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United States Department of Agriculture

Agricultural Research Service

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

Title: Sirti Deficiency in Mice Impairs Energy Balance by Disrupting Hypothalamic Melanocortin Signaling

Authors
item Shi, Xuemei -
item Wang, Yi -
item Li, Xiaojie -
item Li, Defa -
item Burrin, Douglas -
item Chan, Lawrence -
item Guan, Xinfu -

Submitted to: Federation of American Societies for Experimental Biology Conference
Publication Type: Abstract Only
Publication Acceptance Date: January 25, 2011
Publication Date: April 1, 2011
Citation: Shi, X., Wang, Y., Li, X., Li, D., Burrin, D., Chan, L., Guan, X. 2011. SIRTI deficiency in mice impairs energy balance by disrupting hypothalamic melanocortin signaling [abstract]. Federation of American Societies for Experimental Biology Conference. 25:351.1.

Technical Abstract: The NAD+-dependent deacetylase SIRT1 is induced to adjust energy metabolism in response to caloric restriction and probably mediates mammalian longevity. Due to extremely high rates of SIRT1-null neonatal mice, the physiological significance of SIRT1 has not been fully defined in whole-body energy homeostasis. Our objective was to critically test if SIRT1 deficiency impairs energy balance partially attributed to disorderly central melanocortin signaling. First, we showed that SIRT1-null mice had relatively higher food intake, augmented whole-body energy expenditure, enhanced locomotor activity, and retarded body size of the same body composition. Then, we demonstrated that the melanocortin system in the SIRT1-null mice was disrupted at the hypothalamic level. In the hypothalamus, SIRT1 protein expressed in both AgRP- and POMC-neurons and linked with AMPK-mTOR signaling. Moreover, SIRT1 protein increased at the fast status and interacted directly with FOXO1 and PGC-1 alpha in the hypothalamus. Furthermore, the relative expression of Agrp to Pomc in the SIRT1-deficient hypothalamus did not respond to energy availability. Finally, we demonstrated that SIRT1 deficiency impaired leptin-mediated AMPK and STAT3 signaling in the hypothalamus. We conclude that SIRT1 as an energy sensor positively regulates energy balance partially through hypothalamic control of whole-body energy metabolism.

Last Modified: 9/23/2014
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