GABAergic RIP-Cre Neurons in the Arcuate Nucleus Selectively Regulate Energy Expenditure

Cell. 2012 Oct 26;151(3):645-57. doi: 10.1016/j.cell.2012.09.020.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Arcuate Nucleus of Hypothalamus / cytology
  • Arcuate Nucleus of Hypothalamus / metabolism*
  • Diet
  • Energy Metabolism*
  • GABAergic Neurons / metabolism*
  • Integrases / metabolism
  • Leptin / metabolism
  • Mice
  • Neural Pathways*
  • Obesity / metabolism
  • Paraventricular Hypothalamic Nucleus / cytology
  • Paraventricular Hypothalamic Nucleus / metabolism
  • Vesicular Glutamate Transport Protein 2 / metabolism
  • Vesicular Inhibitory Amino Acid Transport Proteins / genetics
  • Vesicular Inhibitory Amino Acid Transport Proteins / metabolism

Substances

  • Leptin
  • Slc17a6 protein, mouse
  • Vesicular Glutamate Transport Protein 2
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • Cre recombinase
  • Integrases