Robert H. Lustig, M.D. Division of Endocrinology Department of Pediatrics University of California, San Francisco   The tr...
<ul><li>No disclosures </li></ul>
•  Obesity continues to worsen, both in prevalence and severity •  Obesity is increasing in all developed (and developing)...
•  Obesity continues to worsen, both in prevalence and severity •  Obesity is increasing in all developed (and developing)...
•  Obesity continues to worsen, both in prevalence and severity •  Obesity is increasing in all developed (and developing)...
•  Energy storage for a rainy day (month, year, decade) What’s the selective advantage to obesity?
•  Energy storage for a rainy day (month, year, decade) What’s the selective advantage to obesity? How is this selective a...
The  neuroendocrinology  of energy balance
If you give a 5 year old kid a cookie:  PARADOX:
PARADOX: If you give a 5 year old kid a cookie:
Leptin stimulates the SNS Mark et al. Acta Physiol Scand 177:345, 2003
But if you give a 5 year old  obese  kid a cookie:  PARADOX:
But if you give a 5 year old  obese  kid a cookie:  PARADOX:
The physiology of leptin: The Starvation Response
Dexfenfluramine
 
 
T)
Leibel et al. N Engl J Med 332:621, 1995 Weight loss lowers REE/FFM by 20%
Energy Expenditure  =  “ Quality of Life ” Decreased energy expenditure: •  hypothyroidism •  starvation Increased energy ...
Autonomic Function during the Starvation Response Aronne et al. Am J Phys 269:R222, 1995 In response to declining leptin: ...
Lustig, In: Donohoue (ed) Obesity Research and Clinical Applications, Humana, 2008
Lustig, In: Donohoue (ed) Obesity Research and Clinical Applications, Humana, 2008
 
Nonogaki et al. Diabetes 52:315, 2003 Lifestyles of the obese (mouse)
Farooqi et al. N Engl J Med 341:913, 1999 Leptin promotes weight loss in a leptin-deficient patient
Leptin Therapy of Leptin Deficiency Age 3.5 years Age 3.5 years Farooqi  et al, JCI Oct. 2002 Age 8 years Age 8 years
Obese subjects are leptin resistant
Heymsfield et al. JAMA 282:1568, 1999 Leptin resistance prevents leptin-induced weight loss in obese adults
Rosenbaum et al. JCEM 87:2391, 2002
Leptin and Leptin Resistance •  Leptin levels are a function of adipocyte energy stores •  Leptin tells your brain how thi...
What causes leptin resistance? •  Genetic •  Anatomic •  Functional
The  neuroendocrinology  of energy balance
Effects of Insulin on the Adipocyte <ul><li>Stimulates Glut4 mRNA and protein </li></ul><ul><li>Stimulates Acetyl-CoA Carb...
Schwartz et al.  Science  307:375, 2005 Leptin and insulin act on the same VMH neurons
Knockout studies of leptin resistance:  leptin pathway Y Y Y Y Insulin Y Y Y  Y Y Y PTEN Ptp1b Ptp1b Leptin JAK2 S T A T 3...
Y Y Y Y Insulin Y Y Y  Y Y Y PTEN Ptp1b Ptp1b Leptin JAK2 S T A T 3 Insulin-induced Gene Transcription Leptin-induced Gene...
Y Y Y Y Insulin Y Y Y  Y Y Y PTEN Ptp1b Leptin JAK2 S T A T 3 Insulin-induced Gene Transcription Leptin-induced Gene Trans...
Hill et al. J Clin Invest 118:1796, 2008 Leptin depolarizes, while insulin hyperpolarizes  POMC neurons through a PI3K-med...
Kellerer et al. Diabetologia, 44:1125, 2001 Can hyperinsulinemia block leptin signaling?
The  neuroendocrinology  of energy balance
Anatomic leptin resistance: Hypothalamic Obesity
Models/Hypotheses of Hypothalamic Obesity Damaged Ventromedial Nucleus Hyperphagia Obesity Insulin Secretion IGF-I Recepto...
Lustig, Rev Endo Metab Dis 4:23, 2003
Hypothalamic Obesity Pilot Study— Purpose 1. To assess the insulin secretory dynamics of patients with hypothalamic obesit...
Hypothalamic Obesity Pilot Study—  Weight and BMI Change Lustig et al. J Pediatr 138:162, 1999
Hypothalamic Obesity Pilot Study— Effects on Glucose and Insulin Responses Lustig et al. J Pediatr 138:162, 1999
Hypothalamic Obesity Pilot Study—  Weight Loss Versus: Lustig et al. J Pediatr 138:162, 1999
Lustig et al. JCEM 88:2586, 2003 Octreotide treatment of hypothalamic obesity Demographics •  Double-blinded, 6 month plac...
Octreotide treatment of hypothalamic obesity  1st Window (6 Months) BMI Weight -5 0 5 10 15 20 -1 0 1 2 3 4 5 P = 0.0008 P...
Octreotide treatment of hypothalamic obesity Insulin dynamics during OGTT (1st Window) Placebo n = 9 0 months 6 months Dru...
Pediatric Cancer Quality of Life PCQL-32, Version 1 32-item proctored questionnaire  Patient and parent reports on : Cogni...
Octreotide Treatment of Hypothalamic Obesity PCQL-32 (6 months – 0 months) Lustig et al. JCEM  88:2586, 2003
PCQL-32 Parent Report Correlation between   Quality of Life and    Insulin Response (6 Months – 0 Months)  Quality of L...
 
