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Obesity Epidemic?

Obesity Epidemic?. Detail of chromosome 15 From the obesity map database. Bacchus, Peter Paul Reubens, 1638. Recent Increases in Obesity. 1985: <15% obese 2000: >30% obese. Is obesity a disease?. -not all obese people have poor health. What’s causing this unusual Increase in obesity?.

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Obesity Epidemic?

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  1. Obesity Epidemic? Detail of chromosome 15 From the obesity map database Bacchus, Peter Paul Reubens, 1638

  2. Recent Increases in Obesity 1985: <15% obese 2000: >30% obese Is obesity a disease? -not all obese people have poor health What’s causing this unusual Increase in obesity? -Our genes? -Environment? fast foods sedentary lifestyle -Dieting, especially low fat diets -Food choices that blind our natural ability to monitor our food intake

  3. Obesity: Environment It’s those damn corporations

  4. again shall be king

  5. Obesity: Environment Sedentary Lifestyle

  6. Obesity: Ridiculousness

  7. Let’s poke carbohydrates in the eyeball Dave Barry Obesity: Environment • Diets too high in fat? • Too much meat and dairy? • Diets too high in carbohydrates? • Too much sugar • Refined flour • Soft drinks • Diet drinks make you hungry!

  8. Good Mouse Bad Mouse Avoiding Obesity: It’s all about self-discipline, will power, determination

  9. Obesity Genes

  10. Recent Increases in Obesity 1985: <15% obese 2000: >30% obese

  11. Sexually Dimorphic Mammalian Species

  12. Humans are Dimorphic • Males • Taller, heavier • Broader shoulder • Smaller hips, buttocks • Smaller breasts • More facial hair • Deeper voice • Larger phallus • Less stamina due to lower subcutaneous fat • More heart disease due to tendency to gain abdominal body fat

  13. Sexual Dimorphism in Body Fat Distribution in HumansAbdominal vs. Subcutaneous FatResults in Apple vs. Pear Shape

  14. Diabetes and Heart Risks if. .  150 mg/dL < 40 mg/dL < 50 mg/dL • Triglycerides • “Good Cholesterol” = High-Density Lipoprotein Cholesterol • Men • Women NCEP Expert Panel. JAMA. 2001;285:2486-2497.

  15. Plasma Triglycerides and HDL-Cin Lean Men and Women and in Obese Subjects with High or Low Visceral Adipose Tissue (AT) 1.50 1.25 1.00 0.75 0.00 1 1 Low High Low High Lean Men Lean Men HDL Cholesterol (mmol/L) Visceral AT AreaObese Men Visceral AT AreaObese Men Triglycerides (mmol/L) 1.2 1.50 1.25 1.00 0.75 0.00 1 1.2 Low High Low High Lean Women Lean Women Visceral AT AreaObese Women Visceral AT AreaObese Women Despres JP, Krauss RM. Handbook of Obesity. 1998;651-675.

  16. Traits Associated with WTH in Women • Trait WTH High WHT Low Ref. Puberty onset late early 1 Testosterone high low 2 Triglycerides high low 1,3 Insulin resistance high low 1,4 Risk for Type II diabetes high mod-low 1,5 For gallbladder disease high mod-low 6 Risk for cancer (ovar.,breast, uterine) high mod-low 7,8 Hypertension, stroke heart disease, mortality high mod-low 3,5,9

  17. Adaptive significance of Sexual Dimorphism in Body Fat Distribution related to female lactation (fat is stored in the hips, thighs, buttocks for use in making milk during lactation)

  18. An enzyme active in weight gain is high in thighs prior to lactation.High LPL = gaining fatLow LPL = losing fat Gaining in thighs Losing in thighs Rebuffe’-Scrive et al., 1974

  19. Nonabdominal fat critical for reproduction And it’s not unhealthy! It might even be “protective” against diabetes and heart disease

  20. Regardless of female body weight(whether the females are very fat, very lean or in between) A large body of data supports the notion that males of North or South American or Europe strongly prefer a LOW W.T.H. ratio

  21. Health Risks and Obesity Abdominal (apple)Subcutaneous (pear) • Insulin resistance • Hyperinsulinemia • Hypercholesterolemia • Low HDL cholesterol • Diabetes mellitus • Coronary artery disease • Hypertension • Stroke No known health risks Science sides with Sir MixAlot

  22. obese Bad Cholesterol lean low high WHT What kind of epidemic has so many healthy people? Marilyn Monroe BMI = overweight to obese

  23. Obesity Genes

  24. Leptin

  25. Significance of Leptin • It appears that body weight is regulated • By a “lipostat” • Leptin commonly thought to be the lipostatic signal • It is still hoped by many that our knowledge of leptin will lead to a cure for obesity

  26. The Seductive Lipostatic Hypothesis Food Intake Mystery Signal Body FAT

  27. It’s OK to sleep with a hypothesis. You should never marry one.

  28. History • Early evidence (1970s) for a lipostat came from mutant mice that were obese • Ob/ob mouse • Db/db mouse • Mutation in a single gene on an autosome • Obese (more than 30% heavier than wild type) • Hyperphagic (ate significantly more than wild type • Diabetic (hyperglycemic) • Infertile (does not undergo puberty, does not mate or have estrous cycles or spermatogenesis, decreases gonadal steroids)

  29. Parabiosis An obese mouse (ob/ob) is sharing its circulation with a lean wild type mouse

  30. How would you explain these results? • ob/ob - +/+mouse: ob/ob lost weight
 • db/db- +/+ :db/db obese, +/+ stopped eating and lost weight • ob/ob -db/db: ob/ob stopped eating and lost weight, whereas the db/db unaffected • An additional experiment showed that when one of a pair of +/+ parabiotic mice was overfed, its "twin" lost weight.

