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Copyright 2007, Elif Oral, Arno Kumagai

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1 Copyright 2007, Elif Oral, Arno Kumagai
Unless otherwise noted, the content of this course material is licensed under a Creative Commons Attribution - Non-Commercial - Share Alike 3.0 License. Copyright 2007, Elif Oral, Arno Kumagai The following information is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. You should speak to your physician or make an appointment to be seen if you have questions or concerns about this information or your medical condition. You assume all responsibility for use and potential liability associated with any use of the material. Material contains copyrighted content, used in accordance with U.S. law. Copyright holders of content included in this material should contact with any questions, corrections, or clarifications regarding the use of content. The Regents of the University of Michigan do not license the use of third party content posted to this site unless such a license is specifically granted in connection with particular content objects. Users of content are responsible for their compliance with applicable law.

2 Update on Obesity Elif Arioglu Oral, M.D.
Assistant Professor of Medicine Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, Ann Arbor, MI.

3 What is obesity? public domain National Library of Medicine

4 Image of cover of New Yorker Magazine removed
What is Obesity ? Image of cover of New Yorker Magazine removed

5 Obesity Measurement and definition Physiology Environmental causes
Genetic causes of obesity Endocrine causes of obesity Medical risks

6 Obesity treatment Goals of treatment Prevention Diet Exercise
Behavior modification Drug Therapy Specific Drugs Drugs on the horizon Gastric surgery

7 Measurement and Definition
Increased amount of body fat. Weight (exceptions, such as body builders) BMI BMI=WEIGHT (in kilograms)/HEIGHT in meters)2 BMI=703 x WEIGHT (pounds)/(HEIGHT-in inches)2.

8 Classification of Obesity
BMI kg/m2 Overweight BMI kg/m2 Grade I BMI kg.m2 Grade II BMI >40 kg/m2 Grade III (morbid) (extreme)

9 Measurement and Definition
Distribution of body fat. Upper body (abdomen and flanks, android obesity, "apples") Lower body obesity (legs and buttocks, gynoid obesity, "pears"). Visceral adiposity

10 Measurement and Definition
Research techniques Skin fold thickness Waist : hip ratio Waist circumference >35 inches (88 cm) in women >40 inches (102 cm) in men Bioelectric impedence Infrared interactance Underwater weighing Isotope distribution DEXA CT MRI

11 Physiology Central weight-control center
Hypothalamus Feed-back control of body weight Leptin and other adipocyte signals Signals from the “gut” Balance between energy intake and expenditure

12 PHYSIOLOGY OF OBESITY (+) (-) Energy expenditure Energy intake
Leptin Insulin (+) (-) Fat stores The Brain CC:BY 3.0 BY: Regents of the University of Michigan Image of brain Public Domain National Library of Medicine Adapted from Schwartz, M. W. et al. J Clin Endocrinol Metab 2004;89:

13 Physiology: Central Pathways
Anorexigenic Orexigenic Leptin a-MSH CART GLP-1 C-NTF CRH/Urocortin Neuromedin U Serotonin CCK Insulin Bombesin Calcitonin Enterostatin TRH IL-1B Neurotensin Oxytocin Vasopressin Neuropeptide Y MCH AGRP Orexin A, B (Hypocretin 1,3) Galanin Dynomorphin Norepinephrine B-endorphin Important to know that complex regulation exists, do not need to know individual factors. Identify Leptin as important.

