SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity.
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.
Ramadori
Giorgio
G
Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Fujikawa
Teppei
T
Fukuda
Makoto
M
Anderson
Jason
J
Morgan
Donald A
DA
Mostoslavsky
Raul
R
Stuart
Ronald C
RC
Perello
Mario
M
Vianna
Claudia R
CR
Nillni
Eduardo A
EA
Rahmouni
Kamal
K
Coppari
Roberto
R
D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism; D005260:Female; D006706:Homeostasis; D020738:Leptin / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism; D009765:Obesity / Q000209:etiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D020738:Leptin; D011333:Pro-Opiomelanocortin; D019869:Phosphatidylinositol 3-Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1