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

Food and MoodMetabolic Underpinnings of CNS Function

Kevin Niswender MD, PhDDiabetes, Endocrinology and Metabolism

Vanderbilt School of Medicine Tennessee Valley Healthcare System

PW: Diabetes Natural History

Aug '05

Feb '0

6

Jun '0

7

Nov '0

8

May

'09

Jan '1

0

Dec '1

0

200

225

250

4

6

8

10HbA1C

We

igh

t (

lbs

) Hb

A1c (%

)

Aug '05

Feb '0

6

Jun '0

7

Nov '0

8

May

'09

Jan '1

0

Dec '1

0

200

225

250

4

6

8

10HbA1C

WeightWe

igh

t (

lbs

) Hb

A1

c (%

)

depression/

sleep

substance

cognition

Diabetes Outcomes: Epidemiology(Niswender clinic)

1) HbA1C 6.0-6.5 with little effort or input from me.

2) HbA1C 7.0-8.0 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…..

Diabesity barriers

Diabetes

Obesity

DepressionAddiction

Cognition

Addiction

Cognition

Obesity Depression

Diabesity barriers

Diabetes

inflammation

Is body weight regulated?

Sims et al. “Experimental obesity in man.”

Adiposity Negative Feedback Signalingregulation of “metabolic drive”

Schwartz MW et al., Nature 2000

Brain areas important inenergy homeostasis

Barsh and Schwartz 2002

0 10 20 30 40275

325

375

425

475

low fat (10%)high fat (60%)

day

bo

dy

we

igh

t (g

ram

s)

Obesity: brain insulin and leptin resistance

low fa

t, ve

hicle

low fa

t, ins

ulin

high

fat,

vehic

le

high

fat,

insuli

n

0

25

50

75

100 *

food i

nta

ke (

Kca

l/2

4 h

r)0

25

50

75

100*

food i

nta

ke (

Kca

l/2

4 h

r)low

fat,

vehic

le

low fa

t, lep

tinhig

h fa

t, ve

hicle

high

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?

0

20

40

60

80

100

120

diet fat content low low high high

*

IKK inhibitor - + - +

foo

d in

take

(Kca

l/24h

r)

PW likes big meals….

…with lots of fat and sugar, and certain illicit substances.

High-fat hyperphagia

-2 -1 0 1 2 3 4 5 6 7

60

70

80

90

100

110

LFHF

*

* ** * ** **

70time (days)

foo

d in

take

(kc

al)

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

Figlewicz, Behav. Neurosci. 2004.

Train Test-50

0

50

100

150

200

-100

Test Only Train Only

CPP

Scor

e

LeptinInsulinCSF

Does high-fat feeding induce midbrain insulin resistance?

*

P-A

kt(T

hr30

8) (

% o

f co

ntro

l)

Striatum

Low Fat High Fat

*

P-A

kt(T

hr30

8) (

% o

f co

ntro

l)

Substania Nigra

Low Fat High Fat

Speed et al., PLoS One 2011

IRSY

IRSY

p85

p110

p110

PIP2 PIP3PDK1

PKC

AKTS

T

Insulin receptor

Y

YY

Y

} PI3K

glut4

glut4

Can insulin resistance be (genetically) rescued?

DAT

DAT

IRS-2 rescues Akt activation…P-Akt (Thr308)

LF GFP LF IRS2 HF GFP HF IRS20

25

50

75

100

125

p-Ak

t (Th

r308

) (%

of c

ontr

ol)

P-Ak

t (Th

r308

) (%

of c

ontr

ol) *

*

Speed et al., PLoS One 2011

LF-GFP

HF-GFP

HF-IRS2

0

100

200

300 *fo

od in

take

(kc

al)

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.

0 7 14 21 28

0.4

0.6

0.8

1.0

1.2 LF (10%)

HF (45%)

p<0.05

days on diet

time

stru

gg

ling

(nor

mal

ized

to

LF

)

High-fat Food and Mood

Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat

-20 0 20 40 60 801001200

200

400

600

LF (10%)

HF (45%)

time (min)

blo

od g

luco

se (

mg

/dl)

Food, Mood, and Diabetes

Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat

0 7 14 21 28 35

50

100

150

LF (10%) HF (45%)

time (days on diet)

food

inta

ke (

kcal

)

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 unique phenotype?

Rick Shelton

Is inflammation a depression target?

0 70.5

1.0

1.5IKK Inh

Veh

days on HF diet

time

stru

gg

ling

(nor

mal

ized

to

t=0

)

High-fat diet

central insulin and leptin resistance

obesity

Lipotoxicity Inflammatory signaling

IKKB >>> NFKB

ModelTargetging inflammation:-food intake-mood

Is it just the fat?(dense calories)

Kolonel, L. N. et al. J Natl Cancer Inst 1999; 91:414-428

1 2 3 4 5 6 7 8 9 100

300

400

500

600

high-saturated fat

low-fat

high-monounsaturatedfat

weeks on diet

bo

dy

we

ight

(g

)

Fat saturation makes a difference

0

50

100

150

200

250 high-saturated fatlow-fat

high-monounsaturatedfat

total fat

**

*

**

p=0.08

wei

ght g

ain

(g)

low-fat high-sat high-mono0

4000

5000

6000

7000

****

tota

l fo

od

inta

ke (

kcal

)

Fat saturation makes a difference

0.5

1.0

1.5

2.0

2.5LFHFMU

p'PERK p'p66shc

a

b

a

bb

rela

tive

in

ten

sity

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

Saturated fat is inflammatory

LF HF-SFA HF-MUFA0

2

4

6 * **

IL-6

mR

NA

(rel

ativ

e ex

pre

ssio

n)

Saturation and Depression• 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

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

O’Reardon 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

TranslationHeidi Silver Richard Shelton David Zald Hakmook Kang

Calum Avison Ron Cowan Robert Kessler