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Sex Differences in Central Expression and Effects of Brain-Derived Neurotrophic Factor. Haifei Shi Department of Biology, Miami University International Conference on Endocrinology October 22, 2014. Arcuate melanocortin system. BDNF. VMH. +. BDNF. ARC. - PowerPoint PPT Presentation
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Sex Differences in Central Expression and Effects of Brain-Derived Neurotrophic Factor
Haifei Shi
Department of Biology, Miami University
International Conference on Endocrinology
October 22, 2014
VMH
3V
BDNF
Leptin
ARC
POMC
Arcuate melanocortin system
Xu, et al., Nat Neurosci 2003 Komori, et al., Neuroscience 2006Wang, et al., AJP 2007, 2010
BDNF
+
+
Expenditure Intake
Lepr
BDNF conditional deficient mice
Transgenic mouse models
Rios, et al., Mol Endocrinol 2001
ControlBdnf deficient
VMH
3V
ARC
Asarian & Geary, Philos T Roy Soc B 2006
Estradiol regulates food intake
estradiol
Expenditure Intake
100 mm
Xu, et al., Nat Neurosci 2003
BDNF in the hypothalamus
BDNF
BDNF and estrogen receptor alpha (ERα) in the hypothalamus
ERa
Arc
VMH
100 mm
Shi Lab
Colocalization of ERα and BDNF in the VMH
ERα: brownBDNF: blueBlurton-Jones, et al., J Comp Neurol 2004
ER α: brown (DAB)BDNF: blue black (nickel-enhanced DAB)BDNF + ER αShi Lab
VMH
3V
BDNF
Leptin
ARC estrogen
POMC
Expenditure Intake
estradiol
Potential regulation of BDNF by estradiol
Hypothesis: Central BDNF expression and action are regulated by estradiol.
Q1: Is central BDNF expression regulated by estradiol?Q2: Is central BDNF action regulated by estradiol?
VMH
3V
BDNF
Leptin
ARC
POMC
Expenditure Intake
estradiol
Hypothesis: Central BDNF expression and action are regulated by estradiol.
Q1: Is central BDNF expression regulated by estradiol?Q2: Is central BDNF action regulated by estradiol?
VMH
3V
BDNF
Leptin
ARC
POMC
Expenditure Intake
estradiol
Ovariectomy (OVX)
Estradiol (E2; subcu)
Q1: Is central BDNF expression regulated by estradiol? (1) Does ovariectomy (OVX) or estradiol (E2) replacement modulate VMH BDNF gene expression?
Experiment groups
Sham-Oil OVX-Oil ad libOVX-Oil pairfeed (PF) (pairfeed to Sham-Oil)OVX-E2
0 2 4 6 8 10 12 14 16 18 20 22200
220
240
260
280
300 Sham-Oil
OVX-Oil
OVX-Oil PF
OVX-E2
*
Days
Bo
dy
wei
gh
t (g
)
0 2 4 6 8 10 12 14 16 18 20 226
8
10
12
14
16
18
20
Sham-Oil
OVX-Oil
OVX-E2
*#
Days
Fo
od
inta
ke (
g)
Sham-O
il
OVX-Oil
OVX-Oil
PF
OVX-E2
0
10
20
30
40
50
60
* *
Pla
sma
estr
adio
l lev
el(p
g/m
l)
Sham-O
il
OVX-Oil
OVX-Oil
PF
OVX-E2
0
50
100
150
* *
Bdnf
mR
NA
lev
el i
n V
MH
(% o
f S
ham
fem
ales
)
Zhu, Liu, et al., Horm Behav 2014
Q1: Is central BDNF expression regulated by estradiol? (1) Does ovariectomy (OVX) or estradiol (E2) replacement modulate VMH BDNF gene expression?
(2) Do male and female rats have different BDNF expression? Does estrous cycle modulate VMH BDNF gene expression?Experiment groups (Ordered 10-week old male and female rats, sacrificed at 12-week of age)
Daily Food Intake
Male D-P P-E E-M M-D10
15
20
25
Fo
od
In
take
(g
)
Dairy Body Weight
Male D-P P-E E-M M-D200
250
300
350
400
Bo
dy
wei
gh
t (g
)Q1: Is central BDNF expression regulated by estradiol?
11
12
13
14
15
Diest
rus
Proest
rus
Estru
s
Mete
stru
s
Diest
rus
*
Fo
od
inta
ke (
g)
240
242
244
246
248
Diest
rus
Proest
rus
Estru
s
Mete
stru
s
Bo
dy
wei
gh
t (g
)
Mal
e
Diest
rus
Proes
trus
Estru
s
Met
estru
s0
10
20
30
40
50
60*
**
Pla
sma
estr
adio
l lev
el(p
g/m
l)M
ale
Diest
rus
Proes
trus
Estru
s
Met
estru
s0
50
100
150
200
250 *
Bdnf
mR
NA
lev
el i
n V
MH
(% o
f m
ale)
Zhu, Liu, et al., Horm Behav 2014; Liu, Zhu, et al., Physiol Behav 2014
Summary 1Q1: Is central BDNF expression regulated by estradiol?
BDNF gene expression is regulated in an estradiol-sensitive manner.
• OVX decreases BDNF gene expression; reversed by estradiol replacement.
• Estrous female rats have greater BDNF expression than males.
