1. Copyright 2007, Elif Oral, Arno Kumagai
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Copyright 2007, Elif Oral, Arno Kumagai
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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 ActivityTV
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.