Comfort food slideshare

Comfort Food:
Effects of Stress and High-Fat Diets on
Neuronal Activity and Mitochondrial
Remodeling in Mice
Matt Robinson, PhD
Assistant Professor
Kinesiology
Oregon State University
Julio Ayala, PhD
Associate Professor
Molecular Physiology & Biophysics
Vanderbilt University

Experts will present their research
focusing on high-fat feeding behavior
in mice and the effects of stress and
exercise on metabolism and obesity.
Comfort Food:
Effects of Stress and High-Fat Diets on
Neuronal Activity and Mitochondrial
Remodeling in Mice

Julio E. Ayala, PhD
Department of Molecular Physiology & Biophysics
Vanderbilt Mouse Metabolic Phenotyping Center
Vanderbilt Center for Addiction Research
Obesity and the Metabolic
Response to Stress
Copyright 2021 J. Ayala and InsideScientific. All Rights Reserved.

14%–17.9% 18%–21.9% 22%–25.9% ≥26%
Obesity in the US
2005 2010 2015
BMI >30:
Stress in the US
Obesity and Stress in the US

American Psychological Association, 2011
American Psychological Association, 2011
Oliver and Wardle, Physiology and Behavior, 1999
Stress affects caloric intake and food selection

Chuang, JC et al., J Clin Invest 2011
Pecoraro, N et al., Endocrinology 2004
Rodents display “comfort feeding” in response to stress

Boggiano MM et al. Appetite 2015 Coulthard H et al. Appetite 2021
Obesity increases the susceptibility to stress and
“comfort feeding”

Outline
• What effect does obesity have on response to stress?
• Energy balance parameters
• How are mechanisms that regulate feeding in response to stress affected by
obesity?
Chow
60% HFD

0
1
2
3
4
5
Food
Intake
(g)
20:0022:00 0:00 2:00 4:00 6:00 8:00 10:0012:00
Time
0
1
2
3
Food
Intake
(g)
20:0022:00 0:00 2:00 4:00 6:00 8:00 10:0012:00
Time
Chow No Restraint
Chow Restraint
0
1
2
3
4
Food
Intake
(g)
Time
Chow No Restraint
Chow Restraint
0
1
2
3
Food
Intake
(g)
Time
HFD No Restraint
HFD Restraint
HFD No Restraint
HFD Restraint
Restraint stress reduces food intake
in chow-fed but not HFD-fed mice
* * *
*
*P<0.05; N=9-12

0.7
0.8
0.9
1
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
EE
(kCal/hr)
Time
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
EE
(kCal/hr)
Time
Rq
(VCO
2
/VO
2
)
Time Time
Rq
(VCO
2
/VO
2
)
Chow No Restraint
Chow Restraint
HFD No Restraint
HFD Restraint
Chow No Restraint
Chow Restraint HFD No Restraint
HFD Restraint
Restraint stimulates energy expenditure and fat
oxidation in chow-fed and HFD-fed mice

0.7
0.8
0.9
1
0.7
0.8
0.9
1
Rq
(VCO
2
/VO
2
)
Time Time
Rq
(VCO
2
/VO
2
)
Chow No Restraint
HFD Restraint
0
1
2
3
4
Food
Intake
(g)
Time
Chow No Restraint
Chow Restraint
0
1
2
3
Food
Intake
(g)
Time
HFD No Restraint
HFD Restraint
Stress-induced fat oxidation is independent of
feeding patterns

0
10
20
30
40
50
60
70
80
Locomotor
Activity
(m)
Time
0
10
20
30
40
50
60
70
80
Locomotor
Activity
(m)
Time
Restraint stress tends to reduce locomotor
activity in both chow-fed an HFD-fed mice
Chow No Restraint
Chow Restraint
HFD No Restraint
HFD Restraint

0
1
2
3
4
Food
Intake
(g)
Time
Chow No Restraint
Chow Restraint
0
1
2
3
Food
Intake
(g)
Time
HFD No Restraint
HFD Restraint
0
1
2
3
4
5
0
1
2
3
Water
Intake
(mL)
Time
Water
Intake
(mL)
Time
Chow No Restraint
Chow Restraint
HFD No Restraint
HFD Restraint
Restraint stress does not affect water intake

Outline
• What effect does obesity have on response to stress?
• Blunted hypophagia with equal increase in energy expenditure and fat
oxidation
• How are mechanisms that regulate feeding in response to stress affected by
obesity?
Brain
Glp1
Glp1r
Pancreas
Glp1r
Gut
Glp1 Insulin Food intake
Glucagon-like peptide-1 (Glp1)

PVN
Ghosal S et al. J Neurosci 2017
BNST
Williams DL et al. Neuropharm 2018
LS
Terrill SJ et al. Physiol Behav 2019
PVN
BNST
LS
NTSPPG
NTSPPG: Nucleus Tractus Solitarius
Preproglucagon
PVN: Paraventricular Hypothalamus
BNST: Bed Nucleus of the Stria
Terminalis
LS: Lateral Septum
Holt M et al. Diabetes 2018
Stress-induced hypophagia requires brain Glp1 action

