PT  - JOURNAL ARTICLE
AU  - Bianca Patel
AU  - Lauryn New
AU  - Joanne C. Griffiths
AU  - Jim Deuchars
AU  - Beatrice M. Filippi
TI  - Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain
AID  - 10.1101/2020.06.26.173641
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.06.26.173641
4099  - http://biorxiv.org/content/early/2020/06/29/2020.06.26.173641.short
4100  - http://biorxiv.org/content/early/2020/06/29/2020.06.26.173641.full
AB  - The dorsal vagal complex (DVC) senses changes in insulin levels and controls glucose homeostasis, feeding behaviour and body weight. Three days of high-fat diet (HFD) in rats is sufficient to induce insulin resistance in the DVC and impair its ability to regulate feeding behaviour. HFD-feeding is associated with increased mitochondrial fission in the DVC and fission is regulated by dynamin-related protein 1 (Drp1). Higher Drp1 activity can inhibit insulin signalling, although the exact mechanisms controlling body weight remain elusive. Here we show that Drp1 activation in DVC leads to higher body weight in rats and Drp1 inhibition in HFD-fed rats reduced body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. Rats expressing active Drp1 in the DVC had higher levels of inducible nitric oxide synthase (iNOS) and knockdown of iNOS in the DVC of HFD-fed rats led to a reduction in body weight gain, cumulative food intake and adipose tissue, and prevented insulin resistance. In obese insulin-resistant animals, inhibition of mitochondrial fission or DVC iNOS knockdown restored insulin sensitivity and decreased food intake, body weight and fat deposition. Finally, we show that inhibiting mitochondrial fission in DVC astrocytes is sufficient to protect rats from developing HFD-dependent insulin resistance, hyperphagia, body weight gain and fat deposition. Our study uncovers new molecular and cellular targets for brain regulation of whole-body metabolism, which could inform new strategies to combat obesity and diabetes.Competing Interest StatementThe authors have declared no competing interest.