Obesity and type 2 diabetes (2DM) affect millions of people and are the cause of major health problems in the United States. Both conditions have a long array of life threatening complications, including cardiovascular diseases. Despite intense research, the primary defects causing obesity and/or 2DM are still largely unknown. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic physiology, neuroendocrinology and behavior of body energy and glucose homeostasis is needed. The hypothalamus and metabolic-sensor proteins exert important functions on energy and glucose balance. Here, by employing neuron-specific, Cre/loxP-mediated manipulations, unique animal models in which SIRT1 (a metabolic-sensor protein) is either overexpressed or deleted only in restricted hypothalamic neurons will be generated. These mice will be subjected to several phenotypic tests to determine whether SIRT1 in hypothalamic neurons is required for normal body weight and glucose homeostasis. Results from these studies are expected to increase our understanding of the molecular mechanisms and neurocircuits that underlie coordinated control of energy and glucose homeostasis.
Obesity and type 2 diabetes affect millions of people and are the cause of major health problems in the United States. To prevent and develop more effective treatments against these pathologies, a better understanding of the basic mechanisms of body energy and glucose homeostasis is needed. The study proposed here is aimed at identifying these mechanisms (proteins and neurons) that in concert govern body weight and glucose balance.
|Fujikawa, Teppei; Berglund, Eric D; Patel, Vishal R et al. (2013) Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin. Cell Metab 18:431-44|
|Ramadori, Giorgio; Coppari, Roberto (2011) Does hypothalamic SIRT1 regulate aging? Aging (Albany NY) 3:325-8|
|Ramadori, Giorgio; Fujikawa, Teppei; Anderson, Jason et al. (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab 14:301-12|
|Yu, Jiujiu; Auwerx, Johan (2010) Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacol Res 62:35-41|
|Ramadori, Giorgio; Fujikawa, Teppei; Fukuda, Makoto et al. (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12:78-87|
|Ramadori, Giorgio; Coppari, Roberto (2010) Pharmacological manipulations of CNS sirtuins: potential effects on metabolic homeostasis. Pharmacol Res 62:48-54|
|Fujikawa, Teppei; Chuang, Jen-Chieh; Sakata, Ichiro et al. (2010) Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. Proc Natl Acad Sci U S A 107:17391-6|
|Ramadori, Giorgio; Gautron, Laurent; Fujikawa, Teppei et al. (2009) Central administration of resveratrol improves diet-induced diabetes. Endocrinology 150:5326-33|