14 Adipose Tissue: An Endocrine Organ
Adiponectin Angiotensinogen Resistin IL-6 TNF-α Leptin other Adipose Tissue: An Endocrine Organ CC:BY 3.0 BY: Regents of the University of Michigan

15 Leptin: Of Mice and Man ? ? Image of before and after leptin replacement in mouse removed Image of before and after leptin replacement in boy removed

16 Physiology: Leptin A 16-KD hormone produced predominantly by adipocytes Circulating levels are determined chiefly by fat mass Increased leptin synthesis/secretion Re-feeding (after fasting) Adiposity Glucocorticoids Insulin Thiazolidinediones while fasting Inhibition of leptin synthesis/secretion Sympathetic stimulation Circulates partially protein- bound

17 Physiology: Leptin Leptin receptor: Leptin’s chief physiologic role:
is a member of the cytokine receptor family exists as a number of splice variants the long form signaling via JAK2 and STAT3 to regulate transcription. short receptor forms important for leptin transport, clearance, and signaling via non-J AK/STAT pathways. Leptin’s chief physiologic role: A read out of adiposity and nutritional status, allowing the body to respond to starvation

18 Physiology: Leptin Leptin's central actions :
Increase energy expenditure (via physical activity, sympathetic nervous system activity) Decrease food intake Decrease body weight Increase insulin sensitivity Help signal the onset of puberty Regulate other pituitary hormone axes Leptin’s peripheral actions Stimulate angiogenesis Hematopoietic cell proliferation T-cell immnunity

19 Two key points—the EO rules!
Fat is not our foe, it is a functional endocrine organ. Too much fat is bad. Too little is also bad “Just Right”

20 Adipose Tissue: An Endocrine Organ
Adiponectin Angiotensinogen Resistin IL-6 TNF-α Leptin other Adipose Tissue: An Endocrine Organ CC:BY 3.0 BY: Regents of the University of Michigan

21 Lipodystrophy Syndromes
Paucity of adipose tissue Insulin resistance Hypertriglyceridemia Fatty infiltration of liver and other tissues ? Image of woman with lipodystrophy removed

22 Satiety Signals from the Gut: CCK, GLP-1, PYY
Ghrelin Others (?) Energy expenditure Energy intake Leptin Insulin (+) (-) Fat stores The Brain CC:BY 3.0 BY: Regents of the University of Michigan Image of brain Public Domain National Library of Medicine Adapted from Schwartz, M. W. et al. J Clin Endocrinol Metab 2004;89:

23 Obesity Is Caused by Long-Term Positive Energy Balance
Fat Stores Obesity is caused by long-term positive energy balance Obesity is caused by ingesting more energy than is expended over a long period of time. The excess calories that are consumed lead to an accumulation of body fat either by being stored as fat or preventing the mobilization and oxidation of endogenous fat. In general, ingesting 3500 kcal more (or less) than expended will lead to a gain (or loss) of approximately 1 lb of fat. Genetic factors may influence the amount of weight gained with overfeeding. In one study, weight gain varied greatly among 12 monozygotic twin pairs who were chronically overfed 1000 kcal/d [1]. However, weight gains were very similar within each member of a twin pair. In another study, body fat gain after 8 weeks of overfeeding also varied among study subjects but was inversely related to changes in non-volitional energy expenditure, such as fidgeting, which may be determined genetically [2]. Bouchard C, Tremblay A, Despres JP, et al. The response to long-term overfeeding in identical twins. N Engl J Med 1990;322: Levine JA, Eberhardt NL, Jensen MD. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science 1999;282:

24 Balancing Intake vs Expenditure
Changes in the environment Energy dense food overabundant Opportunity for expenditure reduced

25 The Origins of Obesity: Environment and temptations
Eating habits are learned early CC:BY BY: pointnshoot CC:BY-NC-SA By: World of Oddy

26 Role of Environment: Increased Food Intake
Wendy’s Sandwich Big Bacon Classic = 570 kcal Wendy’s Potatoes, Chili, & Nuggets Total 1680 kcal Great Biggie Fries = 530 kcal Wendy’s Beverages & Desserts Large “Frosty” = 440 kcal Cola = 140 kcal

27 Decreased Physical Activity
TV CC:BY-NC 2.0 BY: Brandon King CC:BY-SA 2.0 BY: dave_7 Cars One big couch potato Computers CC:BY-NC 2.0 BY: Joe Hatfield

