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Food and Mood Metabolic Underpinnings of CNS Function Kevin Niswender MD, PhD Diabetes, Endocrinology and Metabolism Va

Food and Mood Metabolic Underpinnings of CNS Function Kevin Niswender MD, PhD Diabetes, Endocrinology and Metabolism Vanderbilt School of Medicine Tennessee Valley Healthcare System. PW: Diabetes Natural History. cognition. substance. d epression/ sleep.

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Food and Mood Metabolic Underpinnings of CNS Function Kevin Niswender MD, PhD Diabetes, Endocrinology and Metabolism Va

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  1. Food and Mood Metabolic Underpinnings of CNS Function Kevin Niswender MD, PhD Diabetes, Endocrinology and Metabolism Vanderbilt School of Medicine Tennessee Valley Healthcare System

  2. PW: Diabetes Natural History cognition substance depression/ sleep

  3. Diabetes Outcomes: Epidemiology(Niswender clinic) HbA1C 6.0-6.5 with little effort or input from me. HbA1C 7.0-8.0 with lots of effort on part of patient, me, and my team. HbA1C >9.0 despite lots of visits, many hours, me, educator, dietician, pleading, bribery, threats, guilt trips etc…..

  4. Diabesity barriers Cognition Obesity Diabetes Addiction Depression

  5. Diabesity barriers Cognition inflammation Obesity Diabetes Depression Addiction

  6. Is body weight regulated? Sims et al. “Experimental obesity in man.”

  7. Adiposity Negative Feedback Signaling regulation of “metabolic drive” Schwartz MW et al., Nature 2000

  8. Brain areas important inenergy homeostasis Barsh and Schwartz 2002

  9. low fat, vehicle low fat, insulin high fat, vehicle high fat, insulin Obesity: brain insulin and leptinresistance low fat, vehicle low fat, leptin high fat, vehicle high fat, leptin Posey, KA Am J PhysiolEndocrinolMetab. 2009

  10. Model High-fat diet Lipotoxicity Inflammatory signaling IKKB >>> NFKB central insulin and leptin resistance obesity

  11. Does CNS inflammation modulate feeding?

  12. PW likes big meals…. …with lots of fat and sugar, and certain illicit substances.

  13. High-fat hyperphagia Kelly Rogers

  14. Feeding is complicated Berthoud, Ann. Rev. Psych. 2008

  15. Feeding is really complicated * * * Berthoud, Ann. Rev. Psych. 2008

  16. Hypothesis: dopaminergic “reward” systems drive overconsumption of high-fat, high-carbohydrate, energy dense foods Cami NEJM 2003

  17. Insulin administration in brain reduces preference for fat 200 150 100 CPP Score 50 0 -50 Train Test Test Only Train Only -100 CSF Insulin Leptin Figlewicz, Behav. Neurosci. 2004.

  18. Does high-fat feeding induce midbrain insulin resistance? Speed et al., PLoS One 2011

  19. PI3K Can insulin resistance be (genetically) rescued? Insulin receptor DAT DAT

  20. IRS-2 rescues Akt activation… * P-Akt (Thr308) * P-Akt (Thr308) (% of control) Speed et al., PLoS One 2011

  21. Rescuing insulin action in “addiction” brain areas normalizes high-fat food intake Speed et al., PLoS One 2011

  22. Reward/addiction areas are targets for obesity therapy! Cami NEJM 2003

  23. PW struggles with depression… ..that has not responded terribly well to treatment.

  24. High-fat Food and Mood Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat

  25. Food, Mood, and Diabetes Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat

  26. Food, Mood, Stress, and more Food Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat

  27. Serotonin Robbins Nat. Neurosci. 2005

  28. Depression and inflammation Shelton and Miller Prog. Neurobiol. 2010

  29. Obesity and depression Rx response Oskooilaret al., J. Clin. Psych. 2009

  30. Obesity, depression and inflammation unique phenotype? Rick Shelton

  31. Is inflammation a depression target?

  32. Model Targetging inflammation: -food intake -mood High-fat diet Lipotoxicity Inflammatory signaling IKKB >>> NFKB central insulin and leptin resistance obesity

  33. Is it just the fat? (dense calories) Kolonel, L. N. et al. J Natl Cancer Inst 1999; 91:414-428

  34. Fat saturation makes a difference

  35. Fat saturation makes a difference

  36. Saturated fat in the diet induces CNS ER stress and oxidant stress

  37. Saturated fat is inflammatory

  38. Saturation and Depression Psaltopoulou et al., An. Neurol. 2013 • Mediterranean diet • Metanalysis of 22 studies • Stroke RR=0.71, 95%CI: 0.57-0.89 • Cognitive impairment RR=0.60, 95%CI: 0.43-0.83 • Depression RR=0.68, 95%CI: 0.54-0.86

  39. PW stays up all night… ..does very little productive in the day.

  40. High-fat diet alters circadian patterns Pendergast et al., Eur. J. Neurosci. 2013

  41. Night Eating Syndrome Lundgren et al., Eating Behavior 2009

  42. NES: Sertraline O’Reardon et al., Am. J. Psych. 2006

  43. Acknowledgements • AurelioGalli • Mike Siuta • Sabrina Robertson • Nicole Speed • Christine Saunders • Calum Avison • Jason Williams • Nelli Byun • Rob Barry • Translation • Heidi Silver Richard Shelton David ZaldHakmook Kang • Calum Avison Ron Cowan Robert Kessler • Kelly Rogers • Jennifer Rojas • Heidi Kocalis • Lindsey Morris • Richard Printz • Maxine Turney • Leena George • Sanaz Saadat • Simon Dosovitz • Jennifer Lukasiewicz

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