Dataset Information

Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

ABSTRACT: The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TR?) is expressed in the ventromedial hypothalamus (VMH), a brain area important for control of energy homeostasis. Here, we report that selective knockdown of TR? in the VMH of adult mice results in severe obesity due to hyperphagia and reduced energy expenditure. The observed increase in body weight is of a similar magnitude to murine models of the most extreme forms of monogenic obesity. These data identify TR? in the VMH as a major physiological regulator of food intake and energy homeostasis.

SUBMITTER: Hameed S

PROVIDER: S-EPMC5478879 | biostudies-other | 2017 Jun

REPOSITORIES: biostudies-other

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Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

Hameed Saira S Patterson Michael M Dhillo Waljit S WS Rahman Sofia A SA Ma Yue Y Holton Christopher C Gogakos Apostolos A Yeo Giles S H GSH Lam Brian Y H BYH Polex-Wolf Joseph J Fenske Wiebke W Bell Jimmy J Anastasovska Jelena J Samarut Jacques J Bloom Stephen R SR Bassett J H Duncan JHD Williams Graham R GR Gardiner James V JV

Cell reports 20170601 11

The obesity epidemic is a significant global health issue. Improved understanding of the mechanisms that regulate appetite and body weight will provide the rationale for the design of anti-obesity therapies. Thyroid hormones play a key role in metabolic homeostasis through their interaction with thyroid hormone receptors (TRs), which function as ligand-inducible transcription factors. The TR-beta isoform (TRβ) is expressed in the ventromedial hypothalamus (VMH), a brain area important for contro ...[more]

PMID: 28614708

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Project description:Prolyl carboxypeptidase (PRCP) plays a role in the regulation of energy metabolism by inactivating hypothalamic ?-melanocyte stimulating hormone (?-MSH) levels. Although detected in the arcuate nucleus, limited PRCP expression has been observed in the arcuate POMC neurons, and its site of action in regulating metabolism is still ill-defined.We performed immunostaining to assess the localization of PRCP in arcuate Neuropeptide Y/Agouti-related Peptide (NPY/AgRP) neurons. Hypothalamic explants were then used to assess the intracellular localization of PRCP and its release at the synaptic levels. Finally, we generated a mouse model to assess the role of PRCP in NPY/AgRP neurons of the arcuate nucleus in the regulation of metabolism.Here we show that PRCP is expressed in NPY/AgRP-expressing neurons of the arcuate nucleus. In hypothalamic explants, stimulation by ghrelin increased PRCP concentration in the medium and decreased PRCP content in synaptic extract, suggesting that PRCP is released at the synaptic level. In support of this, hypothalamic explants from mice with selective deletion of PRCP in AgRP neurons (PrcpAgRPKO) showed reduced ghrelin-induced PRCP concentration in the medium compared to controls mice. Furthermore, male PrcpAgRPKO mice had decreased body weight and fat mass compared to controls. However, this phenotype was sex-specific as female PrcpAgRPKO mice show metabolic differences only when challenged by high fat diet feeding. The improved metabolism of PrcpAgRPKO mice was associated with reduced food intake and increased energy expenditure, locomotor activity, and hypothalamic ?-MSH levels. Administration of SHU9119, a potent melanocortin receptor antagonist, selectively in the PVN of PrcpAgRPKO male mice increased food intake to a level similar to that of control mice.Altogether, our data indicate that PRCP is released at the synaptic levels and that PRCP in AgRP neurons contributes to the modulation of ?-MSH degradation and related metabolic control in mice.

Dataset Information

Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

Publications

Thyroid Hormone Receptor Beta in the Ventromedial Hypothalamus Is Essential for the Physiological Regulation of Food Intake and Body Weight.

Similar Datasets

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