Central control of metabolism by thyroid hormone Miguel Lpez - - PowerPoint PPT Presentation

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Central control of metabolism by thyroid hormone Miguel Lpez - - PowerPoint PPT Presentation

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NeurObesity Group Department of Physiology Central control of metabolism by thyroid hormone Miguel Lpez m.lopez@usc.es PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Department of Physiology

Central control of metabolism by thyroid hormone

Miguel López m.lopez@usc.es NeurObesity Group

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Disclosure Nothing to disclose

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Learning objectives

  • 1. Thyroid hormones regulate energy balance and metabolism

by acting at central level

  • 2. Thyroid hormones modulate the autonomous nervous

system

  • 3. Thyroid hormones modulate hypothalamic energy sensors

to regulate feeding

  • 4. Thyroid hormones modulate hypothalamic energy sensors

to regulate thermogenesis in BAT

  • 5. Thyroid hormones act on the hypothalamus to regulate

hepatic glucose metabolism

  • 6. Thyroid hormomes act on the hypothalmus to regulate

cardiac function

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Central regulation of energy balance

WAT Liver Vagus nerve

Gut signals

Hypothalamus Cerebral cortex

Metabolic signals

NTS

Leptin Insulin

Pancreas

Ghrelin, PYY

WAT Liver Vagus nerve

Gut signals Gut signals

Hypothalamus Cerebral cortex Cerebral cortex

Metabolic signals Metabolic signals

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)

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Hypothalamic regulation of energy balance and metabolism

Brain Hypothalamus

Liver Skeletal muscle BAT WAT Beta-cell (pancreas)

Autonomic Nervous System Glucose and lipid metabolism Energy expenditure Hormonal and nutritional signals

DMH

PVH PVH LHA LHA DMH DMH VMH VMH ARC ARC 3V

DMH

PVH PVH LHA LHA DMH DMH VMH VMH ARC ARC 3V

Food intake

Orexigenic neuropeptides (AgRP, NPY, MCH, OXs) Anorexigenic neuropeptides POMC (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)

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AMPK

LKB1 PP2Cα α α α

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

α α α α γ β

AMPK

LKB1 PP2Cα α α α

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

α α α α 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)

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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)

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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)

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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)

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Central thyroid hormones and BAT thermogenesis

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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)

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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)

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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)

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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)

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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)

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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)

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Central T3 inhibits hypothalamic AMPK and induces BAT thermogenesis

López M et al (2010). Nat Med 16: 1001-1008

Time (d)

  • 30
  • 20
  • 10

10 20 30

Body weight change (g)

1 2 3 4 5

* *** ***

10 20 30 40 50 60

Food intake (g) Time (d)

1 2 3 4 5 10 20 30 40 50 60

Food intake (g) Time (d)

1 2 3 4 5

Vehicle ICV T3 ICV Vehicle ICV T3 ICV

50 100 150 200 250 UCP1 UCP3 PGC1α

mRNA levels/Hprt (% vehicle)

*** ** **

PGC1β 50 100 150 200 250 UCP1 UCP3 PGC1α

mRNA levels/Hprt (% vehicle)

*** ** **

PGC1β 20 40 60 80 100 120 pAMPKα AMPKα1 AMPKα2 pACCα ACCα

Protein levels/β-actin (% vehicle)

*** ** ***

20 40 60 80 100 120 pAMPKα AMPKα1 AMPKα2 pACCα ACCα

Protein levels/β-actin (% vehicle)

*** ** ***

Vehicle ICV T3 ICV

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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)

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T3 in the VMH induces BAT thermogenesis and weight lost

50 100 150 200 Vehicle VMH T3 VMH

**

UCP1 /β-actin (% Vehicle VMH) 50 100 150 200 Vehicle VMH T3 VMH

**

UCP1 /β-actin (% Vehicle VMH)

*

5 10 15 20 Vehicle VMH T3 VMH Body weight change (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)

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T3 in the VMH inhibits AMPK signalling

López M et al (2010). Nat Med 16: 1001-1008

T3 VMH Vehicle pACCα ACCα ACCα β-actin β-actin AMPKα1 AMPKα1 AMPKα2 AMPKα2 pAMPKα pAMPKα

20 40 60 80 100 120 AMPKα1 AMPKα2 pACCα ACCα

Protein levels/β-actin (% vehicle)

pAMPKα

** *

VMH

Vehicle VMH T3 VMH

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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T3 in the VMH activates SNS

