Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Sugar, Hormones, and Addiction

233 views

Published on

Dr. Robert Lustig explores the science of food addiction.

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Sugar, Hormones, and Addiction

  1. 1. Sugar, hormones, and addictionSugar, hormones, and addiction Robert H. Lustig, M.D., M.S.L.Robert H. Lustig, M.D., M.S.L. Division of EndocrinologyDivision of Endocrinology Department of PediatricsDepartment of Pediatrics Institute for Health Policy StudiesInstitute for Health Policy Studies University of California, San FranciscoUniversity of California, San Francisco
  2. 2. DisclosuresDisclosures
  3. 3. Is food addictive?Is food addictive? The lay public seems to know….The lay public seems to know….
  4. 4. Similarities between obesity and addictionSimilarities between obesity and addiction Volkow et al. Philos Trans R Soc Lond B Biol Sci. 2008 363:3191, 2008
  5. 5. Similarities between obesity and addictionSimilarities between obesity and addiction Volkow et al. Philos Trans R Soc Lond B Biol Sci. 2008 363:3191, 2008
  6. 6. 05/23/18 RiverMend Health, LLC 7 Drive OFC Saliency NAc Memory Amygdala Control CG Non-Addicted Brain STOP GODrive Memory Saliency Control CG Drive OFC Memory Amygdala Saliency NAc Adapted from: Volkow et al., J Clin Invest 2003. Neuroendocrine circuits in addictionNeuroendocrine circuits in addiction
  7. 7. Yale Food Addiction ScaleYale Food Addiction Scale • In 2009, the Yale Food Addiction ScaleIn 2009, the Yale Food Addiction Scale (YFAS) was created to study food addiction(YFAS) was created to study food addiction by applying the DSM-IV criteria for substanceby applying the DSM-IV criteria for substance dependence to eating behaviorsdependence to eating behaviors Gearhardt et al. Arch Psychiatr 2009
  8. 8. YFAS correlates with neuroimagingYFAS correlates with neuroimaging  YFAS related to greater responsivity of reward regionsYFAS related to greater responsivity of reward regions (caudate, ACC, medial OFC, amygdala)(caudate, ACC, medial OFC, amygdala) and lower responsivity of an inhibitory control regionand lower responsivity of an inhibitory control region (lateral OFC)(lateral OFC)
  9. 9. Palatable food cues trigger these areas as wellPalatable food cues trigger these areas as well  Greater reward region responseGreater reward region response to palatable food cues predictsto palatable food cues predicts future weight gainfuture weight gain  Similar effects for substanceSimilar effects for substance use onsetuse onset Chouinard et al. 2010; Demos et al. 2012; Stice et al. 2010; Yokum et al. 2011; Stice et al. 2013
  10. 10. Overlap between Binge Eating Disorder andOverlap between Binge Eating Disorder and AddictionAddiction  79 women with BED79 women with BED 92.4% met the DSM-IV criteria for substance dependence92.4% met the DSM-IV criteria for substance dependence whenwhen questions substituted “substance” with “bingequestions substituted “substance” with “binge eating”eating” (Cassin and von Ranson, Appetite 48:687, 2007)(Cassin and von Ranson, Appetite 48:687, 2007)  Bariatric surgery candidates with BED had addictiveBariatric surgery candidates with BED had addictive personality scores similar to what has been reported forpersonality scores similar to what has been reported for individuals with substance dependence disorderindividuals with substance dependence disorder (Lent and Swencionis, Eat Behav 13:67, 2012)(Lent and Swencionis, Eat Behav 13:67, 2012)
  11. 11. Nature Rev Neurosci 13:279, 2012 Honest Debate Among Scientists
  12. 12. Nature Rev Neurosci 13:514, 2012
  13. 13. Nature Rev Neurosci 13:514, 2012
  14. 14. Puts the onus on the individual, not the food
