Journal
CELL
Volume 151, Issue 3, Pages 645-657Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.09.020
Keywords
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Categories
Funding
- BNORC & BADERC Transgenic Core Grant [P30DK046200, P30DK057521]
- P&F from BADERC BNORC Grant [P30DK057521, P30DK0460200, R01 DK092605, AHA SDG3280017, NS0736313]
- [R01 DK089044]
- [R01 DK071051]
- [R01 DK075632]
- [R37 DK053477]
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Neural regulation of energy expenditure is incompletely understood. By genetically disrupting GABAergic transmission in a cell-specific fashion, and by combining this with selective pharmacogenetic activation and optogenetic mapping techniques, we have uncovered an arcuate-based circuit that selectively drives energy expenditure. Specifically, mice lacking synaptic GABA release from RIP-Cre neurons have reduced energy expenditure, become obese and are extremely sensitive to high-fat diet-induced obesity, the latter due to defective diet-induced thermogenesis. Leptin's ability to stimulate thermogenesis, but not to reduce feeding, is markedly attenuated. Acute, selective activation of arcuate GABAergic RIP-Cre neurons, which monosynaptically innervate PVH neurons projecting to the NTS, rapidly stimulates brown fat and increases energy expenditure but does not affect feeding. Importantly, this response is dependent upon GABA release from RIP-Cre neurons. Thus, GABAergic RIP-Cre neurons in the arcuate selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity.
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