In this study, we find that male Crhr2-/- and Crhr2 haploinsufficient mice have worse glucose and insulin tolerance, microvesicular hepatic steatosis, and dyslipidemia than female Crhr2 mice, strongly suggesting that the Crhr2 locus modulates the sex-specific expression of multiple genes influencing diabetes and metabolic syndrome in humans and mice. Here, CRHR2 is linked to diabetes mellitus.