 
Octreotide x 1 yr
 
 
Functional studies of leptin resistance: Octreotide for adult obesity   Hypotheses: <ul><li>Insulin hypersecretion occurs ...
Octreotide-LAR 40 mg IM q 28d  Effects on Weight and BMI Stratified By Response Patients who completed 24 weeks (n=44) P <...
Octreotide-LAR 40 mg IM q28d  Effects on Specific Nutrient Daily Intake (  0.001) Velasquez-Mieyer et al. Int J Obesity 27...
Octreotide-LAR 40 mg IM q 28d  Insulin Dynamics During OGTT Velasquez-Mieyer et al. Int J Obesity 27:216, 2003 de
Lustig et al. Int J Obesity 28:1342, 2004 Octreotide-LAR 40 mg IM q 28d  Changes in Plasma Leptin  epti
Octreotide-LAR 40 mg IM q28d  Changes in Resting Energy Expenditure (REE) Lustig et al. Int J Obesity 28:1342, 2004 d
 
Octreotide-LAR x 6 months
Improvement of functional leptin sensitivity <ul><li>Forced weight loss (Rosenbaum) </li></ul><ul><li>Drug-induced reducti...
<ul><li>Forced weight loss (Rosenbaum) </li></ul><ul><li>Drug-induced reduction in insulin (Lustig) </li></ul>What ’s the ...
Lustig et al. Int J Obesity 28:1342, 2004 Octreotide-LAR 40 mg IM q28d Changes in the REE:Leptin Ratio
Insulin is an endogenous leptin antagonist (?)
Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely,  by allowing hyperins...
Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely,  by allowing hyperins...
Where did the hyperinsulinemia come from? •  Genetics i.e. VNTR of insulin gene •  Epigenetics i.e. SGA, LGA promote insul...
Fructose is not glucose •  Hepatic fructose metabolism is different than glucose •  Hypothesis: chronic fructose exposure ...
Hepatocyte 24 kcal 96 kcal
 
 
 
 
 
 
 
 
60 kcal (+ 12 kcal glucose) 48 kcal
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fructose induces insulin resistance,  which induces leptin resistance
Does this make Darwinian sense? Seasonal insulin resistance: •  Fructose was available at harvest, 1-2 months per year •  ...
Does this make Darwinian sense? Seasonal insulin resistance: •  Fructose was available at harvest, 1-2 months per year •  ...
•  Obesity means leptin resistance, or  “brain starvation” •  The starvation response causes recidivism •  Energy expendit...
Nat Rev Gastroenterol Hepatol 7:251, 2010  J Am Diet Assoc 110:1305, 2010 Further reading Arterioscler Throm Vasc Biol 25:...
 
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  • pretty nice. Keep going on.
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  • Looks like the video ’hiccup’ starts on slide 18 (I think) and skips to slide 103 (I think).
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  • Hey guys, profound thanks for posting this.

    I gotta believe the slides are a bit out of order with respect to the video . . . pretty sure it's the video which is messed up.

