Upload
stefan-soper
View
215
Download
3
Tags:
Embed Size (px)
Citation preview
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