1. Understanding Obesity: Neuropeptides, Hormones and the Endocannabinoid System Laure Sayyed Kassem Senior Talk August 2008

2. Objectives Briefly discuss energy intake, expenditure and nutrient partitioning Describe the current therapeutic options for obesity and overweight Understand the multiple signals involved in metabolism: satiety signals, insulin, CNS control, leptin and ghrelin Understand the basics of the ECS Appreciate the role of ECS in obesity Identify the therapeutic implications

3. The Well Known Truth… Prevalence steadily rising for 20 yrs Trend is across the globe USA: lifetime risk of overweight is 50%, obesity 25% Health and cost implications: insulin resistance, type 2 diabetes, CV disease

4. Not all fat is created equal Visceral fat versus gluteofemoral fat Visceral fat is drained by portal vein Has higher rate of lipolysis → more fatty acids into liver Consequences: ↑ Glc ProductionGlc intolerance ↓ Insulin BreakdownHyperinsulinemia ↑ TG productionDyslipidemia

5. Why we get fat- the obvious: Imbalance in the determinants of body fat stores: - Intake (type, amount, CNS control) - Expenditure (depends mostly on lean mass) - Partitioning of proteins and lipids

6. Intake: Carbohydrate Metabolism Very limited stores Immediate availability is crucial- lipids do not convert to CHO Intricate system for sensing and preserving CHO Excess CHO drives more CHO utilization Excess CHO generally does not convert to lipids

7. Intake: Lipid Metabolism No feedback mechanism for sensing/adjusting intake or expenditure Increased intake does not change the choice of tissue fuel Increased intake therefore leads to long term storage

8. Partitioning Muscle mass: 40-45% of body weight Muscle mass determines resting energy expenditure Decreased muscles production causes spill over of nutrients into fat stores Factors that decrease muscle synthesis: - lack of exercise - genetics - hypogonadism, glucocorticoid excess - leptin, insulin, IGF-1

9. Expenditure: 1+1 ≠ 2 I start eating 250 Kcal of chips every night, keeping all else the same I gain 1750 Kcal/week (almost 0.25 Kg) Do I gain 13 Kg for the first year? Will I gain 130 Kg in the next 10 yrs? Expenditure adapts to new weights, so that weight stabilizes after 10% changes

11. Current therapeutic approaches Caloric Restriction – generally ineffective, high attrition rate Low-Fat Diets Low- CHO Diets Exercise: effective only if combined with diet, important for long term maintenance Pharmacologic agents

12. Fat Absorption Inhibitors: Orlistat (Xenical®) Sympathomimetics (appetite suppressants) - Sibutramine (Meridia®): FDA approved, modest results, avoid in HTN, CV d/o, CVA - Phentermine and Diethylpropion: approved only for short-term - Ephedrine and Ephedra Alkaloids: removed from market Combination: 2 trials not showing added benefit

13. Antidepressants (fluoxetine, bupropion): not FDA approved Antiepileptics (topiramate, zonisamide): not FDA approved Dietary supplements (green tea, chromium, chitosan, guar gum, St John’s Wart): limited data and some with serious safety concerns

14. Why we get fat- the not so obvious

15. Lessons from genetic disorders: -Agouti gene -Leptin gene -Leptin receptor gene -Carboxypepetidase E -Melanocortin receptor gene -Serotonin receptor gene -Many others…

16. Metabolic Homeostasis is complex Nature, 2000;404:661-671

17. Satiety Signals Major signal is CCK Secreted by stomach after intake → signal transmitted by vagus to the NTS → stop food intake Control of meal size is controlled only by forebrain and hindbrain under normal conditions- hypothalamus is not involved

18. Signals from adipose tissue Leptin and (indirectly) insulin Both have receptors in the hypothalamic arcuate nucleus (Arc) Effect: activate catabolic pathways Mediators: NPY and AgRP (inhibition)

19. Leptin Discovered in 1994 by Jeffrey Friedman Cytokine, produced by fat cells, placenta and ?stomach Diurnal variation: peak in nighttime Receptors (gp130) located in most tissues, with a long form of the receptor in hypothalamus Bigger fat cells produced more leptin Leptin levels correlate with body fat content

20. Leptin Overeating: leptin ↑ by 40% in 12 hours Fasting: leptin ↓ by 60-70% in 48 hrs Changes before body fat stores change

21. Leptin Clinical entities: -Congenital leptin deficiency: hyperphagia, massive obesity, hyperinsulinemia -Receptor deficiency: similar but less severe -3% of people with early onset severe obesity have nonsense/missense mutations

22. Leptin Injecting leptin into rat brains ↓ food intake, ↑ HR, BP and energy expenditure Obese subjects have high leptin levels, suggesting leptin resistance Postulated ideas: -Elevated leptin levels are related to insulin resistance -Elevated leptin levels are correlated with increased proinflammatory state

23. Ghrelin “Opposite” of Leptin Protein made by endocrine cells of stomach and GI tract Hypothalamic receptors Rises just before meals and falls after Ghrelin administration in rats strongly stimulates feeding, Anti-Ghrelin Abs suppress feeding High Ghrelin levels in Prader-Willi syndrome

24. Hypothalamic effects of Leptin/Ghrelin Nature, 2000;404:661-671

25. Hypothalamic effects of Leptin/Ghrelin Catabolic cell group: POMC and CART (cocaine- and amphetamine regulated transcript) → ACTIVATED by leptin, INHIBITED by ghrelin Anabolic cell group: NPY and AgRP → ACTIVATED by ghrelin, INHIBITED by leptin

27. Endocrinology, Sep 2003, 144(9):3749-3756

28. ECS: the basics Ligands (endocannabinoids) + receptors (cannabinoid receptors) CB1 and CB2 Ligands are ‘neurotransmitters’: Anandemide and Arachidonoyl glycerol System is normally in the “off mode” Transiently activated by stressful stimuli Results: food ingestion, relaxation, pain reduction, and extinction of aversive memories.

