Department of Physiology Central control of metabolism by thyroid hormone Miguel López [email protected] NeurObesity Group PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Feb 17, 2018
Department of Physiology
Central control of metabolism by thyroid hormone
Miguel Ló[email protected]
NeurObesity Group
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Disclosure
Nothing to disclose
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Learning objectives
1. Thyroid hormones regulate energy balance and metabolismby acting at central level
2. Thyroid hormones modulate the autonomous nervoussystem
3. Thyroid hormones modulate hypothalamic energy sensorsto regulate feeding
4. Thyroid hormones modulate hypothalamic energy sensorsto regulate thermogenesis in BAT
5. Thyroid hormones act on the hypothalamus to regulatehepatic glucose metabolism
6. Thyroid hormomes act on the hypothalmus to regulatecardiac function
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central regulation of energy balance
WAT
Liver
Vagus nerve
Gut signals
Hypothalamus
Cerebral cortex
Metabolicsignals
NTS
Leptin
Insulin
Pancreas
Ghrelin, PYY
WAT
Liver
Vagus nerve
Gut signalsGut signals
Hypothalamus
Cerebral cortexCerebral cortex
Metabolicsignals
Metabolicsignals
NTS
Leptin
Insulin
Pancreas
Ghrelin, PYY
Modified from Schwartz M et al (2000). Nature 404:661-671
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Hypothalamic regulation of energy balance and metabolism
Brain
Hypothalamus
Liver Skeletal muscle
BATWATBeta-cell (pancreas)
Autonomic Nervous System
Glucose and lipid metabolism Energy expenditure
Hormonal and nutritional signals
DMH
PVH PVHLHALHA
DMH DMH
VMH VMH
ARC ARC3V
DMH
PVH PVHLHALHA
DMH DMH
VMH VMH
ARC ARC3V
Food intake
Orexigenic neuropeptides(AgRP, NPY, MCH, OXs)
Anorexigenic neuropeptidesPOMC (α-MSH), CART
López et al (2013). TMM 19: 418-427
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
AMPK
LKB1 PP2Cαααα
Thr172
Ca+2
ATP-producing processes
ATP-consuming processes
Energy production (i.e. Food intake)
Energy expenditure
Cellular level
Whole body level
CaMKKβ
Cidea
AMP:ATP
TAK1
αααα γ
β
AMPK
LKB1 PP2Cαααα
Thr172
Ca+2
ATP-producing processes
ATP-consuming processes
Energy production (i.e. Food intake)
Energy expenditure
Cellular level
Whole body level
CaMKKβ
Cidea
AMP:ATP
TAK1
αααα γ
β
Lage R et al (2008) TMM 14:539-549
Hypothalamic AMPK: a whole body metabolic gauge
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Hypothalamic AMPK modulates food intake
Andersson M et al (2004) JBC 279:12005-12008
Sakkou M et al (2007) Cell Metab 5, 450-463
Kola M et al (2008) PLoS ONE 3:e1797
López M et al (2008) Cell Metab 7:389-399
Andrews ZB et al (2008) Nature 454:846-851
Lage R et al (2010) FASEB J 24:2670-2679
Velásquez DA et al (2011) Diabetes 60:1177-85
Ramírez S et al (2013) Diabetes (in press)
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Xue B et al (2009). MCB 20:4563-4573
Hypothalamic AMPK modulates BAT thermogenesis
� PT1B1: Protein tyrosine phosphatase 1B (attenuates leptin signaling by dephosphorylating JAK2)
role of SNS?role of SNS?
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central regulation of BAT thermogenesis
Whittle A et al (2012). TMM. 17:405-411
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central thyroid hormones and BAT thermogenesis
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Classical peripheral view of thyroid thermogenesis
Cannon B & Nedergaard J (2010). Nat Med 16: 965-967
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Thyroid hormones induce BAT thermogenesis
de Jesus LA et al (2001). JCI 108: 1379–1385
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Nedergaard J et al (1997). Ann N Y Acad Sci. 15:712-7.
Could thyroid-induced thermogenesis be regulated at central level?
Central thyroid hormones and BAT thermogenesis
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
TRα1 aporeceptor mice
Sjögren et al (2007). EMBO J 26: 4535-4545
Warner et al (2013). PNAS 110: 16241–16246
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
TRα1 aporeceptor mice
Sjögren et al (2007). EMBO J 26: 4535-4545
Warner et al (2013). PNAS 110: 16241–16246
“Functional blockage (30 ºC) of sympathetic signaling to BAT normalizes the metabolic
phenotype. Thus central signaling overrides peripheral action on thyroid hormones”
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Does hypothalamic AMPK mediate thyroid-induced thermogenesis in BAT?