  15. 15. 2012
  16. 16. IndirectIndirect effects on the reward system:effects on the reward system: Leptin and InsulinLeptin and Insulin
  17. 17. The neuroendocrinologyneuroendocrinology of energy balance Lustig, Endo Clin NA, 2001
  18. 18. The integration of the starvation and addiction pathwaysThe integration of the starvation and addiction pathways Cota et al. Neuron 51:678, 2006 LepR
  19. 19. PARADOX:PARADOX: If you give a 5 year old kid a cookie:
  20. 20. PARADOX:PARADOX: If you give a 5 year old kid a cookie:
  21. 21. Leptin is supposed to keep us in energy balanceLeptin is supposed to keep us in energy balance Mark et al. Acta Physiol Scand 177:345, 2003
  22. 22. But if you give a 5 year old obese kid a cookie: PARADOX:PARADOX:
  23. 23. But if you give a 5 year old obese kid a cookie: PARADOX:PARADOX:
  24. 24. Fulton et al. Neuron 51:811, 2006 Leptin upregulates pSTAT-3 in the VTA and in the hypothalamus
  25. 25. RNA-i mediated knockdown of leptin receptor in the VTA increases palatability of sucrose and fat Hommel et al. Neuron 51:801, 2006
  26. 26. Farooqi et al., Science 317:1355, 2007 Leptin regulates brain responses to food images
  27. 27. Insulin and leptin receptors in dopaminergicInsulin and leptin receptors in dopaminergic neurons of the Ventral Tegmental Area (VTA)neurons of the Ventral Tegmental Area (VTA) Figlewicz et al. Brain Res 964:107, 2003 Tyrosine hydroxylase (enzyme that makes dopamine) Insulin receptor Co-localization Leptin receptor
  28. 28. Carvelli et al. J Neurochemistry 81:859, 2002 Insulin stimulates [Insulin stimulates [33 H]dopamine uptakeH]dopamine uptake in FLAG-hDAT cellsin FLAG-hDAT cells
  29. 29. Figlewicz et al. Am J Physiol 284:R882, 2003 Insulin infusion into the Ventral Tegmental Area (VTA)Insulin infusion into the Ventral Tegmental Area (VTA) blocks acute opiate effects on food intakeblocks acute opiate effects on food intake
  30. 30. What does CNS insulin resistance do to reward?What does CNS insulin resistance do to reward?
  31. 31. The NIRKO (Brain Insulin Receptor Knockout) MouseThe NIRKO (Brain Insulin Receptor Knockout) Mouse Brüning et al. Science 289:2122, 2000
  32. 32. Han et al. J Pediatr 152:612, 2008 Hyperinsulinemia correlates with energy intake in obese childrenHyperinsulinemia correlates with energy intake in obese children
  33. 33. Knockout studies of leptin resistance: leptin pathwayKnockout studies of leptin resistance: leptin pathway Y Y Y Y P P P P Insulin PtdIns-4,5-P2PtdIns-3,4,5-P3 PtdIns-4-PPtdIns-3,4-P2 PI 3-kinase PI 3-kinase P P P P P P Y 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 P P P P IRS2PtdIns-3,4,5-P3K+ channel X SH2-B Lustig, Nature Clin Pract Endo Metab 2:447, 2006
  34. 34. Y Y Y Y P P P P Insulin PtdIns-4,5-P2PtdIns-3,4,5-P3 PtdIns-4-PPtdIns-3,4-P2 PI 3-kinase PI 3-kinase P P P P P P Y 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 P P P P IRS2PtdIns-3,4,5-P3K+ channel X P SH2-B Lustig, Nature Clin Pract Endo Metab 2:447, 2006 Knockout studies of leptin resistance: insulin pathwayKnockout studies of leptin resistance: insulin pathway
  35. 35. Hill et al. J Clin Invest 118:1796, 2008 Leptin depolarizes, while insulin hyperpolarizesLeptin depolarizes, while insulin hyperpolarizes POMC neurons through a PI3K-mediated mechanismPOMC neurons through a PI3K-mediated mechanism
  36. 36. Kellerer et al. Diabetologia, 44:1125, 2001 Hyperinsulinemia blocks leptin signalingHyperinsulinemia blocks leptin signaling
  37. 37. Chronic hyperinsulinemia promotes obesity by: • driving energy into adipose tissue • interfering with leptin signaling in the VMH (starvation) • interfering with leptin extinguishing of dopamine clearance in the NA (addiction)
