By regulating Akt membrane compartmentalization, ClipR-59 modulates adipocyte glucose transport. To elucidate the role of ClipR-59 in the regulation of whole body glucose homeostasis, we have generated adipose tissue specific transgenic mice and examined how forcing expression of ClipR-59 in adipose tissue affects body glucose homeostasis. We found that ClipR-59 adipose transgenic mice showed lower blood glucose level with increased glucose tolerance and enhanced insulin sensitivity. Moreover, ClipR-59 adipose transgenic mice were lean with reduced fat mass and against diet induced obesity. Finally, we examined the potential impact of ClipR-59 on adipose endocrine function and found that ClipR-59 expression enhanced adiponectin secretion in both 3T3-L1 adipocytes and adipose tissue, accompanied with increased circulating adiponectin and enhanced AMPKα phosphorylation at Thr172 in adipose tissue and skeletal muscle. Overall, these studies demonstrate that ClipR-59 is likely an important regulator of body glucose homeostasis and adipocyte function.