Hypothalamic AMPK, thyroid hormones and BAT thermogenesis
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central T3 inhibits hypothalamic AMPK and induces BAT thermogenesis
López M et al (2010). Nat Med 16: 1001-1008
Time (d)
-30
-20
-10
0
10
20
30
Bod
y w
eigh
t cha
nge
(g)
1 2 3 4 5
* ******
0
10
20
30
40
50
60
Foo
d in
take
(g)
Time (d)
1 2 3 4 50
10
20
30
40
50
60
Foo
d in
take
(g)
Time (d)
1 2 3 4 5
Vehicle ICVT3 ICVVehicle ICVT3 ICV
0
50
100
150
200
250
UCP1 UCP3 PGC1αm
RN
A le
vels
/Hpr
t(%
veh
icle
)
***
****
PGC1β0
50
100
150
200
250
UCP1 UCP3 PGC1αm
RN
A le
vels
/Hpr
t(%
veh
icle
)
***
****
PGC1β0
20
40
60
80
100
120
pAMPKα AMPKα1 AMPKα2 pACCα ACCα
Pro
tein
leve
ls/β
-act
in(%
veh
icle
)
********
0
20
40
60
80
100
120
pAMPKα AMPKα1 AMPKα2 pACCα ACCα
Pro
tein
leve
ls/β
-act
in(%
veh
icle
)
********
Vehicle ICVT3 ICV
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Stereotaxic administration in VMH and ARC
VMH
ARC
85-90%
75-80%
VMH
ARC
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the VMH induces BAT thermogenesis and weight lost
0
50
100
150
200
Vehicle VMH T3 VMH
**
UC
P1
/β-a
ctin
(%
Veh
icle
VM
H)
0
50
100
150
200
Vehicle VMH T3 VMH
**
UC
P1
/β-a
ctin
(%
Veh
icle
VM
H)
*
0
5
10
15
20
Vehicle VMH T3 VMH
Bod
y w
eigh
tcha
nge
(g)
(no changes in the ARC were found)
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the VMH inhibits AMPK signalling
López M et al (2010). Nat Med 16: 1001-1008
T3 VMHVehicle
pACCα
ACCαACCα
β-actinβ-actin
AMPKα1AMPKα1
AMPKα2AMPKα2
pAMPKαpAMPKα
0
20
40
60
80
100
120
AMPKα1 AMPKα2 pACCα ACCαPro
tein
leve
ls/β
-act
in(%
veh
icle
)pAMPKα
** *¶
VMH
Vehicle VMHT3 VMH
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the VMH activates SNS
López M et al (2010). Nat Med 16: 1001-1008
∆∆ ∆∆B
AT
SN
A (
%)
-50
0
50
100
150
200
250
300
0 45 90 135 180 225 270 315 360
Time (min)
***
-50
0
50
100
150
200
250
300
0 45 90 135 180 225 270 315 360
Time (min)
***
VehicleT3 VMH
VMH
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
New model of central T3 actions on energy balance
López M et al (2010). Nat Med 16: 1001-1008
Thyroid gland
Energy expenditure
SNS
Hypothalamus
3V
ARC
RPaIO
Body weightBody weight
SNS
3V
ARC
T3
Complexlipids
Malonyl-CoA
Acetyl-CoA
AMPK
ACC
FAS
Ucp1 Ppargc1a
Ppargc1bUcp3
VMH
X
XTR
β3-AR
BAT
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
BMP8B induces BAT thermogenesis through AMPK in the VMH
Whittle AJ et al (2012). Cell 149:871-885
BMP8B (ICV)Vehicle (ICV)
Vehicle ICVBMP8B ICV
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
39 ºC
26 ºC
Vehicle Nicotine
BAT
39 ºC
26 ºC
39 ºC
26 ºC
Vehicle Nicotine
BAT
Martínez de Morentin PB et al (2012). Diabetes 61:807-817
Nicotine induces BAT thermogenesis through AMPK in the VMH
Tem
pera
ture
chan
ge(º
C)
0
0.4
0.2
0.90.8
0.60.7
0.5
0.3
0.1
***
Veh Nic
Tem
pera
ture
chan
ge(º
C)
0
0.4
0.2
0.90.8
0.60.7
0.5
0.3
0.10
0.4
0.2
0.90.8
0.60.7
0.5
0.3
0.1
***
Veh Nic
mR
NA
leve
ls/H
PR
T (
% v
ehic
le)
100
0
150
50
200
250
UCP1
*
**
PGC1α PGC1β
**
mR
NA
leve
ls/H
PR
T (
% v
ehic
le)
100
0
150
50
200
250
UCP1
*
**
PGC1α PGC1β
**
mR
NA
leve
ls/H
PR
T (
% v
ehic
le)
100
0
150
50
200
250
100
0
150
50
200
250
UCP1
*
**
PGC1α PGC1β
**
VehicleNicotine
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
The hypothalamic AMPK-BAT axis: a canonical mechanism
Peripheral and central signals
Energy expenditure
SNS
Hypothalamus
3V
RPaIO
Body weightBody weight
SNS
3V
Ucp1 Ppargc1a
Ppargc1bUcp3
β3-AR
BAT
Acetyl-CoA
ACC
VMH