  38. 38. TheThe “limbic triangle”“limbic triangle” Mietus-Snyder and Lustig, Ann Rev Med 59:147, 2008
  39. 39. Direct effects on the reward system:Direct effects on the reward system: •• Controlled by the Ventral Tegmental AreaControlled by the Ventral Tegmental Area and Nucleus Accumbensand Nucleus Accumbens •• dopaminedopamine •• endogenous opioids (mu and delta receptors)endogenous opioids (mu and delta receptors) •• acetylcholineacetylcholine •• stressstress allall equally important, but will not be discussedequally important, but will not be discussed
  40. 40. (Luscher, 2004)(Luscher, 2004)
  41. 41. The Ventral Tegmental Area and the Nucleus Accumbens:The Ventral Tegmental Area and the Nucleus Accumbens: Sites of opiate and nicotine effects on rewardSites of opiate and nicotine effects on reward Mansvelder et al. Eur J Pharmacol 480:117, 2003
  42. 42. Kelly et al. Physiol Behav 76:365, 2002 The Ventral Tegmental Area and the Nucleus Accumbens:The Ventral Tegmental Area and the Nucleus Accumbens: Sites of opiate and nicotine effects on rewardSites of opiate and nicotine effects on reward
  43. 43. Volkow et al. Philos Trans R Soc Lond B Biol Sci. 2008 363:3191, 2008 DD22 receptor binding correlates with glucose metabolismreceptor binding correlates with glucose metabolism both in drug addiction and obesityboth in drug addiction and obesity CTL Cocaine D2 receptors CTL Obesity Cocaine Metamphet- amine Cingulate OFC
  44. 44. Volkow et al. Philos Trans R Soc Lond B Biol Sci. 2008 363:3191, 2008 DD22 receptor binding availability indicates cravingreceptor binding availability indicates craving both inboth in ddrug addiction and obesityrug addiction and obesity Cocaine-addicted D2 receptors Control subjects DA receptor availability DA receptor availability craving craving
  45. 45. Decreased DDecreased D22 Receptors in ObeseReceptors in Obese Human, Monkey and RodentHuman, Monkey and Rodent PET [11 C]raclopride High Low Bonnet macaquesHuman Autoradiography [3 H]spiperone BMI = 42BMI = 50 Weight = 650 g BMI = 23BMI = 23 Weight = 400 g Zucker rat2 Wang et al. J Nucl Med. 49(Suppl 1):208P, 2008; Thanos et al. Synapse. 62:50, 2008
  46. 46. Evidence of down-regulation of DEvidence of down-regulation of D22 receptorsreceptors • Women who gainedWomen who gained weight showed aweight showed a reduction in striatalreduction in striatal response to “sweet” vs.response to “sweet” vs. women who werewomen who were weight stable or weightweight stable or weight loserslosers Stice et al., J Neurosci. 2010 30:13105,.2010
  47. 47. Blood oxygen level-depdendent fMRI: hypofunctioning dopaminergic activity in caudate, esp. with the Taq 1A allele (assoc. with low D2 receptors) Stice et al. Science 322:449, 2008
  48. 48. Genetics of DGenetics of D22 receptors and weight gainreceptors and weight gain Stice et al. Science 322:449, 2008 Weight gain over one year correlated negatively with DA activity in those with the TaqA1 allele, and positively in those without the A1 allele
  49. 49. DirectDirect effects on the reward system:effects on the reward system: Is fast food addictive?Is fast food addictive? Garber and Lustig, Curr Drug Abuse Rev 4:190, 2011
  50. 50. • Current evidence does not allow us to conclude that a single food substance via a single specific neurobiological mechanism (e.g. specific brain receptors or specific neuronal pathways) can account for the fact that people overeat and develop obesity. •In humans, there is no evidence that a specific food, food ingredient or food additive causes a substance-based type of addiction (the only currently known exception is caffeine which via specific mechanisms can potentially be addictive).
