“Beyond the brain: α-Synuclein’s role as a key regulator of insulin signaling and adipogenesis” Carolina A. Figueroa and Clifford J. Rosen. Rosen Musculoskeletal Laboratory, Maine Medical Research Institute (MMCRI), Scarborough, Maine, USA, 04074. α-Synuclein is a polypeptide encoded by the Snca gene, highly expressed in neurons, but also found in detectable levels in the skeleton and adipose tissue. Aggregation of α-Synuclein is the principal component of Lewy bodies in the central nervous system of PD (Parkinson’s Disease), LDB (Lewy Body Dementia) and some Alzheimer’s disease patients. PD symptoms include progressive immobilization and a range of -often unnoticed - nonmotor symptoms, including osteopenia, body composition alterations and importantly, insulin resistance. In respect to the latter, a recently published trial in PD patients of a GLP-1 agonist showed improved gait and motor function(reference). Previously we used co-expression analyses to show that Snca regulates skeletal homeostasis, and its deletion reduced estrogen deficiency-induced bone loss as well as weight gain in mice (reference). Moreover, we found that Snca expression increases markedly during terminal differentiation of primary adipocytes. To determineα-Synuclein’s intrinsic role in body composition and as a regulator of insulin signaling and lipid metabolism, we generated both conditionally deleted and overexpressing models of α-Synuclein . AdipoCre;Sncafl/fl mice on a high fat diet (HFD) showed no increase in inguinal adipose accrual, markedly reduced weight gain and increased insulin sensitivity compared to mice on a low fat diet (LFD). In vitro models of loss and overexpression of α-Synuclein showed a dose dependent effect on adipocyte differentiation and insulin signaling. For example, loss of α-Synuclein in vitro revealed a decrease in adipogenesis, and pAKT and, increased levels of AKT, pIRβ and pSHC. Mutated α-Synuclein overexpression (A53Ttg/tg) led to greater adipogenesis and increased levels of IRS1, IRS2 and pAKT/AKT. After insulin treatment of primary adipocytes, α-Synuclein expression increased and the protein relocated to the nucleus in control cells, but not in A53Ttg/tg cells, likely due to aggregation of α-Synuclein complexes. In sum, α-Synuclein regulates adipogenesis in a cell autonomous manner, and modulates insulin responsiveness by affecting the levels of pAKT/AKT, IRS1/2 and insulin receptor β. Future research is essential to understand the local and systemic effects of α-Synuclein signaling in adipose metabolism to shed light on potential treatments for insulin resistance in PD patients.