Overall - Project Summary Obesity is approaching epidemic proportions as a nutritional and pathological disorder in the U.S. and is closely associated with important syndromes including type 2 diabetes, insulin resistance, hepatic steatosis, dyslipidemias, hypertension, coronary heart disease, osteoarthritis and cancer. Obesity rates in the U.S. have continued to worsen whereby nearly 70% of the adult population is overweight and the yearly medical cost of treatment for obesity-related disease is estimated at $190 billion, currently 6X the annual NIH budget. Consequently, obesity is anticipated to overtake smoking as the most preventable cause of adult mortality. Therefore, public health initiatives focused on identifying therapeutic options to combat the detrimental effects of obesity-related disease rely on an improved understanding of how alterations in metabolic tissue crosstalk alters metabolism to favor energy accretion and deposition. Our highly synergistic and integrated Program Project team has identified previously unappreciated molecular mechanisms that highlight the coordinated actions of the hypothalamus (brain), liver and white adipose tissues as gatekeepers of metabolic energy balance that become dysregulated by overnutrition. By focusing on the metabolic actions of the Steroid Receptor Coactivator (SRC) family as amplifiers of nuclear hormone receptor (NR)/transcription factor (TF) function in this triad of energy- responsive tissues, we have exposed transcriptional reprogramming as a key molecular determinant in the disruption of normal energy homeostasis arising from chronic exposure to caloric excess. Such a complex metabolic regulatory axis, which involves the interplay of multiple tissue systems (i.e. brain, liver, adipose), and underlying transcriptional machinery (NR/SRCs) that maintain their homeostatic balance, can only be adequately studied by a multidisciplinary research team with unique, yet synergistic, expertise. Leveraging the collaborative framework of the NIDDK P01 Program Project, we have assembled such a team of scientists who are dedicated to the overall objective of understanding the ‘mechanisms’ for the downstream tissue-specific metabolic functions of NR/SRC action that govern whole body energy balance.