central control of metabolism by thyroid hormone · pdf filecentral control of metabolism by...

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


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


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


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


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


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)


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?


Central regulation of BAT thermogenesis

Whittle A et al (2012). TMM. 17:405-411


Central thyroid hormones and BAT thermogenesis


Classical peripheral view of thyroid thermogenesis

Cannon B & Nedergaard J (2010). Nat Med 16: 965-967


Thyroid hormones induce BAT thermogenesis

de Jesus LA et al (2001). JCI 108: 1379–1385


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


TRα1 aporeceptor mice

Sjögren et al (2007). EMBO J 26: 4535-4545

Warner et al (2013). PNAS 110: 16241–16246


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”


Does hypothalamic AMPK mediate thyroid-induced thermogenesis in BAT?

Hypothalamic AMPK, thyroid hormones and BAT thermogenesis


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


Stereotaxic administration in VMH and ARC

VMH

ARC

85-90%

75-80%

VMH

ARC


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)


T3 in the VMH inhibits AMPK signalling


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


T3 in the VMH activates SNS


∆∆ ∆∆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


New model of central T3 actions on energy balance


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


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


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


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


Central thyroid hormones and food intake


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)


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)



T3 in the ARC induces mTOR signalling


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)

****

**


New central view of thyroid hormones actions on energy balance


Thyroid gland

Energy expenditure

Body weight

BAT

Food intake

T3

AMPK

VMH

3V

ARCmTOR

NPYAgRP

Hypothalamus

POMC


Central thyroid hormones and glucose homeostasis


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)


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


Central thyroid hormones and cardiovascular function


Central T3 modulates cardiovascular function

Mittag et al (2013). JCI 123: 509-516

Forrest & West (2013). JCI 123: 117-120


Summary

“Take home message”

Thyroid hormones act within the hypothalamus to modulate energy balance, metabolism and cardiovascular function

through the autonomous nervous system


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


Miguel Ló[email protected]

Department of Physiology NeurObesity Group


central control of metabolism by thyroid hormone · pdf filecentral control of metabolism by...

Documents