  51. 51. • Within this context we specifically point out that we do not consider alcoholic beverages as food, despite the fact that one gram of ethanol has an energy density of 7 kcal. • Addictive (over)eating is clearly distinct from substance use disorders that cause addiction via specific mechanisms (e.g. nicotine, cocaine, cannabinoids, opioids, etc). So, NeuroFAST exempts both alcohol and caffeine, even though both are in food
  52. 52. Caffeine
  53. 53. SaltSalt • In rodents, dopamine signaling (reward) inIn rodents, dopamine signaling (reward) in response to salt, bingeing, cross-sensitizationresponse to salt, bingeing, cross-sensitization with amphetamineswith amphetamines • In humans,In humans, – Lower threshold physiologically fixedLower threshold physiologically fixed – Higher levels attributed to “preference”, can retrainHigher levels attributed to “preference”, can retrain – Salt-losing congenital adrenal hyperplasiaSalt-losing congenital adrenal hyperplasia
  54. 54. Caffeine
  55. 55. Caffeine
  56. 56. FatFat • Rodents binge but no signs of dependenceRodents binge but no signs of dependence • In humans, binge foods are high fat but alsoIn humans, binge foods are high fat but also high carb/sugar (e.g. pizza, ice cream)high carb/sugar (e.g. pizza, ice cream) – Likely synergy, adding sugar increasesLikely synergy, adding sugar increases preference for fatty foodspreference for fatty foods [Drewnowski et al.][Drewnowski et al.] • Atkins diet does not show dependenceAtkins diet does not show dependence • Energy density: stronger association withEnergy density: stronger association with obesity, metabolic syndromeobesity, metabolic syndrome
  57. 57. Caffeine
  58. 58. Caffeine
  59. 59. CaffeineCaffeine • ““Model drug” of dependenceModel drug” of dependence • In humans, dependence shown in children,In humans, dependence shown in children, adolescents and adultsadolescents and adults – 30% who consume it meet DSM criteria for30% who consume it meet DSM criteria for dependencedependence – Physiologic addiction established: headachePhysiologic addiction established: headache (increased cerebral blood flow). Impaired task(increased cerebral blood flow). Impaired task performance, fatigueperformance, fatigue
  60. 60. Caffeine
  61. 61. Caffeine
  62. 62. Direct effects on the reward system:Direct effects on the reward system: Is sugar (fructose) addictive?Is sugar (fructose) addictive? Garber and Lustig, Curr Drug Abuse Rev 4:190, 2011
  63. 63. Hebebrand et al. 2014 Neurofast (a review, not a study)
  64. 64. Sugar and opioidsSugar and opioids Sweet-Ease increases endogenous opioids to reduce pain, Even in neonates
  65. 65. Is there really such a thing as sugarIs there really such a thing as sugar addiction?addiction? Need to look for similarities to drugs of dependenceNeed to look for similarities to drugs of dependence •• nicotinenicotine •• morphinemorphine •• amphetamineamphetamine •• cocainecocaine •• cannabiscannabis •• ethanolethanol
  66. 66. What makes a milkshake so rewarding?What makes a milkshake so rewarding? • Normal weight young adult subjects, fMRINormal weight young adult subjects, fMRI • Milkshakes with graded doses of fat vs. sugarMilkshakes with graded doses of fat vs. sugar • The fat stimulated the somatosensory cortex (e.g. mouthfeel)The fat stimulated the somatosensory cortex (e.g. mouthfeel) • Only sugar stimulated the nucleus accumbensOnly sugar stimulated the nucleus accumbens • Adding more fat was not additive to the effect of sugar on rewardAdding more fat was not additive to the effect of sugar on reward Stice et al. Am J Clin Nutr 98:1377, 2013
  67. 67. PLoS One 10(6):e0130280, 2014 No satiety or fullness with fructose compared with glucose No insulin rise with fructose compared with glucose fMRI: Glucose: caudate, putamen, precuneus, lingual gyrus Fructose: amygdala, hippocampus, parahippocampus, orbitofrontal cortex precentral gyrus
  68. 68. Criteria for addictionCriteria for addiction Cross-sensitization IncreasedIncreased ConsumptionConsumption EnhancedEnhanced locomotionlocomotion BINGEING WITHDRAWAL Tolerance CRAVING Negative emotion Anticipation Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel)
