Dynamin-related protein 1 (DRP1) is a key protein in mitochondrial and peroxisome fission and has been shown to affect systemic metabolism. However, whether these changes are dependent on effects of developmental effects of loss-of-function or on changes in body weight are currently unknown. Here we confirm prior studies that germline loss of hepatocyte DRP1 (using Alb-CRE) reduces body weight and fat gain and improves glucose homeostasis on an obesogenic high-fat diet. Hyperinsulinaemic-euglycaemic clamp studies revealed a selectively reduced endogenous glucose production rate, explaining the improved glucose metabolism in the liver DRP1 KO mice. When the same study was conducted in female mice, the liver DRP1 knockout mice gained equal body and fat weight as controls but had improved glucose metabolism. Similarly, when DRP1 was silenced in hepatocytes of adult obese male mice, improvements in glucose metabolism were seen independent from any difference in body weight. Lastly, studies of male germline hepatic DRP1 KO mice placed on an obesogenic diet for just a few days showed improvements in glucose metabolism before measurable differences in body weight. Taken together, these data suggest that there is an intrinsic effect of hepatic DRP1 silencing on systemic glucose metabolism via reduced hepatic glucose production that is independent from developmental effects or body weight.