28 Prevalence of Obesity Among Adults:1989
< 10% 10-15% > 15% Source: Mokdad, et al. Mokdad A H, et al. J Am Med Assoc 2001;286:10

29 Prevalence of Obesity Among Adults: 1994
< 10% 10-15% > 15% Source: Mokdad, et al. Mokdad A H, et al. J Am Med Assoc 2001;286:10

30 Prevalence of Obesity Among Adults:1998
< 10% 10-15% > 15% Source: Mokdad, et al. Mokdad A H, et al. J Am Med Assoc 2001;286:10

31 Genetic bases of obesity
Big genetic component Estimated at 40-70% Most of obesity polygeneic or oligogeneic Thrifty gene hypothesis Monogeneic forms of obesity Isolated genes Syndromic obesity

32 Monogeneic obesity Leptin Leptin receptor MC4-Receptor A few families
A single family MC4-Receptor Most common defect

33 Endocrine Causes of Obesity
Hypothalamic injury or tumor Cushing’s syndrome Hypothyroidism Hypogonadism Growth hormone deficiency Polycystic ovarian syndrome Manifestation of obesity versus cause

34 Heterogeneity Important concept Not all obese are equal

35 Medical Risks of Obesity
Mortality (less in African Americans) Insulin resistance/Type 2 diabetes Hypertension Hyperlipidemia Arthritis Obesity/hypoventilation syndrome=sleep apnea Gallbladder disease Cancer (breast, colon, prostate, ovarian, endometrial) Not increased: osteoporosis or psychiatric disease

36 Obesity treatment Goals of treatment Prevention Diet Exercise
Behavior modification Drug Therapy Specific Drugs Drugs on the horizon Surgical therapy

37 Goals of treatment 5-year success only 5% Reduce co-morbidities
Maintain minimum of 5% weight loss 5-year success only 5%

38 Key Features of Long-Term Losers
Adopted a routine exercise regimen Weighed routinely (and taking action) Eating breakfast, not skipping meals

39 Diet Caloric restriction (fat <30%, unsaturated fat <10%)
High fat, low carbohydrate diets Regaining popularity CHO<20%, fat >50% Many variations Two views: Simple law of thermodynamics Human metabolism is complex and futile cycles between CHO and fat metabolism exist. Thus, composition of diet matters.

40 Exercise More benefit than just the calories burned
Goal: make long-lasting Minimum regimen: 30 minutes of brisk walking 5 times a week (Diabetes Prevention Program) More active lifestyle: fidget, walk more for chores, use stairs, etc.

41 Behavior Modification
Self-monitoring Goal setting Slow eating rate Food log Adequate sleep –especially age <40 years individualized

42 Obesity treatment Drug Therapy Approved Drugs Drugs on the horizon

43 Approved Drugs Sibutramine (Meridia) Orlistat (Xenical)
Other FDA Approved drugs

44 Two important questions
Whom to treat? For how long? Focus on co-morbidities “Metabolic fitness “ For FDA and insurance carriers: BMI>30 or >27 kg/m2 with comorbidities

45 Sibutramine (Meridia)
Approved : 1998 Mechanism: Serotonin, norepinephrine and dopamine reuptake inhibitor, does not promote serotonin release Responders lose >4 pounds in the first 4 weeks of treatment Side-effects: hypertension, increased heart rate, dry mouth, constipation, insomnia, and headache Contraindicated with PPH, valvular heart disease, MAOI or serotoninergics

46 Orlistat (Xenical) Approved: 1999
Mechanism: non-absorbed inhibitor of pancreatic lipase. Administered with meals Side-effects: GI bloating, flatus, oily stools, urgency, fat leakage, deficiency of B-carotene and A,D,E,K vitamins Contraindicated in chronic malabsorbtion, cholestasis, known hypersensitivity Improves lipid status and slows progression to diabetes

47 Phentermine (Adipex, Ionomin, Fastin)
Approved for short-term use only Mechanism: Adrenergic Side-effects: over-stimulation and nervousness, insomnia, and headache Contraindicated with PPH, valvular heart disease, symptomatic cardiovascular disease, glaucoma, moderate hypertension

48 Drugs not indicated Fluoxetine (Prozac) Thyroid hormone Androgens
Growth hormones Amphetamines Diueritcs Digitalis

49 Other approved drugs with weight loss potential
Exanatide - -(Byetta) Metformin- - (Glucophage) Pramlinitide- - (Symlin) Topiramate – (Topamax) Zonisamide Other mood-stabilizers (Buprapion, etc).

