ObesityisapproachingepidemicproportionsasanutritionalandpathologicaldisorderintheU.S.andisclosely 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,publichealthinitiativesfocusedonidentifyingtherapeuticoptionstocombatthedetrimentaleffectsof obesity-relateddiseaserelyonanimprovedunderstandingofhowalterationsinmetabolictissuecrosstalkalters metabolism to favor energy accretion and deposition. Our highly synergistic and integrated Program Project teamhasidentifiedpreviouslyunappreciatedmolecularmechanismsthathighlightthecoordinatedactionsofthe hypothalamus(brain),liverandwhiteadiposetissuesasgatekeepersofmetabolicenergybalancethatbecome dysregulatedbyovernutrition.ByfocusingonthemetabolicactionsoftheSteroidReceptorCoactivator(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 metabolicregulatoryaxis,whichinvolvestheinterplayofmultipletissuesystems(i.e.brain,liver,adipose),and underlyingtranscriptionalmachinery(NR/SRCs)thatmaintaintheirhomeostaticbalance,canonlybeadequately studiedbyamultidisciplinaryresearchteamwithunique,yetsynergistic,expertise.Leveragingthecollaborative frameworkoftheNIDDKP01ProgramProject,wehaveassembledsuchateamofscientistswhoarededicated totheoverallobjectiveofunderstandingthe?mechanisms?forthedownstreamtissue-specificmetabolicfunctions ofNR/SRCactionthatgovernwholebodyenergybalance.
The proposed research is relevant to public health initiatives and to the overarching mission of the NIH and NIDDK as it seeks to improve our understanding of the transcriptional events that underlie the complex progression of metabolic disease through studying the coordinated actions of the brain, liver and fat. It is our expectation that expanding our knowledge of the transcriptional mechanisms that disrupt metabolic tissue function will be an important step in guiding the development of new therapeutics to treat obesity-driven diseases.
