Determining the Cellular Mechanisms of Catecholamine Resistance in Obesity

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Project Summary Obesity is a major risk factor for numerous diseases and has reached epidemic proportions worldwide. It is accompanied by a reduction in adipocyte responsiveness to epinephrine and norepinephrine, termed catecholamine resistance. Catecholamine signaling in adipocytes is governed by - and -adrenergic receptors. In mice, the 3-adrenergic receptor (ADRB3) is expressed at hundred folds higher levels than other ADRBs and can regulate whole body metabolism. Subsequently, ADRB3 agonists have been explored clinically to treat obesity; however, they have had limited success due to low durability of their effects. Interestingly, ADRB3 is resistant to classical desensitization but may become desensitized by regulating its own expression, which we hypothesize is important for the limited effects of ADRB3 agonists in obese patients. My preliminary data suggest that activation of inflammatory pathways or direct activation of ADRB3 dramatically downregulates ADRB3 mRNA and protein in adipocytes. In both cases this downregulation is dependent on EPAC, a guanine exchange factor for the small G-proteins RAP1/2. This proposal will investigate the novel hypothesis that resistance to catecholamines produced physiologically during obesity (heterologous desensitization) and pharmacologically during adrenergic agonist administration (homologous desensitization) results from EPAC/RAP-dependent downregulation of ADRB3. I will utilize sophisticated techniques including mass spectroscopy, RNAseq, adipocyte-specific knockout mouse models, primary pre-adipocytes differentiated in vitro, as well as molecular biology, biochemistry, small molecule/siRNA, and physiological assays to test this overarching hypothesis. I will determine the signaling pathways and transcriptional regulators responsible for downregulation of ADRB3 during homologous and heterologous desensitization in adipocytes. This project represents an excellent training opportunity for me, because it will not only expose me to cutting edge ideas and technologies in metabolism/adipocyte biology, but also in career development (grant writing, communication, lab management, etc) that will prepare me for the transition to independence.