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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 Vanderbilt School of Medicine Tennessee Valley Healthcare System
PW: Diabetes Natural History cognition substance depression/ sleep
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…..
Diabesity barriers Cognition Obesity Diabetes Addiction Depression
Diabesity barriers Cognition inflammation Obesity Diabetes Depression Addiction
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 inenergy homeostasis Barsh and Schwartz 2002
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
Model High-fat diet Lipotoxicity Inflammatory signaling IKKB >>> NFKB central insulin and leptin resistance obesity
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. 2008
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 200 150 100 CPP Score 50 0 -50 Train Test Test Only Train Only -100 CSF Insulin Leptin Figlewicz, Behav. Neurosci. 2004.
Does high-fat feeding induce midbrain insulin resistance? Speed et al., PLoS One 2011
PI3K Can insulin resistance be (genetically) rescued? Insulin receptor DAT 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 Oskooilaret al., J. Clin. Psych. 2009
Obesity, depression and inflammation unique phenotype? Rick Shelton
Model Targetging inflammation: -food intake -mood High-fat diet Lipotoxicity Inflammatory signaling IKKB >>> NFKB central insulin and leptin resistance obesity
Is it just the fat? (dense calories) Kolonel, L. N. et al. J Natl Cancer Inst 1999; 91:414-428
Saturated fat in the diet induces CNS ER stress and oxidant stress
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
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 O’Reardon et al., Am. J. Psych. 2006
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