Inhibition of Mitochondrial Fission and iNOS in the Dorsal Vagal Complex Protects from Overeating and Weight Gain

Abstract

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

Nutrient infusion in the dorsal vagal complex controls hepatic lipid and glucose metabolism in rats

“…DVC is a highly permeable region in the brainstem which contains a circumventricular organ termed the area postrema as well as the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. DVC relays signals from the gut and midbrain to facilitate energy and nutrient homeostasis (Blouet et al, 2009;Grill and Hayes, 2012;Waise et al, 2018;Wang et al, 2008; but also senses insulin (Filippi et al, 2012(Filippi et al, , 2014Patel et al, 2021;), glucagon (LaPierre et al, 2015, leptin (Hayes et al, 2010;Kanoski et al, 2012), and GLP-1 (Alhadeff et al, 2017;Hayes et al, 2008Hayes et al, , 2009 to regulate metabolism. DVC senses amino acid to lower food intake (Blouet and Schwartz, 2012), while DVC glucoprivation activates counter-regulation and increases food intake as well (Andrew et al, 2007;Ritter et al, 2000).…”

Insulin action on astrocytes: From energy homeostasis to behaviour

“…42 Interestingly, mitochondrial fission in DVC astrocytes was reported as one of the mechanisms mediating high fat diet (HFD)-dependent insulin resistance, hyperphagia, weight gain and fat deposition. 46 In addition, studies carried out on rats have highlighted that that DVC astrocytes partly mediate the anorectic effects of leptin and pharmacological glucagonlike peptide-1 receptor ligands. 47,48 Overall, these findings suggest that NTS astrocytes are involved in the integration of peripheral satiety signals to control feeding behaviour.…”