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 with little effort or input from me.
HbA1C 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 Obesity Diabetes inflammation Cognition Addiction
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 in energy homeostasis
Barsh and Schwartz 2002

9. Obesity: brain insulin and leptin resistance
low fat, vehicle
low fat, insulin
high fat, vehicle
high fat, insulin
low fat, vehicle
low fat, leptin
high fat, vehicle
high fat, leptin
Posey, KA Am J Physiol Endocrinol Metab

10. Model High-fat diet central insulin and leptin resistance obesity
Lipotoxicity
Inflammatory signaling
IKKB >>> NFKB
Evolving out of this is a model of how neurons develop biochemical ins and lep resistant(highlight long chain accum key aspect of this)—ANIMATE ARROW TO POINT TO LCFACOA
A key aspect involved in this process is the accumulation of LCFACoA in response to high fat feeding. LCFACoAs act to activate inflammatory signaling pathways including several serine/threonine kinases which phosphorylate and inhibit molecules in the hypothalamic insulin and leptin pathways on arc nucleus neurons controlling feeding, resulting in obesity.
central insulin and leptin resistance
obesity 10 10

11. Does CNS inflammation modulate feeding?

12. …with lots of fat and sugar, and certain illicit substances.
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
-50
Train Test
Test Only
Train Only
-100
CSF
Insulin
Leptin
Figlewicz, Behav. Neurosci

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

19. Can insulin resistance be (genetically) rescued?
Insulin receptor
DAT
PI3K
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
Oskooilar et al., J. Clin. Psych. 2009

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

31. Is inflammation a depression target?

32. Model High-fat diet central insulin and leptin resistance obesity
Targetging inflammation:
-food intake
-mood
Lipotoxicity
Inflammatory signaling
IKKB >>> NFKB
Evolving out of this is a model of how neurons develop biochemical ins and lep resistant(highlight long chain accum key aspect of this)—ANIMATE ARROW TO POINT TO LCFACOA
A key aspect involved in this process is the accumulation of LCFACoA in response to high fat feeding. LCFACoAs act to activate inflammatory signaling pathways including several serine/threonine kinases which phosphorylate and inhibit molecules in the hypothalamic insulin and leptin pathways on arc nucleus neurons controlling feeding, resulting in obesity.
central insulin and leptin resistance
obesity 32 32

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

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
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

39. ..does very little productive in the day.
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 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 Zald Hakmook Kang
Calum Avison Ron Cowan Robert Kessler