  31. Conclusion?

  32. Conclusion of Parabiosis Experiment • The ob/ob has a mutation in the gene that codes for a circulating factor that stops the rat from eating. • The db/db has a mutation in the gene that codes for the receptor for this factor

  33. Conclusions of Parabiosis Experiment • Ob/ob lacks a factor that stops eating • The db/db lacks the receptor for that factor

  34. Leptin (Ob protein) Cloned by J. Friedman’s lab in 1994 (Zhang et al., 1995) Adipocyte protein secreted in proportion to body fat content in response to influx of fuels into adipocytes ( Plasma concentrations high in fat, fed animals low in lean or fasted animals Peripheral and central treatment decreases food intake (FI) and body weight (BW) in many different species Ob/ob (leptin decreases food intake and bw) Db/db (leptin treatment has no effect) Wild type mouse (leptin decrease FI and BW) Rats Hamsters Monkeys

  35. So Is leptin the cure for obesity? • Percentage of people who are obese because they have a mutation in the gene for leptin = miniscule (only a few people in the world have this mutation) • Clinical trials a failure • gave daily leptin injections to obese patients. • Only a third of the patients lost weight. • Some patients dropped out of the study finding the injections irritating • Some reported decrdased appetite at first, and increased appetite after continued use (they developed leptin resistance). • The people gained back the weight they had lost when the leptin injections ceased.

  36. Why is Leptin Not The Miracle Cure for Obestiy? In addtion to leptin, there are many hormones and neuropeptides that influence appetite and obesity Giving leptin alone does not curtail obesity Obese people have higher leptin than normal weight people

  37. Some Factors Involved in Energy BalanceOrganizational System • Metabolic Stimuli • glucose oxidation • ffa oxidation • ketone body formation, oxidation • influx of fuels into adipocytes, muscles, liver, etc. • lipolysis • Hormones • insulin • glucagon • leptin • glucocorticoids (cortisol, corticosterone) • ghrelin • growth hormone • cholecystokinin (gut peptide) • Neuropeptides • NPY • AgRP • Orexin • CART • a-MSH

  38. RED = INHIBITORYGREEN = STIMULATORY • Leptin Insulin Ghrelin • NPY/AGRP POMC (MSH) Decreases appetite Increases appetite


  40. Leptin Re-wires the NPY and POMC Circuitry • Wildtype mice tend to have more excitatory synapses in the leptin-to-POMC circuit, and more inhibitory synapses in the leptin-to-NPY circuit • Ob/ob mice tend to have more excitatory synapses in the leptin-to-NPY circuit and more inhibitory synapses in the leptin-to-POMC circuit

  41. Increase Food Intake • Orexin (lateral hypothalamus) • NPY (arcuate and PVN) • AgRP (arcuate and PVN) • MCH (lateral hypothalamus)

  42. Decrease Food Intake • POMC (MSH) (arcuate and PVN) • CART (arcuate nucleus) • CRH (PVN)

  43. Current Research • Any particular obese individual might have mutations or variations at these obesity-related loci • You cannot assume any one obese person is just lazy • Many genes, peptides and neurocircuits involved • Redundancy in the system • A drug that influences one of these peptides can be overridden by the others • As soon as you stop taking the “antiobesity” drug, you gain all the weight back • Single gene approach unlikely to solve the obesity problem.

  44. A Pause That Refreshes

  45. Dieting Doesn’t Work Dieting is a signal to the brain to become better at storing fat

  46. Energy Balance • Intake • Motivational (appetite) • Consumption • Storage • Glycogen in muscle and liver • Lipid in adipose tissue and other tissues • Amino acids in muscle and bone (used with glycerol to make new glucose) • Expenditure • Resting • Thermogenesis • Reproduction • Immune function • Other cellular processes (mitosis, miosis, digestion, metabolism, cell repair)

  47. - + Energy Balance-No Free Rides • Intake • Storage • Glycogen in muscle and liver • Lipids in adipose tissue and other tissues • Protein (Amino acids )in muscle and bone (used with glycerol to make new glucose) • Expenditure • Resting (Basal Metabolic Rate) • Thermogenesis • Reproduction, Immune function

  48. Restricting Food IntakeDecreases Energy Expenditure

  49. Rebound results from increased appetite coupled with decreased expenditure

  50. Dieting Makes you Fat eventually

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