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

The Rowett Institute of Nutrition and Health

Centro de Investigaciones Medicas de la Universidad de Santiago (CIMUS)

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

561 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
Number of pages	8
Journal	Nature Medicine
Volume	16
Issue number	9
DOIs	https://doi.org/10.1038/nm.2207
Publication status	Published - Sept 2010

Keywords

AMP-Activated Protein Kinases
Adipose Tissue, Brown
Agouti-Related Protein
Animals
Arcuate Nucleus of Hypothalamus
Cerulenin
Energy Metabolism
Fatty Acid Synthesis Inhibitors
Fatty Acids
Hyperphagia
Hyperthyroidism
Hypothalamus
Paraventricular Hypothalamic Nucleus
Pro-Opiomelanocortin
RNA, Messenger
Rats
Thermogenesis
Thyroid Gland
Thyrotropin-Releasing Hormone
Thyroxine
Triiodothyronine

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López, M., Varela, L., Vázquez, M. J., Rodríguez-Cuenca, S., González, C. R., Velagapudi, V. R., Morgan, D. A., Schoenmakers, E., Agassandian, K., Lage, R., Martínez de Morentin, P. B., Tovar, S., Nogueiras, R., Carling, D., Lelliott, C., Gallego, R., Oresic, 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(9), 1001-1008. https://doi.org/10.1038/nm.2207

López, M, Varela, L, Vázquez, MJ, Rodríguez-Cuenca, S, González, CR, Velagapudi, VR, Morgan, DA, Schoenmakers, E, Agassandian, K, Lage, R, Martínez de Morentin, PB, Tovar, S, Nogueiras, R, Carling, D, Lelliott, C, Gallego, R, Oresic, 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, no. 9, pp. 1001-1008. https://doi.org/10.1038/nm.2207

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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.",

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AU - López, Miguel

AU - Varela, Luis

AU - Vázquez, María J

AU - Rodríguez-Cuenca, Sergio

AU - González, Carmen R

AU - Velagapudi, Vidya R

AU - Morgan, Donald A

AU - Schoenmakers, Erik

AU - Agassandian, Khristofor

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 - Oresic, Matej

AU - Chatterjee, Krishna

AU - Saha, Asish K

AU - Rahmouni, Kamal

AU - Diéguez, Carlos

AU - Vidal-Puig, Antonio

PY - 2010/9

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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.

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KW - Animals

KW - Arcuate Nucleus of Hypothalamus

KW - Cerulenin

KW - Energy Metabolism

KW - Fatty Acid Synthesis Inhibitors

KW - Fatty Acids

KW - Hyperphagia

KW - Hyperthyroidism

KW - Hypothalamus

KW - Paraventricular Hypothalamic Nucleus

KW - Pro-Opiomelanocortin

KW - RNA, Messenger

KW - Rats

KW - Thermogenesis

KW - Thyroid Gland

KW - Thyrotropin-Releasing Hormone

KW - Thyroxine

KW - Triiodothyronine

U2 - 10.1038/nm.2207

DO - 10.1038/nm.2207

M3 - Article

C2 - 20802499

SN - 1078-8956

VL - 16

SP - 1001

EP - 1008

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

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

Abstract

Keywords

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