    As of today (August 13), there is a 'hiccup' in the video (on Vimeo) at about 9:00 . . . a black screen for a second, then a re-start at a point significantly further on in the talk. Before the video hiccup at 9:00, Dr. Lustig is on slide 18 (I think). Afterwards (at 9:01), it seems like he's jumped to somewhere around slide 88 or 89. He goes on from there through the apparent end of his talk (i.e., a Darwinian overview, a summary, further reading, thanking collaborators), all of which correspond to slides 100 - 109.

    In the video, Dr. Lustig then goes on to take a couple of questions, tells a great story about Gatorade, but at 18:36, we're suddenly back in the main presentation again, (I think picking up right at the 9:00 mark, where the previous hiccup was). It's clear that at that point, (18:36 and following), we're back to the discussion starting on slide 19. His presentation from there goes on through slide 95 (I think), until another hiccup at 47:25.

    At that moment, we go back to the question being asked at 18:36, which Dr. Lusting answers in the last 2 minutes of the video.

    Net net, I believe the video is out of sequence (but the slides are in order).

    The video can be rendered 'in sequence' (I think) by viewing it as follows:

    00:00 - 09:00 (talk starts, slides up to 18)
    18:37 - 47:25 (talk continues, slides 19 - 95 (I think))
    09:01 - 18:36 (end of talk and first two questions, slides 95 - 109)
    47:25 - end (49:19) (completion of questions, no slides)

    Apologize if I got this wrong, and again, many thanks for getting the video out there.
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    Your message goes here
  • http://vimeo.com/27563465
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AHS Slides_Robert Lustig

