Metabolism is to a large extent controlled by a complex transcriptional regulatory circuitry. Transcriptional coactivators modulate the activity of almost all transcription factors and therefore influence metabolic pathways. This Program Project Grant proposal focuses on the roles of members of the steroid receptor coactivator (SRC) family in mediating the biological functions of nuclear receptors (NRs) and their ligands This Project, which will extend and complement Project 3, will characterize alterations of in vivo metabolism in SRC null mutant (or knockout, KO) mice by determining a comprehensive set of morphometric and serum parameters of metabolism, hence generating a metabolic fingerprint in these animals. This fingerprint will consist of evaluation of evaluation of body weight and food intake and a measurement of a number of serum parameters, such as glucose, insulin, leptin, cholesterol and triglyceride levels under fasting conditions. Metabolic fingerprints will be determined under basal and stimulated conditions (in which the SRC-/- mice will be treated with agonists for the NRs for estrogen, progesterone and androgens, at regular intervals throughout adult life). Should abnormal """"""""metabolic fingerprints) be observed in SRC Kos, a detailed metabolic analysis will be performed. This will consist of determination of insulin sensitivity and/or secretion defects, and characterization of lipoprotein and apolipoproteins. Analysis will be performed under basal conditions and during dietary interventions aimed at inducing metabolic disorders in these animals. These studies will be complemented by morphological analysis of the organs involved in abnormal homeostasis, and further mechanistic studies to identify the signaling factors and target genes involved. We anticipate that understanding of the contribution of coactivators to metabolic homeostasis will shed light on their role in common metabolic disorders such as obesity, type 2 diabetes, hyperlipidemia, and atherosclerosis.
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