Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Miguel López; Luis Varela; María J. Vázquez; Sergio Rodríguez-Cuenca; Carmen R. González; Vidya Velagapudi; Donald A. Morgan; Erik Schoenmakers; Kristofor Agassandian; Ricardo Lage; Pablo Blanco Martínez de Morentin; Sulay Tovar; Rubén Nogueiras; David Carling; Christopher Lelliott; Rosalía Gallego; Matej Orešič; Krishna Chatterjee; Asish K. Saha; Kamal Rahmouni; Carlos Diéguez; Antonio Vidal-Puig

doi:10.1038/nm.2207

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Miguel López (Corresponding Author), Luis Varela, María J. Vázquez, Sergio Rodríguez-Cuenca, Carmen R. González, Vidya Velagapudi, Donald A. Morgan, Erik Schoenmakers, Kristofor Agassandian, Ricardo Lage, Pablo Blanco Martínez de Morentin, Sulay Tovar, Rubén Nogueiras, David Carling, Christopher Lelliott, Rosalía Gallego, Matej Orešič, Krishna Chatterjee, Asish K. Saha, Kamal RahmouniCarlos Diéguez, Antonio Vidal-Puig (Corresponding Author)

VTT Technical Research Centre of Finland

Research output: Contribution to journal › Article › Scientific › peer-review

582 Citations (Scopus)

Abstract

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

Original language	English
Pages (from-to)	1001-1008
Journal	Nature Medicine
Volume	16
DOIs	https://doi.org/10.1038/nm.2207
Publication status	Published - 2010
MoE publication type	A1 Journal article-refereed

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López, M., Varela, L., Vázquez, M. J., Rodríguez-Cuenca, S., González, C. R., Velagapudi, V., Morgan, D. A., Schoenmakers, E., Agassandian, K., Lage, R., Martínez de Morentin, P. B., Tovar, S., Nogueiras, R., Carling, D., Lelliott, C., Gallego, R., Orešič, M., Chatterjee, K., Saha, A. K., ... Vidal-Puig, A. (2010). Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nature Medicine, 16, 1001-1008. https://doi.org/10.1038/nm.2207

@article{a55a2dea2d3a4973916a865a7de445e6,

title = "Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance",

abstract = "Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.",

author = "Miguel L{\'o}pez and Luis Varela and V{\'a}zquez, {Mar{\'i}a J.} and Sergio Rodr{\'i}guez-Cuenca and Gonz{\'a}lez, {Carmen R.} and Vidya Velagapudi and Morgan, {Donald A.} and Erik Schoenmakers and Kristofor Agassandian and Ricardo Lage and {Mart{\'i}nez de Morentin}, {Pablo Blanco} and Sulay Tovar and Rub{\'e}n Nogueiras and David Carling and Christopher Lelliott and Rosal{\'i}a Gallego and Matej Ore{\v s}i{\v c} and Krishna Chatterjee and Saha, {Asish K.} and Kamal Rahmouni and Carlos Di{\'e}guez and Antonio Vidal-Puig",

year = "2010",

doi = "10.1038/nm.2207",

language = "English",

volume = "16",

pages = "1001--1008",

journal = "Nature Medicine",

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López, M, Varela, L, Vázquez, MJ, Rodríguez-Cuenca, S, González, CR, Velagapudi, V, Morgan, DA, Schoenmakers, E, Agassandian, K, Lage, R, Martínez de Morentin, PB, Tovar, S, Nogueiras, R, Carling, D, Lelliott, C, Gallego, R, Orešič, M, Chatterjee, K, Saha, AK, Rahmouni, K, Diéguez, C & Vidal-Puig, A 2010, 'Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance', Nature Medicine, vol. 16, pp. 1001-1008. https://doi.org/10.1038/nm.2207

TY - JOUR

T1 - Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

AU - López, Miguel

AU - Varela, Luis

AU - Vázquez, María J.

AU - Rodríguez-Cuenca, Sergio

AU - González, Carmen R.

AU - Velagapudi, Vidya

AU - Morgan, Donald A.

AU - Schoenmakers, Erik

AU - Agassandian, Kristofor

AU - Lage, Ricardo

AU - Martínez de Morentin, Pablo Blanco

AU - Tovar, Sulay

AU - Nogueiras, Rubén

AU - Carling, David

AU - Lelliott, Christopher

AU - Gallego, Rosalía

AU - Orešič, Matej

AU - Chatterjee, Krishna

AU - Saha, Asish K.

AU - Rahmouni, Kamal

AU - Diéguez, Carlos

AU - Vidal-Puig, Antonio

PY - 2010

Y1 - 2010

N2 - Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

AB - Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone–induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

U2 - 10.1038/nm.2207

DO - 10.1038/nm.2207

M3 - Article

SN - 1078-8956

VL - 16

SP - 1001

EP - 1008

JO - Nature Medicine

JF - Nature Medicine

ER -

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Abstract

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