Changes in Mitochondrial Dynamics and iNOS in the Dorsal Vagal Complex of the Brain affects Insulin Sensing, Feeding Behaviours and Body Weight Gain in Rats

Worldwide obesity has nearly tripled since 1975, with over 650 million cases in 2016. Obesity can lead to many adverse metabolic effects in the cardiovascular, brain and endocrine systems. It has been previously shown, the dorsal vagal complex (DVC) of the brain regulates glucose homeostasis and controls food intake through insulin signalling in rats. In these rats, a 3-day high fat diet (HFD) has been shown to induce insulin resistance and diminishes 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 modulates the insulin signalling pathway. Activation of Drp1 has been correlated with increased levels of inducible nitric oxide synthase (iNOS), increased endoplasmic reticulum (ER) stress and insulin resistance in the DVC. This study has shown that activation of Drp1 in the DVC leads to an increase in body weight gain, cumulative food intake and adipose tissue, these rats are also insulin resistant compared to regular chow (RC)- fed littermates and displayed higher levels of iNOS in the DVC. Conversely inhibiting Drp1, or knocking down iNOS, in the DVC in HFD-fed rats decreased body weight gain, cumulative food intake and adipose tissue, and prevented the development of insulin resistance. In addition to this, selective inhibition of Drp1 in astrocytes of the DVC in HFD-fed rats resulted in a decrease in food intake and body weight and prevented HFD-induced insulin resistance. Finally, in diet-induced obese, insulin resistant rats, inhibition of mitochondrial fission or knocking down iNOS in the DVC restored insulin sensitivity and decreased fat deposition. This study has determined the integral role Drp1 and iNOS in the DVC and the effect this has on feeding behaviours and body weight gain, in particular I demonstrated that it is sufficient to target astrocytes in the DVC to affect insulin sensing, feeding behaviours and fat deposition