G s α deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling

Min Chen, Eric A. Wilson, Zhenzhong Cui, Hui (Herb) Sun, Yogendra B. Shrestha, Brandon Podyma, Christina H. Le, Benedetta Naglieri, Karel Pacak, Oksana Gavrilova, Lee S. Weinstein

Research output: Contribution to journalArticle

Abstract

Objective: G s α couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating G s α mutations lead to obesity in humans and mice. Mice with brain-specific G s α deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Methods: We created mice (DMHGsKO) with G s α deficiency limited to the dorsomedial hypothalamus (DMH) and examined the effects on energy balance and thermogenesis. Results: DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/G s α signaling contributes to abnormal energy balance but not to abnormal locomotor activity or cold-induced thermogenesis. Instead, DMHGsKO mice had impaired leptin signaling along with increased expression of the leptin signaling inhibitor protein tyrosine phosphatase 1B in the DMH, which likely contributes to the observed hyperphagia and reductions in energy expenditure, locomotor activity, and cold-induced thermogenesis. Conclusions: DMH G s α signaling is critical for energy balance, thermogenesis, and leptin signaling. This study provides insight into how distinct signaling pathways can interact to regulate energy homeostasis and temperature regulation.

Original languageEnglish (US)
JournalMolecular Metabolism
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Hyperphagia
Thermogenesis
Leptin
Hypothalamus
Obesity
Receptor, Melanocortin, Type 4
Locomotion
Energy Metabolism
Non-Receptor Type 1 Protein Tyrosine Phosphatase
Brown Adipose Tissue
Homeostasis
Mutation
Temperature
Brain

Keywords

  • G protein
  • Hypothalamus
  • Obesity
  • Sympathetic nervous system
  • Thermogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

G s α deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling . / Chen, Min; Wilson, Eric A.; Cui, Zhenzhong; Sun, Hui (Herb); Shrestha, Yogendra B.; Podyma, Brandon; Le, Christina H.; Naglieri, Benedetta; Pacak, Karel; Gavrilova, Oksana; Weinstein, Lee S.

In: Molecular Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

Chen, Min ; Wilson, Eric A. ; Cui, Zhenzhong ; Sun, Hui (Herb) ; Shrestha, Yogendra B. ; Podyma, Brandon ; Le, Christina H. ; Naglieri, Benedetta ; Pacak, Karel ; Gavrilova, Oksana ; Weinstein, Lee S. / G s α deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling In: Molecular Metabolism. 2019.
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abstract = "Objective: G s α couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating G s α mutations lead to obesity in humans and mice. Mice with brain-specific G s α deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Methods: We created mice (DMHGsKO) with G s α deficiency limited to the dorsomedial hypothalamus (DMH) and examined the effects on energy balance and thermogenesis. Results: DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/G s α signaling contributes to abnormal energy balance but not to abnormal locomotor activity or cold-induced thermogenesis. Instead, DMHGsKO mice had impaired leptin signaling along with increased expression of the leptin signaling inhibitor protein tyrosine phosphatase 1B in the DMH, which likely contributes to the observed hyperphagia and reductions in energy expenditure, locomotor activity, and cold-induced thermogenesis. Conclusions: DMH G s α signaling is critical for energy balance, thermogenesis, and leptin signaling. This study provides insight into how distinct signaling pathways can interact to regulate energy homeostasis and temperature regulation.",
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author = "Min Chen and Wilson, {Eric A.} and Zhenzhong Cui and Sun, {Hui (Herb)} and Shrestha, {Yogendra B.} and Brandon Podyma and Le, {Christina H.} and Benedetta Naglieri and Karel Pacak and Oksana Gavrilova and Weinstein, {Lee S.}",
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AU - Chen, Min

AU - Wilson, Eric A.

AU - Cui, Zhenzhong

AU - Sun, Hui (Herb)

AU - Shrestha, Yogendra B.

AU - Podyma, Brandon

AU - Le, Christina H.

AU - Naglieri, Benedetta

AU - Pacak, Karel

AU - Gavrilova, Oksana

AU - Weinstein, Lee S.

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N2 - Objective: G s α couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating G s α mutations lead to obesity in humans and mice. Mice with brain-specific G s α deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Methods: We created mice (DMHGsKO) with G s α deficiency limited to the dorsomedial hypothalamus (DMH) and examined the effects on energy balance and thermogenesis. Results: DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/G s α signaling contributes to abnormal energy balance but not to abnormal locomotor activity or cold-induced thermogenesis. Instead, DMHGsKO mice had impaired leptin signaling along with increased expression of the leptin signaling inhibitor protein tyrosine phosphatase 1B in the DMH, which likely contributes to the observed hyperphagia and reductions in energy expenditure, locomotor activity, and cold-induced thermogenesis. Conclusions: DMH G s α signaling is critical for energy balance, thermogenesis, and leptin signaling. This study provides insight into how distinct signaling pathways can interact to regulate energy homeostasis and temperature regulation.

AB - Objective: G s α couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating G s α mutations lead to obesity in humans and mice. Mice with brain-specific G s α deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Methods: We created mice (DMHGsKO) with G s α deficiency limited to the dorsomedial hypothalamus (DMH) and examined the effects on energy balance and thermogenesis. Results: DMHGsKO mice developed severe, early-onset obesity associated with hyperphagia and reduced energy expenditure and locomotor activity, along with impaired brown adipose tissue thermogenesis. Studies in mice with loss of MC4R in the DMH suggest that defective DMH MC4R/G s α signaling contributes to abnormal energy balance but not to abnormal locomotor activity or cold-induced thermogenesis. Instead, DMHGsKO mice had impaired leptin signaling along with increased expression of the leptin signaling inhibitor protein tyrosine phosphatase 1B in the DMH, which likely contributes to the observed hyperphagia and reductions in energy expenditure, locomotor activity, and cold-induced thermogenesis. Conclusions: DMH G s α signaling is critical for energy balance, thermogenesis, and leptin signaling. This study provides insight into how distinct signaling pathways can interact to regulate energy homeostasis and temperature regulation.

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