Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling
Objective: Gsα couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating Gsα mutations lead to obesity in humans and mice. Mice with brain-specific Gsα deficiency also develop obesity with reduced energy expenditure and locomoto...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-07-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877819302856 |
| _version_ | 1818338716755689472 |
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| author | Min Chen Eric A. Wilson Zhenzhong Cui Hui Sun Yogendra B. Shrestha Brandon Podyma Christina H. Le Benedetta Naglieri Karel Pacak Oksana Gavrilova Lee S. Weinstein |
| author_facet | Min Chen Eric A. Wilson Zhenzhong Cui Hui Sun Yogendra B. Shrestha Brandon Podyma Christina H. Le Benedetta Naglieri Karel Pacak Oksana Gavrilova Lee S. Weinstein |
| author_sort | Min Chen |
| collection | DOAJ |
| description | Objective: Gsα couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating Gsα mutations lead to obesity in humans and mice. Mice with brain-specific Gsα 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 Gsα 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/Gsα 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 Gsα 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. Keywords: G protein, Obesity, Thermogenesis, Hypothalamus, Sympathetic nervous system |
| first_indexed | 2024-12-13T15:15:32Z |
| format | Article |
| id | doaj.art-89acb52d5bae4dd38d177087aca8704b |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-13T15:15:32Z |
| publishDate | 2019-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-89acb52d5bae4dd38d177087aca8704b2022-12-21T23:40:44ZengElsevierMolecular Metabolism2212-87782019-07-0125142153Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signalingMin Chen0Eric A. Wilson1Zhenzhong Cui2Hui Sun3Yogendra B. Shrestha4Brandon Podyma5Christina H. Le6Benedetta Naglieri7Karel Pacak8Oksana Gavrilova9Lee S. Weinstein10Metabolic Diseases Branch, Bethesda, MD, 20892, USA; Corresponding author. NIDDK/NIH, Bldg 10 Rm 8C101, 10 Center Drive, Bethesda, MD, 20892-1752, USA.Metabolic Diseases Branch, Bethesda, MD, 20892, USAMouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USASection on Medical Neuroendocrinology, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USAMouse Metabolism Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USAMetabolic Diseases Branch, Bethesda, MD, 20892, USA; Corresponding author. NIDDK/NIH, Bldg 10 Rm 8C101, 10 Center Drive, Bethesda, MD, 20892-1752, USA.Objective: Gsα couples multiple receptors, including the melanocortin 4 receptor (MC4R), to intracellular cAMP generation. Germline inactivating Gsα mutations lead to obesity in humans and mice. Mice with brain-specific Gsα 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 Gsα 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/Gsα 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 Gsα 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. Keywords: G protein, Obesity, Thermogenesis, Hypothalamus, Sympathetic nervous systemhttp://www.sciencedirect.com/science/article/pii/S2212877819302856 |
| spellingShingle | Min Chen Eric A. Wilson Zhenzhong Cui Hui Sun Yogendra B. Shrestha Brandon Podyma Christina H. Le Benedetta Naglieri Karel Pacak Oksana Gavrilova Lee S. Weinstein Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling Molecular Metabolism |
| title | Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling |
| title_full | Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling |
| title_fullStr | Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling |
| title_full_unstemmed | Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling |
| title_short | Gsα deficiency in the dorsomedial hypothalamus leads to obesity, hyperphagia, and reduced thermogenesis associated with impaired leptin signaling |
| title_sort | gsα deficiency in the dorsomedial hypothalamus leads to obesity hyperphagia and reduced thermogenesis associated with impaired leptin signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2212877819302856 |
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