ARCARC
Complexlipids
Malonyl-CoA AMPK
FAS
X
X
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central thyroid hormones and food intake
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Hypothalamic mTOR: a whole body energy sensor
Woods et al (2008). Annu.Rev.Nutr. 28: 295-311
Cota D et al (2006). Science 312: 927-930 Varela L et al (2012). J Pathol 227:209-222
Martínez de Morentin PB et al (2013). Current Mol Med (in press)
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the ARC induces food intake
Varela L et al (2012). J Pathol 227:209-222
**
0
2
4
6
8
10
12
14
16
Fo
od
inta
ke (
g)
Vehicle ARC T3 ARC
**
0
2
4
6
8
10
12
14
16
Fo
od
inta
ke (
g)
Vehicle ARC T3 ARC
ARCVMH
Vehicle VMH T3 VMHVehicle VMH T3 VMH02
4
68
10
12
1416
Foo
din
take
(g)
López M et al (2010). Nat Med 16: 1001-1008
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the ARC induces mTOR signalling
Varela L et al (2012). J Pathol 227:209-222
Vehicle ARCT3 ARC
Euthyr Hyperthyr
S6K1S6K1
S6S6
pS6K1pS6K1
β-Actinβ-Actin
pS6pS6
mTORmTOR
pmTOR Ser2448pmTOR Ser2448
peiF4GpeiF4G 0
20
40
60
80
100
120
140
160
180
pmTOR mTOR pS6K1 S6K1 pS6 S6 peif4G
Pro
tein
leve
ls/ß
-Ac
tin (
% v
ehic
le)
****
**
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
New central view of thyroid hormones actions on energy balance
Varela L et al (2012). J Pathol 227:209-222
Thyroid gland
Energy expenditure
Body weight
BAT
Food intake
T3
AMPK
VMH
3V
ARCmTOR
NPYAgRP
Hypothalamus
POMC
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central thyroid hormones and glucose homeostasis
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
T3 in the PVH induces hepatic glucose production through SNS
Fliers E et al (2012). TEM 21:230-236
Klieverik LP et al (2008). AJP-EM 295:E513-E520
Klieverik LP et al (2009). PNAS 106:5966-5971
(effect independent of plasma T3, insulin, glucagon and CORT)
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Thyroid gland
Energy expenditure
Body weight
BAT
Food intake
T3
AMPK
VMH
3V
ARCmTOR
NPYAgRP
POMC
β3-AR
PVH
RPaIO
SNS
Complex lipids?Malonyl-CoA?
Liver
Glucose productionInsulin resistance
DMV
PSNS (vagus nerve)SNS
IML
AMPK?mTOR?
UCP2
T4
T3
T4
T3
Plasma Plasma
Energy balance regulation by thyroid hormones at central level
López et al (2013). TMM 19: 418-427
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central thyroid hormones and cardiovascular function
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Central T3 modulates cardiovascular function
Mittag et al (2013). JCI 123: 509-516
Forrest & West (2013). JCI 123: 117-120
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Summary
“Take home message”
Thyroid hormones act within the hypothalamus to modulate energy balance, metabolism and cardiovascular function
through the autonomous nervous system
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Funded by:
Consortiums:
Starting Grants
Gema Medina-GómezSergio Rodríguez-Cuenca
Erik SchoenmakersAndy Whittle
Krish ChatterjeeToni Vidal-Puig
Juan RoaManuel Tena-Sempere
Diego Pérez-TilveMatthias Tschöp
Pablo BlancoNoelia MartínezRicardo LageLuís MartinsLuis Varela
Clara ÁlvarezRubén NogueirasCarlos Diéguez
Donald MorganKamal Rahmouni
David Carling Johan Fern ø
University of BergenUniversity of Bergen
Andries KalsbeekEric Fliers
Sara RamírezNuria Casals
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
Miguel Ló[email protected]
Department of Physiology NeurObesity Group
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)