Investigation of the role of Drosophila SOCS36E in energy homeostatis and obesity
Pennington Biomedical Research Center
Pilot Project (May 1, 2015 – Present)
Our overall objective is the discovery of the molecular mechanisms by which obesity induces disease. Diet- induced obesity in humans and animal models does not guarantee comorbidities, but it does substantially heighten the risk of diabetes, cardiovascular disease, and neurological decline. The ability of obesity to cause disease has been intensely studied in mammals, revealing mechanisms that include chronic inflammation and aberrant cell signaling. An extreme state resembling mammalian obesity results when Drosophila melanogaster are allowed to feed upon solid medium that is high in sugar (HSD). Exposed flies have increased triglyceride levels, increased circulating glucose, reduced insulin response despite increased expression, cardiac abnormalities, a severely reduced lifespan, and are impeded in climbing ability. As one of the newer models of obesity, and yet among the most genetically accessible to researchers, Drosophila melanogaster is useful in the dissection of specific connections between obesity and its comorbidities. In mammals, leptin is released from adipose tissue in direct proportion to their metabolite content. When leptin reaches the hypothalamus, it conveys the energy state of the organism, inhibiting appetite centrally and promoting signaling components of the insulin response peripherally. Following activation of the leptin receptor, JAK-Stat3 signaling results in the transcription of a range of genes, the suppressor of cytokine signaling 3 (SOCS3) among them. SOCS3 acts as a classical negative feedback inhibitor of the leptin receptor and a range of other cytokines. Among these cytokines are components of the insulin response. Interestingly, SOCS3 is also produced in response to inflammatory agents, such as IL-6 or TNF-α, which provides a direct mechanism by which the chronic inflammation of obesity can promote leptin and insulin resistance. In Drosophila melanogaster, unpaired 2 (Upd2) is released from the fat body in proportion to nutrient content, binds to the receptor Domeless upon GABAergic neurons that precede the median neurosecretory cells, and promotes drosophila insulin-like peptide 2 (Dilp2) release through Hop-Stat92e signaling. Drosophila also possess SOCS proteins, among them the classical negative feedback inhibitor SOCS36E, which also seems to be induced during immune and/or stress responses. In this study, we reduce the adult expression of SOCS36E in both the whole fly and exclusively in neurons. We hypothesize that either of these interventions will result in increased Upd2 effectiveness and thus Dilp2 responsiveness, conveying a greater tolerance to HSD as evinced by increased lifespan, improved mobility, increased fat stores, altered starvation resistance, and reduced circulating metabolites. Herein we also conduct RNA-Sequencing of whole flies to obtain genomic profiles that compare the transcriptome of normal vs HSD, as well as the transcriptome response to knockout of SOCS36E in each dietary context. Regardless of the nature of the results, our study stands to advance the understanding of the pathophysiology of diet-induced obesity and will enhance our awareness of the conserved physiology between human and fly.