• BDNF expression is dynamically regulated across estrous cycle with a temporal elevation at estrous phase.
Hypothesis: Central BDNF expression and action are regulated by estradiol.
Q1: Is central BDNF expression regulated by estradiol?Q2: Is central BDNF action regulated by estradiol?
VMH
3V
BDNF
Leptin
ARC
POMC
Expenditure Intake
estradiol
Clegg, et al., Diabetes 2006de Souza, et al., Eur J Pharmacol 2011Gao, et al., Nat Med 2007
Experiment groups
Male-OilSham-OilOVX-Oil ad libOVX-Oil pairfeed (PF) (pairfeed to Sham-Oil Female)OVX-E2
Q2: Is central BDNF action regulated by estradiol?
(1) Is central BDNF’s anorexic effect regulated by estradiol?
Experiment procedure
Lights i3vt Lights out; 4-hour 24-hourOn 0.1μg, 0.3μg food intake food intake
BDNF orvehicle
LightDarkLight
Plasma Estradiol Levels
Mal
e
Sham F
emal
e
OVX-Oil
Femal
e
OVX-Oil
PF Fem
ale
OVX-E2
Femal
e0
20
40
60
* **
Pla
sma
E2
leve
l (p
g/m
l)
Baseline 24-Hour Food Intake
Mal
e Sham
-Oil
Femal
e Sham
-Oil
OVX-Oil
OVX-Oil
PF
OVX-E2
0
5
10
15
20
25 *
Fo
od
Inta
ke (
g)
Baseline Body Weights
Mal
e Sham
-Oil
Femal
e Sham
-Oil
OVX-Oil
OVX-Oil
PF
OVX-E2
200
250
300
350
400 *
Bo
dy
Wei
gh
t (g
)
#
Zhu, Liu, et al., Horm Behav 2014
Q2: Is central BDNF action regulated by estradiol?
(1) Is central BDNF’s anorexic effect regulated by estradiol?
Mal
e Sham
-Oil
Femal
e Sham
-Oil
0
2
4
6
8 0 g BDNF0.1 g BDNF0.3 g BDNF
*
* *
4-h
ou
r fo
od
inta
ke (
g)
Mal
e Sham
-Oil
Femal
e Sham
-Oil
02468
1012141618202224 0 g BDNF
0.1 g BDNF0.3 g BDNF
*
* *
24-h
ou
r fo
od
inta
ke (
g)
Zhu, Liu, et al., Horm Behav 2014
Q2: Is central BDNF action regulated by estradiol?
(1) Is central BDNF’s anorexic effect regulated by estradiol?
OVX-E2
OVX-Oil
PF
OVX-Oil
0
2
4
6 0 g BDNF0.1 g BDNF0.3 g BDNF
* *
**
4-h
ou
r fo
od
inta
ke (
g)
OVX-E2
OVX-Oil
PF
OVX-Oil
02468
101214161820
0 g BDNF0.1 g BDNF0.3 g BDNF
* **
*
24-h
ou
r fo
od
inta
ke (
g)
Q2: Is central BDNF action regulated by estradiol?
(2) Does ovariectomy or estradiol replacement regulate BDNF’s
anorexic effect?
Zhu, Liu, et al., Horm Behav 2014
Experiment procedure
Lights i3vt Lights out; 24-hour On 0.1μg energy expenditure
BDNF or vehicle
LightDarkLight
Q2: Is central BDNF action regulated by estradiol?
(3) Is central BDNF’s effect on energy expenditure different between
males and females?
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
15
20
25
30
35
40
saline0.1 g BDNF
*
**
Time (hour)
VO
2 m
l/kg
BW
/min
Dark Light0
10
20
30
40
saline0.1 g BDNF
**
VO
2 m
l/kg
BW
/min
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 2415
20
25
30
35
40saline0.1 g BDNF
Time (hour)
VO
2 m
l/kg
BW
/min
Dark Light0
10
20
30
40 saline0.1 g BDNF
VO
2 m
l/kg
BW
/min
Male Rats
Dark Light
0.7
0.8
0.9
1.0 saline
0.1 g BDNF
RQ
*
Female Rats
Dark Light
0.7
0.8
0.9
1.0 saline
0.1 g BDNF
RQ
* *
Liu, Zhu, Shen, Shi. Unpublished.
Q2: Is central BDNF action regulated by estradiol?
(3) Is central BDNF’s effect on energy expenditure different between
males and females?
Summary 2Q2: Is central BDNF’s action regulated by estradiol?
• Estrous female rats respond to a lower dose of BDNF than male rats to reduce food intake.
• Estradiol-replaced OVX rats respond to a lower dose of BDNF than oil-injected OVX rats to reduce food intake.
• Central administration of a low dose (0.1 µg) of BDNF increased energy expenditure in female but not male rats.
• Central administration of a low dose (0.1 µg) of BDNF increased lipid oxidation during dark and light phases in females and only during light phase in males.
VMH
3V
BDNF
Leptin
ARC
POMC
Expenditure Intake
estradiol
ConclusionEstradiol increases BDNF central expression and action.
Acknowledgement
Graduate students:Zheng ZhuXian LiuMinqian ShenShiva Senthil-Kumar
Undergraduate students:Ashley Goudjo-AkoSean Pugh
SDG4520028
R15DK090823
Funding:
Summer research fellowship
Undergraduate research funding