50 Drugs on the horizon: in later stages of development
Leptin Cannabinoid Receptor 1 Antagonist: Rimonabant (ACCOMPLIA) Newer generation under development New intestinal lipase inhibitor-ATL692 PYY 3-36 Growth hormone fragment AOD9604 (aa 177 to 191) Bray G: Medical Clinics of North America 91 (2007):

51 LEPTIN (recombinant human methionyl leptin METRELEPTIN ; AMYLIN CORP.)
Administered subcutaneously Very effective in leptin-deficiency related obesity (mutations in ob gene) Phase II in general obesity with a wide range of effect in individuals Factors that determine responders not clear (relative deficiency at baseline?) Role in long-term weight maintenance? Role in combination therapies? Surprising metabolic benefits in lipodystrophy, role in HIV lipodystrophy?

52 Cannabinoid Receptor 1 Antagonist: Rimonabant (ACCOMPLIA, Sanofi)
Works by selectively blocking the CB1 receptors, helping normalize the over-activation of the Endocannabinoid System Weight loss Less food-craving Less tobacco-craving Improved lipid profiles with raised HDL levels Improved insulin sensitivity Side-effect tolerability (?): profound nausea / dysphoria or depression, increased suicide (?) US market projected date: FDA rejected in 2007, but approved in Europe and Canada

53 Emerging Concepts in Medical Therapy
Chronic therapy (continuous or intermittent) Individualized therapy (one-drug-for-all not realistic) Combination therapy (very successful preclinical results with Symlin and Leptin combination)

54 Surgical Treatment of Obesity
Highly effective and reduces mortality 1% mortality Life-long commitment with behavior modification Life-long need for medical follow-up Indications: BMI>40 (or >35 with co-morbidities) Failure of previous weight loss attempts Well-informed and highly motivated patient

55 Some considerations Patients need to understand
What is going to happen Requirement of a support system Eating disorders and emotional eating need to be addressed Lifelong need for supplementation Unknown medical risks Exaggerated reactive hypoglycemia?

56 PEDIATRIC OBESITY Extreme cases deserve work-up for specific monogeneic or syndromic causes Major goal: prevent adult obesity and co-morbidities Focus on diet/exercise and behavior modification (stress adequate sleep) Only approved drug: Orlistat

57 CONCLUSIONS Treatment of obesity should be directed at achieving metabolic fitness. Diet, exercise, behavior modification are rarely effective for long-term. No magic bullet exists so far.

58 Sample Question 1 If a patient has height of 150 cm and a weight of 150 kg, how would you classify this patient’s habitus? A) Normal weight B) Overweight C) Mildly obese D) Morbidly obese

59 Sample Question 2 What would you like to know before you assume that patient needs therapy for his condition?

60 Sample Question 3 What would you recommend as the first step of his management? For how long? What would be the goal for his therapy? If he returns to his 6 month f/u visit with a weight of 140 kg, what would you recommend next? What if he had returned at 160 kg?

61 Sample Question 4 What gene defect is responsible from the most common monogeneic form of obesity?

62 Sample Question 5 What are the predictors of successful weight maintenance for long-term?

63 Disclaimer—remember when evaluating the lecture quality…
Dr. Kumagai is responsible for the contents of this lecture, though he will adamantly refuse responsibility and blame Dr. Lash for how boring it is. Dr. Oral is a very pleasant person and cannot take criticism very well.


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