Dynamin-related protein 1 in Leptin Receptor Neurons Regulates Metabolic Homeostasis

Leptin receptor (LepRb) signaling in the brain plays a pivotal role in the regulation of food intake and energy expenditure. Mitochondria dysfunction is implicated in many diseases including obesity and diabetes. Dynamin-related protein1 (Drp1) is an essential player in mitochondria fission/fusion and implicated in mitochondria dysfunction. However, its role in LepRb neurons is not known. Here, we investigated whether loss of Drp1 in LepRb-expressing neurons affects metabolic and glucose homeostasis. For this, we crossed female mice harboring floxed alleles of the Drp1 gene (Drp1fl/fl) with male mice expressing Cre recombinase in LepRb (LepRCre). Using immunofluorescence staining, we confirmed that Drp1 is expressed in the LepRb positive cells of the hypothalamus and conditional knock-out (CKO, LepRCre/Drp1fl/fl) mice have selective loss of Drp1 protein expression in the LepRb expressing cells. Next, we found that both male and female CKO mice fed normal chow diet have similar body weight compared to control littermates. However, their fat mass was significantly higher in both male (5.9 ± 0.9g vs 3.6 ± 0.6g) and female CKO (3.1 ± 0.4g vs 2.0 ± 0.3g) mice compared to controls. Interestingly, lean mass of male, but not female, CKO mice was significantly reduced compared to controls (19.1 ± 0.4g vs 20.3 ± 0.4g). Both male and female CKO mice exhibited similar glucose handling measured by glucose tolerance test. On the other hand, CKO mice displayed impaired insulin sensitivity compared to control animals measured by insulin tolerance test. Striking, we found that CKO mice are sensitized to diet-induced obesity. Indeed, body weight of both male and female CKO mice fed high-fat high-sucrose diet (HFHSD) for 16 weeks was significantly increased compared to controls (47.4 ± 1.6g vs 40.4 ± 2.1g for males, and 40.8 ± 2.6g vs 34 ± 1.6g for females). This excess weight gain was primary due to increased fat mass, but not lean mass. Our results also indicate that HFHSD fed male and female CKO mice have improved glucose handling, but impaired insulin sensitivity. These results demonstrate that Drp1 in leptin receptor expressing neurons regulate body weight and glucose homeostasis with increased fat mass that may cause insulin insensitivity. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.