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The Journal of Neuroscience, July 28, 2010, 30(30):10220-10232; doi:10.1523/JNEUROSCI.1385-10.2010

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Behavioral/Systems/Cognitive
SIRT1 Promotes the Central Adaptive Response to Diet Restriction through Activation of the Dorsomedial and Lateral Nuclei of the Hypothalamus

Akiko Satoh,¹ Cynthia S. Brace,¹ Gal Ben-Josef,⁵ Tim West,² David F. Wozniak,^3,4 David M. Holtzman,^1,2,4 Erik D. Herzog,^4,5 and Shin-ichiro Imai¹

¹Departments of Developmental Biology, ²Neurology, and ³Psychiatry and ⁴Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and ⁵Department of Biology, Washington University, St. Louis, Missouri 63130

Correspondence should be addressed to Dr. Shin-ichiro Imai, Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110. Email: imaishin{at}wustl.edu

Diet restriction retards aging and extends lifespan by triggering adaptive mechanisms that alter behavioral, physiological, and biochemical responses in mammals. Little is known about the molecular pathways evoking the corresponding central response. One factor that mediates the effects of diet restriction is the mammalian nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1. Here we demonstrate that diet restriction significantly increases SIRT1 protein levels and induces neural activation in the dorsomedial and lateral hypothalamic nuclei. Increasing SIRT1 in the brain of transgenic (BRASTO) mice enhances neural activity specifically in these hypothalamic nuclei, maintains a higher range of body temperature, and promotes physical activity in response to different diet-restricting paradigms. These responses are all abrogated in Sirt1-deficient mice. SIRT1 upregulates expression of the orexin type 2 receptor specifically in these hypothalamic nuclei in response to diet-restricting conditions, augmenting response to ghrelin, a gut hormone whose levels increase in these conditions. Our results suggest that in the hypothalamus, SIRT1 functions as a key mediator of the central response to low nutritional availability, providing insight into the role of the hypothalamus in the regulation of metabolism and aging in mammals.

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Received March 17, 2010; revised June 10, 2010; accepted June 17, 2010.

Correspondence should be addressed to Dr. Shin-ichiro Imai, Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO 63110. Email: imaishin{at}wustl.edu

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