López M et al (2010). Nat Med 16: 1001-1008

∆ ∆ ∆ ∆ BAT SNA (%)

  • 50

50 100 150 200 250 300 45 90 135 180 225 270 315 360

Time (min)

***

  • 50

50 100 150 200 250 300 45 90 135 180 225 270 315 360

Time (min)

***

Vehicle T3 VMH

VMH

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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 RPa IO Body weight Body weight SNS 3V ARC

T3

Complex lipids Malonyl-CoA Acetyl-CoA

AMPK ACC FAS Ucp1 Ppargc1a Ppargc1b Ucp3 VMH

X X

TR β3-AR BAT

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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BMP8B induces BAT thermogenesis through AMPK in the VMH

Whittle AJ et al (2012). Cell 149:871-885

BMP8B (ICV) Vehicle (ICV)

Vehicle ICV BMP8B ICV

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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

Temperature change (ºC) 0.4 0.2 0.9 0.8 0.6 0.7 0.5 0.3 0.1

***

Veh Nic Temperature change (ºC) 0.4 0.2 0.9 0.8 0.6 0.7 0.5 0.3 0.1 0.4 0.2 0.9 0.8 0.6 0.7 0.5 0.3 0.1

***

Veh Nic mRNA levels/HPRT (% vehicle) 100 150 50 200 250 UCP1

* **

PGC1α PGC1β

**

mRNA levels/HPRT (% vehicle) 100 150 50 200 250 UCP1

* **

PGC1α PGC1β

**

mRNA levels/HPRT (% vehicle) 100 150 50 200 250 100 150 50 200 250 UCP1

* **

PGC1α PGC1β

**

Vehicle Nicotine

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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The hypothalamic AMPK-BAT axis: a canonical mechanism

Peripheral and central signals Energy expenditure SNS Hypothalamus 3V RPa IO Body weight Body weight SNS 3V Ucp1 Ppargc1a Ppargc1b Ucp3 β3-AR BAT

Acetyl-CoA

ACC VMH ARC ARC

Complex lipids Malonyl-CoA

AMPK FAS

X X

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Central thyroid hormones and food intake

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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)

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T3 in the ARC induces food intake

Varela L et al (2012). J Pathol 227:209-222

**

2 4 6 8 10 12 14 16

Food intake (g) Vehicle ARC T3 ARC

**

2 4 6 8 10 12 14 16

Food intake (g) Vehicle ARC T3 ARC

ARC VMH

Vehicle VMH T3 VMH Vehicle VMH T3 VMH

2 4 6 8 10 12 14 16

Food intake (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)

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T3 in the ARC induces mTOR signalling

Varela L et al (2012). J Pathol 227:209-222

Vehicle ARC T3 ARC

Euthyr Hyperthyr S6K1 S6K1 S6 S6 pS6K1 pS6K1 β-Actin β-Actin pS6 pS6 mTOR mTOR pmTOR Ser2448 pmTOR Ser2448 peiF4G peiF4G 20 40 60 80 100 120 140 160 180 pmTOR mTOR pS6K1 S6K1 pS6 S6 peif4G Protein levels/ß-Actin (% vehicle)

** ** **

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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

ARC

mTOR NPY AgRP

Hypothalamus

POMC

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Central thyroid hormones and glucose homeostasis

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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)

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Thyroid gland

Energy expenditure Body weight

BAT

Food intake

T3

AMPK

VMH

3V

ARC

mTOR NPY AgRPPOMC β3-AR

PVH

RPa IO SNS

Complex lipids? Malonyl-CoA?

Liver

Glucose production Insulin 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)

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Central thyroid hormones and cardiovascular function

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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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)

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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)

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Funded by:

Consortiums:

Starting Grants

Gema Medina-Gómez Sergio Rodríguez-Cuenca Erik Schoenmakers Andy Whittle Krish Chatterjee Toni Vidal-Puig Juan Roa Manuel Tena-Sempere Diego Pérez-Tilve Matthias Tschöp Pablo Blanco Noelia Martínez Ricardo Lage Luís Martins Luis Varela

Clara Álvarez Rubén Nogueiras Carlos Diéguez

Donald Morgan Kamal Rahmouni David Carling Johan Fernø

University of Bergen University of Bergen

Andries Kalsbeek Eric Fliers Sara Ramírez Nuria Casals

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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Miguel López m.lopez@usc.es

Department of Physiology

NeurObesity Group

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)

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PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)