  1. 1. Robert H. Lustig, M.D. Division of Endocrinology Department of Pediatrics University of California, San Francisco The trouble with fructose: A Darwinian perspective Ancestry Health Symposium Aug 6, 2011
  2. 2. <ul><li>No disclosures </li></ul>
  3. 3. • Obesity continues to worsen, both in prevalence and severity • Obesity is increasing in all developed (and developing) countries • Obesity is increasing in all age groups, and especially in children • Recidivism is high Introduction
  4. 4. • Obesity continues to worsen, both in prevalence and severity • Obesity is increasing in all developed (and developing) countries • Obesity is increasing in all age groups, and especially in children • Recidivism is high The obvious explanation: Gluttony and sloth Introduction
  5. 5. • Obesity continues to worsen, both in prevalence and severity • Obesity is increasing in all developed (and developing) countries • Obesity is increasing in all age groups, and especially in children • Recidivism is high The obvious explanation: Gluttony and sloth The evolutionary explanation: A mismatch between our environment and our biochemistry Introduction
  6. 6. • Energy storage for a rainy day (month, year, decade) What’s the selective advantage to obesity?
  7. 7. • Energy storage for a rainy day (month, year, decade) What’s the selective advantage to obesity? How is this selective advantage achieved? • Leptin resistance •  Insulin resistance
  8. 8. The neuroendocrinology of energy balance
  9. 9. If you give a 5 year old kid a cookie: PARADOX:
  10. 10. PARADOX: If you give a 5 year old kid a cookie:
  11. 11. Leptin stimulates the SNS Mark et al. Acta Physiol Scand 177:345, 2003
  12. 12. But if you give a 5 year old obese kid a cookie: PARADOX:
  13. 13. But if you give a 5 year old obese kid a cookie: PARADOX:
  14. 14. The physiology of leptin: The Starvation Response
  15. 15. Dexfenfluramine
  16. 18. T)
  17. 19. Leibel et al. N Engl J Med 332:621, 1995 Weight loss lowers REE/FFM by 20%
  18. 20. Energy Expenditure = “ Quality of Life ” Decreased energy expenditure: • hypothyroidism • starvation Increased energy expenditure: • exercise • caffeine • ephedrine (banned)
  19. 21. Autonomic Function during the Starvation Response Aronne et al. Am J Phys 269:R222, 1995 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
  20. 22. Lustig, In: Donohoue (ed) Obesity Research and Clinical Applications, Humana, 2008
  21. 23. Lustig, In: Donohoue (ed) Obesity Research and Clinical Applications, Humana, 2008
  22. 25. Nonogaki et al. Diabetes 52:315, 2003 Lifestyles of the obese (mouse)
  23. 26. Farooqi et al. N Engl J Med 341:913, 1999 Leptin promotes weight loss in a leptin-deficient patient
  24. 27. Leptin Therapy of Leptin Deficiency Age 3.5 years Age 3.5 years Farooqi et al, JCI Oct. 2002 Age 8 years Age 8 years
  25. 28. Obese subjects are leptin resistant
  26. 29. Heymsfield et al. JAMA 282:1568, 1999 Leptin resistance prevents leptin-induced weight loss in obese adults
  27. 30. Rosenbaum et al. JCEM 87:2391, 2002
  28. 31. Leptin and Leptin Resistance •  Leptin levels are a function of adipocyte energy stores •  Leptin tells your brain how thin you are, not how fat you are •  The brain perceives leptin deficiency as a state of starvation • Leptin deficiency causes energy expenditure to decrease, and thyroid levels to decline, while leptin repletion corrects them • Caloric restriction leads leptin decline before weight loss, and promotes drive to resume caloric intake •  Obese subjects are hyperleptinemic and &quot;leptin resistant&quot; • If we could fix leptin resistance, there wouldn't be obesity
  29. 32. What causes leptin resistance? • Genetic • Anatomic • Functional
  30. 33. The neuroendocrinology of energy balance
  31. 34. Effects of Insulin on the Adipocyte <ul><li>Stimulates Glut4 mRNA and protein </li></ul><ul><li>Stimulates Acetyl-CoA Carboxylase </li></ul><ul><li>Stimulates Fatty Acid Synthase </li></ul><ul><li>Stimulates Lipoprotein Lipase </li></ul><ul><li>Hypothalamic actions inhibits lipolysis by suppressing SNS tone and Hormone-Sensitive Lipase </li></ul>Scherer et al. Cell Metab doi10.1016/j.cmet.2011.01.008
  32. 35. Schwartz et al. Science 307:375, 2005 Leptin and insulin act on the same VMH neurons
  33. 36. Knockout studies of leptin resistance: leptin pathway Y Y Y Y Insulin Y Y Y Y Y Y PTEN Ptp1b Ptp1b Leptin JAK2 S T A T 3 Insulin-induced Gene Transcription Leptin-induced Gene Transcription Y Y 985 1138 Y Y SOCS3 IRS2 PtdIns-3,4,5-P 3 K+ channel X SH2-B Lustig, Nature Clin Pract Endo Metab 2:447, 2006 Leptin resistance P P P P PtdIns-4,5-P 2 PtdIns-3,4,5-P 3 PtdIns-4-P PtdIns-3,4-P 2 PI 3-kinase PI 3-kinase P P P P P P Y P P P P
