Coiled-coil domain containing 80 (Ccdc80) is a secreted protein highly enriched in mouse and human white adipose tissue (WAT) that plays an important role during adipocyte differentiation in vitro. To investigate the physiological function of Ccdc80 in energy and glucose homeostasis, we generated mice in which the gene encoding Ccdc80 was disrupted. Mice lacking Ccdc80 showed increased sensitivity to diet-induced hyperglycemia and glucose intolerance while displaying reduced glucose-stimulated insulin secretion in vivo. Gene expression analysis by microarray revealed that only 10 transcripts were simultaneously altered in pancreas, skeletal muscle, and WAT from Ccdc80(-/-) mice, including some components of the circadian clock. Expression of the core clock member Arntl/Bmal1 was reduced whereas that of the oscillating transcription factors Dbp and Tef was increased in all tissues examined. Furthermore, knockdown of Ccdc80 in 3T3-L1 cells led to an increase of Dbp mRNA levels during adipocyte differentiation, suggesting that Ccdc80 might be involved in the regulation of this gene in a cell-autonomous manner. Importantly, transcriptional alterations in Ccdc80(-/-) mice were associated with changes in feeding behavior, increased caloric intake, decreased energy expenditure, and obesity. Taken together, our results suggest that Ccdc80 is a novel modulator of glucose and energy homeostasis during diet-induced obesity.