SIRT1 Deacetylase in SF1 Neurons Protects against Metabolic Imbalance

Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in ster...

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Bibliographic Details
Published in:Cell metabolism 2011-09, Vol.14 (3), p.301-312
Main Authors: Ramadori, Giorgio, Fujikawa, Teppei, Anderson, Jason, Berglund, Eric D., Frazao, Renata, Michán, Shaday, Vianna, Claudia R., Sinclair, David A., Elias, Carol F., Coppari, Roberto
Format: Article
Language:English
Subjects:
Animals
Diabetes mellitus
Diabetes Mellitus, Type 2 - complications
Diabetes Mellitus, Type 2 - metabolism
Diabetes Mellitus, Type 2 - pathology
Diet, High-Fat - adverse effects
Dietary Fats - metabolism
Dietary Fats - pharmacology
Diets
Energy expenditure
Energy Metabolism
Feeding
Female
Gene Expression
Gene Knockdown Techniques
Hormones
Hypothalamus - cytology
Hypothalamus - drug effects
Hypothalamus - metabolism
Immunohistochemistry
Insulin
Insulin - metabolism
Insulin - pharmacology
Insulin Resistance
Intracellular Signaling Peptides and Proteins - pharmacology
Leptin
Leptin - pharmacology
Medical importance
Mice
Mice, Transgenic
Motor Activity - drug effects
Neurons
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neuropeptides
Neuropeptides - pharmacology
Obesity
Obesity - complications
Obesity - metabolism
Obesity - pathology
Orexins
Patch-Clamp Techniques
SIRT1 protein
Sirtuin 1 - deficiency
Sirtuin 1 - genetics
Skeletal muscle
steroidogenic factor 1
Steroidogenic Factor 1 - genetics
Steroidogenic Factor 1 - metabolism
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Summary:Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance. ► Loss of SIRT1 in SF1 neurons predisposes to dietary obesity and diabetes ► Enhanced SIRT1 in SF1 neurons protects against diet-induced metabolic imbalance ► SIRT1 in SF1 neurons controls insulin sensitivity in skeletal muscle ► SIRT1 in SF1 neurons is required for normal antidiabetic actions of orexin-A
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2011.06.014