SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity

Giorgio Ramadori, Teppei Fujikawa, Makoto Fukuda, Jason Anderson, Donald A. Morgan, Raul Mostoslavsky, Ronald C. Stuart, Mario Perello, Claudia R. Vianna, Eduardo A. Nillni, Kamal Rahmouni, Roberto Coppari

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Feeding on high-calorie (HC) diets induces serious metabolic imbalances, including obesity. Understanding the mechanisms against excessive body weight gain is critical for developing effective antiobesity strategies. Here we show that lack of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1 in pro-opiomelanocortin (POMC) neurons causes hypersensitivity to diet-induced obesity due to reduced energy expenditure. The ability of leptin to properly engage the phosphoinositide 3-kinase (PI3K) signaling in POMC neurons and elicit remodeling of perigonadal white adipose tissue (WAT) is severely compromised in mutant mice. Also, electrophysiological and histomorphomolecular analyses indicate a selective reduction in sympathetic nerve activity and brown-fat-like characteristics in perigonadal WAT of mutant mice, suggesting a physiologically important role for POMC neurons in controlling this visceral fat depot. In summary, our results provide direct genetic evidence that SIRT1 in POMC neurons is required for normal autonomic adaptations against diet-induced obesity.

Original languageEnglish (US)
Pages (from-to)78-87
Number of pages10
JournalCell Metabolism
Volume12
Issue number1
DOIs
StatePublished - Jul 7 2010

Keywords

  • HUMDISEASE
  • MOLNEURO

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Ramadori, G., Fujikawa, T., Fukuda, M., Anderson, J., Morgan, D. A., Mostoslavsky, R., Stuart, R. C., Perello, M., Vianna, C. R., Nillni, E. A., Rahmouni, K., & Coppari, R. (2010). SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metabolism, 12(1), 78-87. https://doi.org/10.1016/j.cmet.2010.05.010