Worldwide obesity has more than doubled since 1980, with over 600 million cases in 2014. Obesity can lead to many adverse metabolic effects of the cardiovascular and endocrine systems and in the brain. In rodents, the dorsal vagal complex (DVC) of the brain regulates glucose homeostasis and controls food intake through insulin signalling. A 3-day high fat diet (HFD) has shown to induce insulin resistance thus affecting the DVC’s ability to regulate glucose metabolism and food intake, though exact mechanistic effects of this are still unknown. HFD feeding is associated with an increase in mitochondrial fission in the DVC. Mitochondrial fission is regulated by dynamin related protein 1 (Drp1), and an increase in Drp1 activity in the DVC has shown to inhibit the insulin signalling pathway. Adenoviruses expressing a constitutively active form of Drp1 (S637A), a dominant negative form of Drp1 (K38A) and a GFP expressing control were injected into the nucleus of the solitary tract (NTS) of the DVC. Our data has shown, rats expressing Drp1-S637A in the DVC, do not decrease food intake in response to an acute insulin treatment, compared to the GFP controls. Confirming that increases in mitochondrial fission results in impaired insulin sensitivity. Furthermore, we found that after 14 days, Drp1-S637A expressing rats were hyperphagic and had an overall increase in body weight and fat accumulation. Following this, we determined if inhibition of Drp1 can restore insulin sensitivity in HFD fed (insulin resistant) rats. Acute insulin treatment, decreased food intake in the HFD fed Drp1-K38A expressing rats, but not in the HFD fed GFP expressing rats, confirming that inhibition of Drp1 can restore insulin sensitivity. In addition, chronic inhibition of Drp1, resulted in a decrease in food intake, body weight and fat accumulation.
- BSc, Pharmacology
- MRes, Translation Medicine