29. “The ECS is postulated to connect the physical and emotional responses to stress with appetite and energy regulation… a general stress- recovery system, which remains silent under normal physiologic conditions.” Curr Opin Endocrinol Diabetes. 2005;12:338-351

32. Central effects CB1 receptor: accounts for all the well known psychotropic effects of cannabis Diffusely populates the CNS, specifically limbic structures, hypothalamus, brainstem Attenuates satiety signals (CCK) whenever modulatory neurons are involved (food is especially good or social context desirable)

33. American Journal of Medicine (2007) Vol 120(2A),S9-17

34. Supporting evidence Administering Anandamide into the hypothalamus of presatiated mice still lead to hyperphagia. Underfed mice lacking CB1 receptors eat less than wild type mice. Similarly with underfed mice given CB1 antagonist

35. Adipocytes and the ECS Human adipocytes have CB1 receptors. Rats given CB1 antagonist (rimonabant) had lower weight, reduced insulin, and increased adiponectin (↑insulin sens, ↓fatty oxid). => Expression of adiponection is normally suppressed by ECS Obese humans have high EC levels at the adipocyte level and low expression of EC degradation enzymes.

36. Insulin attenuates the ECS The relationship has been recently elucidated in 2007 by Tara et al Insulin normally decreased EC levels and increased their degradation enzymes But, insulin resistant adipocytes were incapable of that Findings were replicated in vivo

39. Liver and the ECS Liver is an important site of lipogenesis Mice given EC agonist had > 2 fold increase in liver lipogenesis Gene cluster involved in lipogenesis has been found to be activated by the ECS

40. Leptin and the ECS Leptin inhibits EC effects in the hypothalamus leading to decreased intake. Injecting rats with leptin decreases the EC levels in hypothalamus by 40-50%.

41. If the ECS is also tightly regulated by insulin, leptin and adipocytes, how can it promote obesity? Endocrinology, Sep 2003, 144(9):3749-3756

42. ECS in obese humans Chronically activated instead of “off mode” Chronically elevated EC levels Individuals with visceral obesity have higher EC levels than lean individuals EC levels α BMI and insulin insensitivity EC levels higher in binge-eaters than anorexics, bulemics and healthy subjects

43. A missense polymorphism in EC degradation was found to be significantly more prevalent in obese and overweight than normal subjects

44. Int J Obes (Lond). 2005;29:755-579

45. A proposed unifying theory High fat diet EC precursors Overproduction of ECs Weight increase Leptin resistance

47. Therapeutic Implications

48. Rimonabant (SR141716)- Acomplia® Human trials: 4 large trials, 2 meta-analyses - consistently show significant weight reductions (mean difference 4.9kg) compared to placebo at 20 mg/day - consistently show improved cardiometabolic risk factors - improved A1c in diabetic patients - concern for significant rate of anxiety and depression

49. Leptin Subcutaneous injection effective in rare individuals with leptin deficiency Trials in obese subjects limited and have many intrinsic limitations Modest weight loss with supraphysiologic doses needed to overcome leptin resistance in obesity

50. Others Peptide YY: gut hormone, appetite suppressant, conflicting trials Oxyntomodulin: gut hormone, limited data Melanocortin-4 receptor agonists: conflicting trials

51. In the meantime NIH, USPSTF, AAFP and many more recommend screening of all adults Waist circumference: <102 inches for men, <88 for women Intensive counseling and behavioral interventions Recommended agents are orlistat then sibutramine (if no CV risk factors)

52. References D’Eon et al. The role of adipocyte insulin resistance in the pathogenesis of obesity-related elevations in endocannabinoids. Diabetes 2008;57:1262-1268 Zigman et al. Minireview: From anorexia to obesity- the yin and yang of body weight control. Endocrinology 2003;144(9):3749-3756 Woods. The endocannabinoid system: mechanisms behind metabolic homeostasis and imbalance. Am J Med 2007;120(2A):S9-S17 Matthias et al. Dysregulation of the peripheral and adipose tissue. Endocannabinoid system in human abdominal obesity. Diabetes 2006;55:3053-3060 Patel S, Hillard CJ. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther. 2006;318:304-311. Weigle et al. Effects of fasting, refeeding and dietary fat restriction on plasma leptin levels. J Clin Endocrinol Metab 1997;82:561Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351. Sipe et al. Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase. Int J Obes (Lond). 2005;29:755-579 Curioni et al. Rimonabant for overweight or obesity, Cochrane Database Syst Rev 2006; :CD006162 Heymsfield et al. Recombinant leptin for weight loss in obese and lean adults. A randomized, controlled, dose-escalation trial. JAMA 1999;282:1568 P Arner. Regional adiposity in man. Journal of Endocrinology (1997) 155, 191–192 F Greenspan and D Gardner. Basic and Clinical Endocrinology 2004. Lange, seventh edition. 794-813