LV
dLS
iLS vLS
DP
SHi
MS
LV
CC
dLS
SHi
Glp1r-mApple Glp1r-Cre;tdTomato
The Glp1r is densely expressed in the
Lateral Septum (LS)

Azevedo EP et al. eLife 2020
Activation of LS Glp1r signaling or LSGlp1r neurons reduces food intake

Glp1r-Cre
Cre-dependent
GCaMP7
to LS
dLS
DP
Glp1r-Cre
Cre-dependent
GCaMP7
to LS
Measure neuronal activity in
response to restraint stress
LV
Fiber optic probe
to LS
3 weeks
Measuring LSGlp1r neuronal activity

5 min
acclimation
10 min
baseline
60 min
restraint
10 min
post-restraint
Restraint
No Restraint
LSGlp1r neurons are rapidly and robustly activated during restraint stress
LED and Camera ON

Lean
Obesity attenuates LSGlp1r neuronal activity in response to restraint stress
Restraint
Obese
Restraint

LS
Obese Lean
Food Intake
Food Intake
Terrill SJ et. al, Physiol & Behav 2019
PVN
NTSPPG
BNST
Are defects in LSGlp1r neurons responsible for “comfort feeding”?
Stress
Other stress phenotypes:
• Energy Expenditure
• Substrate Oxidation
• Locomotor Activity
Other stressors:
• Chronic Restraint Stress
• Social Defeat Stress
Other brain regions:
• NTS
• BNST
• PVN

0
1
2
3
4
0
1
2
3
4
Food
Intake
(g)
20:0022:00 0:00 2:00 4:00 6:00 8:00 10:0012:00
Time
Food
Intake
(g)
20:0022:00 0:00 2:00 4:00 6:00 8:00 10:0012:00
Time
Chronic restraint stress promotes loss of hypophagia
and LS activity
*
*P<0.05; N=9-12
*
*
* * *

0.7
0.8
0.9
1
0.7
0.8
0.9
1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
EE
(kCal/hr)
Time
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
EE
(kCal/hr)
Time
Rq
(VCO
2
/VO
2
)
Time Time
Rq
(VCO
2
/VO
2
)
Chow No Restraint
Chow Restraint
HFD No Restraint
HFD Restraint
Chow No Restraint
HFD Restraint
Chronic stress stimulates energy expenditure and fat
oxidation in chow-fed and HFD-fed mice

Combining Fiber Photometry and Promethion

Ayala Lab
Michelle Bales
Thao Le
Payam Fathi
Merrygay James
Louise Lantier
Winder Lab
Danny Winder
Sam Centanni
James Melchior
Greg Salimando
Thank You!
1S10OD028455

Matt Robinson, PhD
Co-Director Translational Metabolism Research Laboratory
School of Biological and Population Health Sciences
College of Public Health and Human Sciences
Skeletal Muscle Mitochondrial
Protein Adaptations to
Obesity and Exercise
Copyright 2021 M. Robinson and InsideScientific. All Rights Reserved.

Translational Metabolism Research Laboratory
Our approach to the questions
Sean Newsom PhD

1 in 11 Americans has Diabetes
Barker L et al. Amer J Prev Med 2011
What is the problem?

Projected to 1 in 3 by 2050

Projected to 1 in 3 by 2050
~189 newly diagnosed people in the hour

Challenges on skeletal muscle muscle
Fat Mass
Exercise
Nutrient excess
Insulin

Q CIII
c
CI
CII
ETF
GpDH
Electron Transfer System
CIV CV
Lipid
Substrate
Non-lipid
Substrate e-

Q CIII
c
CI
CII
ETF
GpDH
CIV CV
Lipid
Substrate
Non-lipid
Substrate e-
Breakdown
Synthesis
Protein Turnover

Say it in a sentence
✓Mitochondria adapt to
-nutrition and exercise
-through turnover of mitochondrial proteins
-that underlies whole body fuel oxidation

What is impact of high-fat diet and exercise on respiration?

Week 4 Week 12
Exercise or Sedentary
Low Fat or High Fat Diet
Week 0
C57BL/6J
Ehrlicher et al FASEBJ 2020
Sarah Ehrlicher, Ph.D.

Mitochondrial respiration
Oxygraph O2K
✓ Add Substrates
✓ Measure O2 consumption
Isolate
Mitochondria

Mitochondrial Respiration
(Lipids)
WT Bcl2AAA
0
1
2
3
4
JO
2
(pmol
O
2
/mg
mito/sec)
NS Leak LFD Relative
SED
EX
EX: P = 0.05

Do mitochondrial adaptations with exercise
depend on autophagy activation?

