NeurObesity Group Department of Physiology Central control of metabolism by thyroid hormone Miguel López m.lopez@usc.es 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 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)
Central regulation of energy balance Cerebral cortex Cerebral cortex Cerebral cortex NTS NTS Hypothalamus Hypothalamus WAT WAT Metabolic Metabolic Metabolic Leptin Leptin signals signals signals Insulin Insulin Ghrelin, PYY Ghrelin, PYY Pancreas Pancreas Vagus nerve Vagus nerve Liver Liver Gut signals Gut signals Gut signals 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 Hypothalamus PVH PVH PVH PVH LHA LHA LHA LHA Orexigenic neuropeptides (AgRP, NPY, DMH DMH DMH DMH DMH DMH MCH, OXs) Food intake Brain VMH VMH VMH VMH Anorexigenic neuropeptides POMC ARC ARC ARC ARC 3V 3V ( α -MSH), CART Autonomic Nervous System Hormonal and nutritional signals WAT BAT Liver Beta-cell Skeletal (pancreas) muscle Glucose and lipid metabolism Energy expenditure 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)
Hypothalamic AMPK: a whole body metabolic gauge PP2C α PP2C α α α α α α α LKB1 LKB1 TAK1 TAK1 CaMKK β CaMKK β Ca +2 Ca +2 Thr172 Thr172 AMP:ATP AMP:ATP α α α α α α α α γ γ Cidea Cidea β β AMPK AMPK ATP-consuming ATP-consuming ATP-producing ATP-producing Cellular level Cellular level processes processes processes processes Whole body Whole body Energy production Energy production Energy expenditure Energy expenditure level level (i.e. Food intake) (i.e. Food intake) Lage R et al (2008) TMM 14:539-549 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)
Hypothalamic AMPK modulates BAT thermogenesis role of SNS? role of SNS? � PT1B1: Protein tyrosine phosphatase 1B (attenuates leptin signaling by dephosphorylating JAK2) Xue B et al (2009). MCB 20:4563-4573 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)
Central thyroid hormones and BAT thermogenesis Could thyroid-induced thermogenesis be regulated at central level? Nedergaard J et al (1997). Ann N Y Acad Sci. 15:712-7. PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
TR α 1 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)
TR α 1 aporeceptor mice “Functional blockage (30 ºC) of sympathetic signaling to BAT normalizes the metabolic phenotype. Thus central signaling overrides peripheral action on thyroid hormones” 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)
Hypothalamic AMPK, thyroid hormones and BAT thermogenesis Does hypothalamic AMPK mediate thyroid-induced thermogenesis in BAT? 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 30 60 60 Vehicle ICV Vehicle ICV Body weight change (g) T3 ICV T3 ICV 50 50 20 Food intake (g) Food intake (g) 10 40 40 0 30 30 * *** -10 20 20 *** -20 10 10 -30 0 0 1 2 3 4 5 1 1 2 2 3 3 4 4 5 5 Time (d) Time (d) Time (d) Vehicle ICV Protein levels/ β -actin (% vehicle) Protein levels/ β -actin (% vehicle) mRNA levels/ Hprt (% vehicle ) mRNA levels/ Hprt (% vehicle ) T3 ICV 120 120 250 250 *** *** 100 100 200 200 ** ** ** ** *** *** 80 80 ** ** *** *** 150 150 60 60 100 100 40 40 50 50 20 20 0 0 0 0 pAMPK α AMPK α 1 AMPK α 2 pAMPK α AMPK α 1 AMPK α 2 pACC α pACC α ACC α ACC α PGC1 α PGC1 α PGC1 β PGC1 β UCP1 UCP1 UCP3 UCP3 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)
Stereotaxic administration in VMH and ARC VMH 85-90% VMH ARC 75-80% 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 200 200 20 UCP1 / β -actin (% Vehicle VMH) UCP1 / β -actin (% Vehicle VMH) ** ** Body weight change (g) 150 150 15 * 100 100 10 50 50 5 0 0 0 Vehicle VMH T3 VMH Vehicle VMH Vehicle VMH T3 VMH T3 VMH (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 VMH Vehicle T3 VMH Protein levels/ β -actin (% vehicle) pAMPK α pAMPK α 120 AMPK α 1 AMPK α 1 ¶ 100 ** * 80 AMPK α 2 AMPK α 2 60 pACC α 40 20 ACC α ACC α 0 pAMPK α AMPK α 1 AMPK α 2 pACC α ACC α β -actin β -actin Vehicle VMH T3 VMH 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 VMH activates SNS 300 300 Vehicle VMH T3 VMH 250 250 ∆ BAT SNA (%) 200 200 150 150 *** *** 100 100 50 50 ∆ ∆ ∆ 0 0 -50 -50 0 0 45 45 90 90 135 135 180 180 225 225 270 270 315 315 360 360 Time (min) Time (min) 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)
New model of central T3 actions on energy balance VMH Acetyl-CoA Hypothalamus ACC X AMPK Malonyl-CoA X FAS TR Complex lipids ARC ARC 3V 3V RPa IO T3 SNS SNS β 3-AR BAT Thyroid gland Ucp1 Ppargc1a Energy expenditure Ucp3 Ppargc1b Body weight Body weight 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)
BMP8B induces BAT thermogenesis through AMPK in the VMH Vehicle ICV BMP8B ICV Vehicle (ICV) BMP8B (ICV) Whittle AJ et al (2012). Cell 149:871-885 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Miguel Lopez)
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