[italic]Pomc-Cre; Sirt1[/italic] Conditional Knock-In Mice Present Lean Phenotype Due to Increased Energy Expenditure

[italic]Pomc-Cre; Sirt1[/italic] Conditional Knock-In Mice Present Lean Phenotype Due to Increased Energy Expenditure Sirt1 is a longevity gene that Sirt1 is a longevity gene that is responsible for improved health and life span mediated by caloric restriction, and encodes NAD[sup]+[/sup]-dependent deacetylase. Sirt1 modulates energy metabolism in various organs, including liver, pancreas, skeletal muscle, adipose tissue, and the brain. Single nucleotide polymorphisms in Sirt1 gene are associated with energy expenditure and obesity. We reported previously that hypothalamic Sirt1 protein level is decreased by fasting via ubiquitination and Sirt1 is stabilized by feeding and that hypothalamic overexpression of Sirt1 by adenoviral microinjection prevents hyperphagia and body weight gain by suppressing orexigenic Agrp expression. However, the contribution of hypothalamic Sirt1 on regulating energy expenditure remained unsolved. In order to address the question, we developed conditional Sirt1 knock-in mice using Rosa26 promoter and Pomc-Cre mice. Male Pomc-Cre; Sirt1 conditional knock-in (KI) mice are significantly leaner than wild-type (WT) littermates on normal chow feeding. KI mice had less perigonadal fat and perigonadal adipocytes were smaller than those of wild-type mice. 24-hour food intake and 2-hour food intake after 24-hour fasting were not different between WT and KI mice. We measured VO2 and heat production of KI mice and WT mice by Oxymax system, and found that KI mice tend to have higher energy expenditure. Meanwhile, there was no increase in locomotor activity, suggesting that the increase in energy expenditure is due the increase in the basic metabolic rate. KI mice had significantly higher plasma T4 level, but no difference in plasma cortisol level was observed. In brown adipose tissue (BAT), the expressions of type 1 beta adrenergic receptor, PGC-1 beta, and UCP2 were increased. Therefore, hypothalamic overexpression of Sirt1 modulates the central melanocortin system and increases energy expenditure in BAT via hypothalamic-pituitary-thyroid axis and sympathetic nervous system. TSUTOMU SASAKI, KOSUKE AMANO, TOMOYA KITAZUMI, OSAMU KIKUCHI, MASAKI KOBAYASHI, TADAHIRO KITAMURA 462-PP Maebashi, Gunma, Japan Obesity - Animal