Synucleins are a family of homologous, predominantly neuronal proteins known for their involvement in synaptic transmission and neurodegeneration. γ-synuclein is predominantly localized in axons and presynaptic terminals of selected populations of peripheral and central neurons but is also highly expressed in human white adipose tissue (WAT) and increased in obesity. We have recently shown that γ-synuclein is nutritionally regulated in murine adipocytes while its loss protects mice from high fat diet (HFD)-induced obesity and associated metabolic complications. This protection was coupled with increased adipocyte lipolysis, lipid oxidation, and energy expenditure in HFD-fed γ-synuclein-null mutant compared with wild-type mice. Cellular studies suggest that relocalization of ATGL to the lipid droplet in γ-synuclein-deficient adipocytes may contribute to increased lipolysis in these cells. Loss of γ-synuclein in adipocytes also attenuates the assembly of SNARE complexes, an important component of lipid droplet fusion machinery, possibly due to reduced chaperoning of SNAP-23 to the assembling SNARE complex by γ-synuclein. Together our data suggests that not only is γ-synuclein a novel regulator of lipid handling in adipocytes but also that the deficiency of this protein has a significant effect on whole body energy expenditure.