Presentation on theme: "Food and Mood Metabolic Underpinnings of CNS Function Kevin Niswender MD, PhD Diabetes, Endocrinology and Metabolism Vanderbilt School of Medicine Tennessee."— Presentation transcript:
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 depression/ sleep substance cognition
Diabetes Outcomes: Epidemiology (Niswender clinic) 1)HbA1C with little effort or input from me. 2)HbA1C with lots of effort on part of patient, me, and my team. 3)HbA1C >9.0 despite lots of visits, many hours, me, educator, dietician, pleading, bribery, threats, guilt trips etc…..
Is body weight regulated? Sims et al. Experimental obesity in man.
Adiposity Negative Feedback Signaling regulation of metabolic drive Schwartz MW et al., Nature 2000
Brain areas important in energy homeostasis Barsh and Schwartz 2002
Obesity: brain insulin and leptin resistance low fat, vehiclelow fat, insulin high fat, vehiclehigh fat, insulin low fat, vehiclelow fat, leptin high fat, vehiclehigh fat, leptin Posey, KA Am J Physiol Endocrinol Metab. 2009
High-fat diet central insulin and leptin resistance obesity Lipotoxicity Inflammatory signaling IKKB >>> NFKB Model
Does CNS inflammation modulate feeding?
PW likes big meals…. …with lots of fat and sugar, and certain illicit substances.
High-fat hyperphagia Kelly Rogers
Feeding is complicated Berthoud, Ann. Rev. Psych. 2008
Feeding is really complicated Berthoud, Ann. Rev. Psych * * *
Hypothesis: dopaminergic reward systems drive overconsumption of high-fat, high- carbohydrate, energy dense foods Cami NEJM 2003
Insulin administration in brain reduces preference for fat Figlewicz, Behav. Neurosci Train Test Test OnlyTrain Only CPP Score LeptinInsulinCSF
Does high-fat feeding induce midbrain insulin resistance? Speed et al., PLoS One 2011
Insulin receptor PI3K Can insulin resistance be (genetically) rescued? DAT
IRS-2 rescues Akt activation… P-Akt (Thr308) P-Akt (Thr308) (% of control) * * Speed et al., PLoS One 2011
Rescuing insulin action in addiction brain areas normalizes high-fat food intake Speed et al., PLoS One 2011
Reward/addiction areas are targets for obesity therapy! Cami NEJM 2003
PW struggles with depression…..that has not responded terribly well to treatment.
High-fat Food and Mood Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat
Food, Mood, and Diabetes Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat
Food, Mood, Stress, and more Food Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat
Serotonin Robbins Nat. Neurosci. 2005
Depression and inflammation Shelton and Miller Prog. Neurobiol. 2010
Obesity and depression Rx response Oskooilar et al., J. Clin. Psych. 2009
Obesity, depression and inflammation Obesity, depression and inflammation unique phenotype? Rick Shelton
Is inflammation a depression target?
High-fat diet central insulin and leptin resistance obesity Lipotoxicity Inflammatory signaling IKKB >>> NFKB Model Targetging inflammation: -food intake -mood
Is it just the fat? (dense calories) Kolonel, L. N. et al. J Natl Cancer Inst 1999; 91:
Fat saturation makes a difference
Saturated fat in the diet induces CNS ER stress and oxidant stress
Saturated fat is inflammatory
Saturation and Depression Mediterranean diet – Metanalysis of 22 studies – Stroke RR=0.71, 95%CI: – Cognitive impairment RR=0.60, 95%CI: – Depression RR=0.68, 95%CI: Psaltopoulou et al., An. Neurol. 2013
PW stays up all night…..does very little productive in the day.
High-fat diet alters circadian patterns Pendergast et al., Eur. J. Neurosci. 2013
Night Eating Syndrome Lundgren et al., Eating Behavior 2009
NES: Sertraline OReardon et al., Am. J. Psych. 2006
Acknowledgements Kelly Rogers Jennifer Rojas Heidi Kocalis Lindsey Morris Richard Printz Maxine Turney Leena George Sanaz Saadat Simon Dosovitz Jennifer Lukasiewicz Aurelio Galli 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 CowanRobert Kessler