  69. 69. Rat model of addictionRat model of addiction Daily Intermittent Sucrose and Chow Rats are food deprived for 12 h, then given 12-h access to rodent chow and a 10% sucrose solution starting 4 h into the active cycle. DARK ONSET (active) LIGHT ONSET (resting) SUGAR + CHOW ACCESS DEPRIVED Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel)
  70. 70. Sugar and addictionSugar and addiction • Bingeing Avena et al. Neurosci Biobehav Rev 32:20,2008 (Courtesy Dr. B. Hoebel) Increased mu-opioid receptor binding in the accumbens shell
  71. 71. Changes in mRNA levels in sucrose-dependent rats are similar to those in morphine-dependent rats • reduction in dopamine 2 receptor mRNA • reduction in opioid mRNAs • increase in dopamine 3 receptor mRNA Suggest that sucrose and morphine might activate similar pathways, either directly in the forebrain, or in regions which project to the forebrain Opiate-like effects of sugar on gene expressionOpiate-like effects of sugar on gene expression in reward areas of the rat brainin reward areas of the rat brain Spangler et al. Mol Brain Res 124, 134, 2004
  72. 72. Sugar and addictionSugar and addiction • Withdrawal Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel) Naloxone-precipitated withdrawal on a plus-maze
  73. 73. Sugar and addictionSugar and addiction • Withdrawal Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel)
  74. 74. Sugar and addictionSugar and addiction • Withdrawal Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel) Cyclic-gluc/chow Saline Ad lib chow Nax- 20
  75. 75. Sugar and addictionSugar and addiction • Craving Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel)
  76. 76. Sugar and addictionSugar and addiction • Cross-sensitization with other drugs of abuse Avena et al. Neurosci Biobehav Rev 32:20, 2008 (Courtesy Dr. B. Hoebel) Amphetamine Challenge Group 0 50 100 150 200 250 300 350 400 Baseline Day 1 Day 21 Test LOCOMOTORACTIVITY %ofBaseline Cycled S/C-A Cycled C-A Al S and C-A Al C-A
  77. 77. Geiger et al. Neuroscience 159:1193, 2009 Rats with access to a Cafeteria-style (junk food) diet are hyper-responsive to amphetamine in terms of dopamine release. However, they do not respond to a lab chow meal. These rats need junk food to release accumbens dopamine. Sugar and addictionSugar and addiction • Cross-sensitization with other drugs of abuse
  78. 78. Defining an addiction: DSM IV criteriaDefining an addiction: DSM IV criteria Substance Dependence
  79. 79. Jastreboff et al. Diabetes 65:1929, 2016 Effects of fructose and glucose on the brain inEffects of fructose and glucose on the brain in normal and obese adolescentsnormal and obese adolescents
  80. 80. How about humans?How about humans? The DSM-V criteria for addictionThe DSM-V criteria for addiction 2 of the 11 following criteria within a 12-month period: 1.Tolerance 2.Withdrawal 3.Craving or a strong desire to use 4.Use resulting in a failure to fulfill major role obligations (work, school, home); 5.Recurrent use in physically hazardous situations (e.g. driving); 6.Use despite social or interpersonal problems caused or exacerbated by use; 7.Taking the substance in larger amounts or over a longer period than intended; 8.Attempt to quit or cut down; 9.Time spent seeking or recovering from use; 10.Interference with life activities; 11.Use despite negative consequences. Physiologic Psychologic (Dependence)
  81. 81. •In humans, there is no evidence that a specific food, food ingredient or food additive causes a substance-based type of addiction (the only currently known exception is caffeine which via specific mechanisms can potentially be addictive). • Within this context we specifically point out that we do not consider alcoholic beverages as food, despite the fact that one gram of ethanol has an energy density of 7 kcal. Alcohol and caffeine are really “food additives”
  82. 82. UCSF Weight Assessment for Teen and Child Health (WATCH) Andrea Garber, Ph.D., R.D. Patrika Tsai, M.D., M.P.H. Stephanie Nguyen, M.D. M.A.S. Kathryn Smith, M.D. Emily Perito, M.D. Luis Rodriguez, R.D. Megan Murphy, R.D. Maryann Christofas, R.D. Touro University Dept. of Biochemistry Jean-Marc Schwarz, Ph.D. San Francisco General Hospital Depts. of Medicine and Radiology Sanjay Basu, M.D., Ph.D. Susan Noworolski, Ph.D. Kathleen Mulligan, Ph.D. UCSF Institute for Health Policy Studies Laura Schmidt, Ph.D., M.S.W. Cristin Kearns, D.D.S., M.B.A. Claire Brindis, Dr.P.H. Stanton Glantz, Ph.D. Columbia University Nicole Avena, Ph.D. CollaboratorsCollaborators

×