  34. 37. Y Y Y Y Insulin Y Y Y Y Y Y PTEN Ptp1b Ptp1b Leptin JAK2 S T A T 3 Insulin-induced Gene Transcription Leptin-induced Gene Transcription Y Y 985 1138 Y Y SOCS3 IRS2 PtdIns-3,4,5-P 3 K+ channel X SH2-B Lustig, Nature Clin Pract Endo Metab 2:447, 2006 Knockout studies of leptin resistance: insulin pathway Leptin resistance P P P P P P P PtdIns-4,5-P 2 PtdIns-3,4,5-P 3 PtdIns-4-P PtdIns-3,4-P 2 PI 3-kinase PI 3-kinase P P P P P P Y P P P P
  35. 38. Y Y Y Y Insulin Y Y Y Y Y Y PTEN Ptp1b Leptin JAK2 S T A T 3 Insulin-induced Gene Transcription Leptin-induced Gene Transcription Y Y 985 1138 Y Y SOCS3 IRS2 PtdIns-3,4,5-P 3 K+ channel X P SH2-B Lustig, Nature Clin Pract Endo Metab 2:447, 2006 Knockout studies of leptin resistance: insulin pathway Ptp1b Leptin resistance Leptin sensitivity P P P P PtdIns-4,5-P 2 PtdIns-3,4,5-P 3 PtdIns-4-P PtdIns-3,4-P 2 PI 3-kinase PI 3-kinase P P P P P P Y P P P P
  36. 39. Hill et al. J Clin Invest 118:1796, 2008 Leptin depolarizes, while insulin hyperpolarizes POMC neurons through a PI3K-mediated mechanism
  37. 40. Kellerer et al. Diabetologia, 44:1125, 2001 Can hyperinsulinemia block leptin signaling?
  38. 41. The neuroendocrinology of energy balance
  39. 42. Anatomic leptin resistance: Hypothalamic Obesity
  40. 43. Models/Hypotheses of Hypothalamic Obesity Damaged Ventromedial Nucleus Hyperphagia Obesity Insulin Secretion IGF-I Receptor Growth Adapted from Sklar. Pediatr Neurosurg. 1994;21:120-123. Damaged Ventromedial Nucleus Vagal Firing Rate Insulin Secretion Glucose Utilization Hyperphagia Obesity Adapted from Bray and Gallagher. Medicine . 1975;54:301-330.
  41. 44. Lustig, Rev Endo Metab Dis 4:23, 2003
  42. 45. Hypothalamic Obesity Pilot Study— Purpose 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 insulin release in patients with hypothalamic obesity 3. To assess the efficacy of octreotide in promoting weight loss in patients with hypothalamic obesity
  43. 46. Hypothalamic Obesity Pilot Study— Weight and BMI Change Lustig et al. J Pediatr 138:162, 1999
  44. 47. Hypothalamic Obesity Pilot Study— Effects on Glucose and Insulin Responses Lustig et al. J Pediatr 138:162, 1999
  45. 48. Hypothalamic Obesity Pilot Study— Weight Loss Versus: Lustig et al. J Pediatr 138:162, 1999
  46. 49. Lustig et al. JCEM 88:2586, 2003 Octreotide treatment of hypothalamic obesity Demographics • 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/P 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
  47. 50. Octreotide treatment of hypothalamic obesity 1st Window (6 Months) BMI Weight -5 0 5 10 15 20 -1 0 1 2 3 4 5 P = 0.0008 P = 0.0005 Octreotide (n = 9) Placebo (n = 9) Octreotide (n = 9) Placebo (n= 9)  weight (kg)  BMI Lustig et al. JCEM 88:2586, 2003
  48. 51. Octreotide treatment of hypothalamic obesity Insulin dynamics during OGTT (1st Window) Placebo n = 9 0 months 6 months Drug n = 9 0 40 80 120 160 200 240 0 15 30 60 90 120 150 180 Insulin (µU/ml) Minutes 0 40 80 120 160 200 240 0 15 30 60 90 120 150 180 Minutes 280 280 Lustig et al. JCEM 88:2586, 2003
  49. 52. Pediatric Cancer Quality of Life PCQL-32, Version 1 32-item proctored questionnaire Patient and parent reports on : Cognitive functioning Physical functioning Psychological functioning Social functioning Validated for ages 8-18 yr
  50. 53. Octreotide Treatment of Hypothalamic Obesity PCQL-32 (6 months – 0 months) Lustig et al. JCEM 88:2586, 2003
  51. 54. PCQL-32 Parent Report Correlation between  Quality of Life and  Insulin Response (6 Months – 0 Months)  Quality of Life -30 -15 0 15 30 l a e b O t r e o t i e -300 -200 -100 0 100 200 P = 0.041 P = 0.77  Insulin Response Lustig et al. JCEM 88:2586, 2003 Placebo Octreotide
  52. 57. Octreotide x 1 yr
  53. 60. Functional studies of leptin resistance: Octreotide for adult obesity Hypotheses: <ul><li>Insulin hypersecretion occurs in a subset of obese adults </li></ul><ul><li>Insulin suppression using octreotide will </li></ul><ul><ul><li>Slow or reverse adipogenesis </li></ul></ul><ul><ul><li>Promote weight loss </li></ul></ul>
  54. 61. Octreotide-LAR 40 mg IM q 28d Effects on Weight and BMI Stratified By Response Patients who completed 24 weeks (n=44) P < 0.0001 ANOVA with repeated measures Velasquez-Mieyer et al. Int J Obesity 27:216, 2003