Exercise effects depend on autophagy?
• Model of impaired autophagy in response to exercise.
Exercise
Bcl2
Beclin-1 Beclin-1
Bcl2
P
Beclin-1
Bcl2
P
He et al., Nature 2012

LFD HFD LFD HFD
0
100
200
300
400
0
2
4
6
8
JO
2
(pmol
O
2
/ml/sec)
JO
2
(pmol
O
2
/mg
mito/sec)
Diet: P < 0.001
EX: P < 0.01
Diet: P < 0.001
EX: P = 0.59
Bcl2AAA
WT Bcl2AAA
0
1
2
3
4
JO
2
(pmol
O
2
/mg
mito/sec)
NS Leak LFD Relative
SED
EX
EX: P = 0.05
Requirements of autophagy with HFD?
Mitochondrial
Respiration
(Lipids)

Respiration
(CI + II)

Respiration
(CI + II)
WT Bcl2AAA WT Bcl2AAA
0
1
2.0
2.5
3.0
3.5
FSR
(%/day)
SED
EX
SSM IMFM
P < 0.05
Interaction: P < 0.05
Mito Protein
Synthesis

Respiration
(CI + II)
WT Bcl2AAA WT Bcl2AAA
0
1
2.0
2.5
3.0
3.5
FSR
(%/day)
SED
EX
SSM IMFM
P < 0.05
Interaction: P < 0.05
Mito Protein
Synthesis
Bcl2 activation not required
for gains in mitochondria

Parkin as alternative activation of autophagy
Week 12
LFD or HFD
Week 0
Acute
Exercise

Week 12
LFD or HFD
Week 0
LFD HFD LFD HFD
0.00
0.01
0.02
0.03
Mitochondrial
Parkin/VDAC
Content
(AU)
WT BCL
Diet: P < 0.05
EX: P = 0.67
Diet: P = 0.77
EX: P < 0.05
Acute
Exercise

Week 12
LFD or HFD
Week 0
LFD HFD LFD HFD
0.00
0.01
0.02
0.03
Mitochondrial
Parkin/VDAC
Content
(AU)
WT BCL
Diet: P < 0.05
EX: P = 0.67
Diet: P = 0.77
EX: P < 0.05
Acute
Exercise
Parkin localization
to mitochondria
with exercise

Rapid changes to mitochondrial fuel oxidation with
aerobic exercise?

Harrison Stierwalt, Ph.D.
Acute exercise on mitochondrial respiration
1 hour at 65% VO2max
15 min post
Newsom et al MSSE 2021

Harrison Stierwalt, Ph.D.
Acute exercise on mitochondrial respiration
1 hour at 65% VO2max
F-linked
PC+M
N(S)
GM+S
S
Succinate
N
Complex I
0
2
4
6
8
Coupled
Oxidative
Phosphorylation
(P-L
O
)
JO
2
pmol/mg
mito/sec
Rest
Exercise
p=0.08
p=0.09
p=0.08
F-linked
PC+M
N(S)
GM+S
S
Succinate
N
Complex I
0
2
4
6
8
Coupled
Oxidative
Phosphorylation
(P-L
O
)
JO
2
pmol/mg
mito/sec
Rest
Exercise
p=0.08
p=0.09
p=0.08
15 min post
Newsom et al MSSE 2021

High-intensity
Interval Training
(2 weeks)
10 x 1 min at 95-
100% VO2max
Meal Tolerance Test
Respiration
Phil Batterson
Short-term HIIT on mitochondrial remodeling

RMR MTT30 MTT120
0.5
0.6
0.7
0.8
0.9
1.0
RER
Response of RER to Mixed Meal Tolerance Test
Pre-Training
Effect of MTT p<0.0001
Effect of Training p=0.08
*p=0.023
*
Post-Training
Lipids
Carbohydrates
Shift in whole-body fuel
reliance after meal

0.0 0.1 0.2 0.3 0.4
0.8 0.9 1.0
0
20
40
60
80
100
120
140
Octanoylcarnitine (mMol)
JO
2
(pmol
O
2
/ml/sec)
Oxphos Oct Km
Pre Training
Post Training
Pre vs Post Vmax: p = 0.066
P=0.066
Erin McGowan
Lipids

Q CIII
c
CI
CII
ETF
GpDH
CIV CV
Lipid
Substrate
Non-lipid
Substrate e-
✓ Greater lipid oxidation with training
✓ Mild increases with acute exercise
✓ Turnover with exercise through autophagy
✓ Role in substrate competition?

Take home goals
✓Mitochondria adapt to
-nutrition and exercise
-through turnover of mitochondrial proteins
-that impacts respiratory function
-with possibility for overload?

Matt Robinson, PhD
Assistant Professor
Kinesiology
Julio Ayala, PhD
Associate Professor
Molecular Physiology & Biophysics
Vanderbilt University
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