphis ed. Endocrine edro Velasquez, M.D. Susan Rose, M.D. isit itukcheewanont, M.D. Michael Christensen, harm.d. George Burghen, M.D. U.T. ediatric CRC Nurses UCSF Chaluntorn reeyasombat, M.D. Ann Lazar, h.d. eter Bacchetti, h.d. Elvira Isganaitis, M.D. Michele Mietus-Snyder, M.D. Andrea Garber, h.d., R.D. Joan Valente, h.d. Cam-Tu Tran, M.D. UCSF ediatric CRC Nurses Novartis harmaceuticals, Inc. 20