  55. 62. Octreotide-LAR 40 mg IM q28d Effects on Specific Nutrient Daily Intake ( 0.001) Velasquez-Mieyer et al. Int J Obesity 27:216, 2003
  56. 63. Octreotide-LAR 40 mg IM q 28d Insulin Dynamics During OGTT Velasquez-Mieyer et al. Int J Obesity 27:216, 2003 de
  57. 64. Lustig et al. Int J Obesity 28:1342, 2004 Octreotide-LAR 40 mg IM q 28d Changes in Plasma Leptin  epti
  58. 65. Octreotide-LAR 40 mg IM q28d Changes in Resting Energy Expenditure (REE) Lustig et al. Int J Obesity 28:1342, 2004 d
  59. 67. Octreotide-LAR x 6 months
  60. 68. Improvement of functional leptin sensitivity <ul><li>Forced weight loss (Rosenbaum) </li></ul><ul><li>Drug-induced reduction in insulin (Lustig) </li></ul>
  61. 69. <ul><li>Forced weight loss (Rosenbaum) </li></ul><ul><li>Drug-induced reduction in insulin (Lustig) </li></ul>What ’s the similarity? The drop in insulin Improvement of functional leptin sensitivity
  62. 70. Lustig et al. Int J Obesity 28:1342, 2004 Octreotide-LAR 40 mg IM q28d Changes in the REE:Leptin Ratio
  63. 71. Insulin is an endogenous leptin antagonist (?)
  64. 72. Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely, by allowing hyperinsulinemia to induce leptin resistance: 1. Puberty 2. Pregnancy Insulin is an endogenous leptin antagonist (?)
  65. 73. Does this make Darwinian sense? Insulin gives the human the ability to modulate weight gain acutely, by allowing hyperinsulinemia to induce leptin resistance: 1. Puberty 2. Pregnancy Insulin is an endogenous leptin antagonist (?) Doesn’t it make sense that the same hormone that promotes the energy storage also inhibits leptin, so that energy can be stored?
  66. 74. Where did the hyperinsulinemia come from? • Genetics i.e. VNTR of insulin gene • Epigenetics i.e. SGA, LGA promote insulin resistance • Social Environment (cortisol) i.e. economic (food insecurity), acculturation, violence, other societal stressors • Exercise Environment i.e. cars; lack of sidewalks, play areas, school activity • Food Environment i.e. fructose (too much), fiber (not enough) Causes insulin resistance, hyperinsulinemia
  67. 75. Fructose is not glucose • Hepatic fructose metabolism is different than glucose • Hypothesis: chronic fructose exposure promotes NAFLD and Metabolic Syndrome Elliot et al. Am J Clin Nutr, 2002 Bray et al. Am J Clin Nutr, 2004 Teff et al. J Clin Endocrinol Metab, 2004 Gaby, Alt Med Rev, 2005 Le and Tappy, Curr Opin Clin Nutr Metab Care, 2006 Wei et al. J Nutr Biochem, 2006 Johnson et al. Am J Clin Nutr 2007 Rutledge and Adeli, Nutr Rev, 2007 Collison et al. Obesity epub 3/12/09
  68. 76. Hepatocyte 24 kcal 96 kcal
  69. 85. 60 kcal (+ 12 kcal glucose) 48 kcal
  70. 104. Fructose induces insulin resistance, which induces leptin resistance
  71. 105. Does this make Darwinian sense? Seasonal insulin resistance: • Fructose was available at harvest, 1-2 months per year •  Followed by 4-5 months of winter, with no food available •  If leptin worked all the time, you couldn’t store energy • Selective advantage by inducing seasonal insulin resistance by gorging on fruit, while it was available Fructose induces insulin resistance, which induces leptin resistance
  72. 106. Does this make Darwinian sense? Seasonal insulin resistance: • Fructose was available at harvest, 1-2 months per year •  Followed by 4-5 months of winter, with no food available •  If leptin worked all the time, you couldn’t store energy • Selective advantage by inducing seasonal insulin resistance by gorging on fruit, while it was available But fructose is now available globally 24/7/365, and consumed in unlimited amounts And unopposed by fiber (read: orange juice) Fructose induces insulin resistance, which induces leptin resistance
  73. 107. • Obesity means leptin resistance, or “brain starvation” • The starvation response causes recidivism • Energy expenditure and quality of life are the same thing • Defects in insulin signaling promote leptin resistance • Insulin appears to be an “endogenous leptin antagonist” • Fructose, by driving de novo lipogenesis, induces hepatic insulin resistance, driving both weight gain and continued consumption • Our environment is insulinogenic; we have to “get the insulin down” Summary: leptin and insulin resistance The Darwinian explanation for the obesity epidemic
  74. 108. Nat Rev Gastroenterol Hepatol 7:251, 2010 J Am Diet Assoc 110:1305, 2010 Further reading Arterioscler Throm Vasc Biol 25:2451, 2005 Is fast food addictive? Andrea K. Garber, Robert H. Lustig Curr Drug Abuse Rev (in press, 2011)

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