Numerousnuclearreceptors(NRs)ortranscriptionfactors(TFs)havebeenidentifiedasimportantregulatorsof bodyweight.However,anti-obesityregimenstargetingtheseindividualmoleculesalonearefarfromsatisfying. Coactivators interact with a broad range of NRs/TFs and may serve as master regulators that coordinate and synergizeactionsofmultiplemetabolicsignals.HighlevelsofSteroidReceptorCoactivator-1and-2(SRC-1and SRC-2)areexpressedinthehypothalamus,thekeybrainregioncontrollingfeedingandbodyweightbalance. ThepilotobservationsledtoahypothesisthathypothalamicSRC-1andSRC-2coactivateSTAT3andFoxO1, repectively, to provide coordinated control of energy metabolism.
Aim 1 will determine whether hypothalamic SRC-1fine-tunesSTAT3transcriptionactivitytomediatetheanti-obesityeffectsofleptin.Mousemodelslacking or overexpressing SRC-1 only in leptin-responsive neurons have been generated. Metabolic parameters in response to different diets or to leptin treatment will be assessed in these mice. Importantly, the molecular mechanisms by which the SRC1-pSTAT3 complex regulates leptin signaling will be delineated.
Aim 2 will determine whether human SRC-1 mutations impair leptin-STAT3 pathway in the hypothalamus and cause obesity. Using the CRISPR technology, a knockin mouse line has been generated to mimic a SRC-1 genetic mutationassociatedwithhumanobesity.Metabolicphenotypesofthesemicewillbecharacterized,andleptin- STAT3 actions and STAT3 transcription activity will be evaluated.
Aim 3 will determine whether hypothalamic SRC-2coativatesFoxO1transcriptionalactivitytofacilitateenergyreservations.Micelackingoroverexpressing SRC-2 in mature POMC neurons have been generated, with/without FoxO1 overexpression. Metabolic phenotypeswillbecharacterizedinallthesemodelsandFoxO1transcriptionalactivitywillalsobeevaluated.
STAT3 and FoxO1 are known to regulate body weight through their actions in the brain hypothalamus, but the molecular mechanisms underlying their functions remain to be elucidated. Using state-of-art technologies, we propose to determine whether two signaling molecules, namely Steroid Receptor Coactivator-1 and -2 (SRC-1 and SRC-2), interact with STAT3 and FoxO1, respectively, in the brain hypothalamus to regulate body weight balance, and therefore results from these studies will provide rational targets for the development of novel therapies for obesity.
