Food and Mood
Metabolic Underpinnings of CNS Function
Kevin Niswender MD, PhD
Diabetes, Endocrinology and Metabolism
Vanderbilt School of Medicine
Tennessee Valley Healthcare System
b
6
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n
N '07
ov
M '08
ay
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Ja 9
n
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0
D
ec
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Ju
Fe
ug
250
HbA1C
225
8
6
200
Weight
4
HbA1c (%)
A
Weight (lbs)
PW: Diabetes Natural History
10
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
Cognition
Obesity
Diabetes
Addiction
Depression
Diabesity barriers
inflammation
Cognition
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 in
energy homeostasis
Barsh and Schwartz 2002
475
425
375
low fat (10%)
high fat (60%)
325
275
0
10
20
day
30
40
food intake
intake (Kcal/24
food
(Kcal/24hr)
hr)
body weight (grams)
Obesity: brain insulin and leptin
resistance
100
100
75
75
50
50
**
25
0
Posey, KA Am J Physiol Endocrinol Metab. 2009
Model
High-fat diet
Lipotoxicity
Inflammatory signaling
IKKB >>> NFKB
central insulin and leptin
resistance
obesity
Does CNS inflammation
modulate feeding?
food intake
(Kcal/24hr)
120
100
*
80
60
40
20
0
diet fat content
IKK inhibitor
low
-
low
+
high
-
high
+
PW likes big meals….
…with lots of fat and sugar, and
certain illicit substances.
High-fat hyperphagia
food intake (kcal)
110
*
LF
HF
100
90
80
*
*
* * * **
*
70
60
-2 -1 0 1 2 3 4 5 6 7
time (days)
70
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, highcarbohydrate, energy dense foods
Cami NEJM 2003
Insulin administration in brain
reduces preference for fat
200
CPP Score
150
100
50
0
-50
-100
Train Test
CSF
Test Only
Insulin
Figlewicz, Behav. Neurosci. 2004.
Train Only
Leptin
Does high-fat feeding induce midbrain
insulin resistance?
Substania Nigra
*
Low Fat
High Fat
P-Akt (Thr308) (% of control)
P-Akt (Thr308) (% of control)
Striatum
*
Low Fat
High Fat
Speed et al., PLoS One 2011
Can insulin resistance be
(genetically) rescued?
Insulin receptor
PIP2
Y
Y
PIP3
PDK1
glut4
DAT
p110
IRS
Y Y
PKC
Y
IRS
Y
p110
p85
}
S
PI3K
AKT
T
glut4
DAT
IRS-2 rescues Akt activation…
P-Akt (Thr308)
p-Akt (Thr308) (% of control)
P-Akt (Thr308) (% of control)
*
*
125
100
75
50
25
0
LF GFP
LF IRS2
HF GFP
HF IRS2
Speed et al., PLoS One 2011
*
300
200
100
S2
FIR
H
FP
FG
H
FP
0
LF
-G
food intake (kcal)
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.
time struggling
(normalized to LF)
High-fat Food and Mood
1.2
1.0
0.8
0.6
0.4
LF (10%)
p<0.05
HF (45%)
0
7
14
21
days on diet
28
Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat
blood glucose (mg/dl)
Food, Mood, and Diabetes
600
HF (45%)
400
200
LF (10%)
0
-20 0 20 40 60 80 100120
time (min)
Rogers, Dunn, Dosovitz, Lukasiewicz, Saadat
food intake (kcal)
Food, Mood, Stress, and
more Food
150
100
50
LF (10%)
0
HF (45%)
7 14 21 28 35
time (days on diet)
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
time struggling
(normalized to t=0)
Is inflammation a depression target?
1.5
IKK Inh
1.0
Veh
0.5
7
0
days on HF diet
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
Fat saturation makes a difference
body weight (g)
600
500
400
low-fat
high-saturated fat
300
high-monounsaturated
fat
0
1
2
3
4 5 6 7
weeks on diet
8
9 10
Fat saturation makes a difference
weight gain (g)
250
**
200
low-fat
high-saturated fat
high-monounsaturated
fat
p=0.08
150
**
100
50
0
total
fat
total food intake (kcal)
*
7000
**
6000
**
5000
4000
0
low-fat
high-sat
high-mono
relative intensity
Saturated fat in the diet induces CNS
ER stress and oxidant stress
2.5
2.0
LF
HF
MU
a
a
1.5
1.0
b
b
b
0.5
p'PERK
p'p66shc
Saturated fat is inflammatory
*
IL-6 mRNA
(relative expression)
6
*
*
4
2
0
LF
HF-SFA
HF-MUFA
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
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Acknowledgements
Kelly Rogers
Jennifer Rojas
Heidi Kocalis
Lindsey Morris
Richard Printz
Maxine Turney
Leena George
Sanaz Saadat
Simon Dosovitz
Jennifer Lukasiewicz
Translation
Heidi Silver
Calum Avison
Richard Shelton
Ron Cowan
• Aurelio Galli
• Mike Siuta
• Sabrina Robertson
• Nicole Speed
• Christine Saunders
• Calum Avison
• Jason Williams
• Nelli Byun
• Rob Barry
David Zald
Robert Kessler
Hakmook Kang