Altered mitochondrial dynamics in the NTS affect brown fat morphology and activity

The nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) of the brain controls body weight, food intake, abdominal fat depositions and hepatic glucose and lipid production.
High-fat diet (HFD) is known to induce mitochondrial fragmentation in the NTS, which triggers insulin resistance, hyperphagia and body weight gain and alterations in hepatic glucose production (HGP). Brown adipose tissue (BAT) is a thermogenic organ which can uptake circulating glucose and fatty acids to drive non-shivering thermogenesis and increase energy expenditure. The BAT uptakes and metabolises glucose to perform thermogenesis, and this process is directly activated by noradrenergic signalling from sympathetic preganglionic neurons in the central nervous system, which is modulated by the NTS. The dysregulation of signalling molecules in the NTS is linked with altered BAT activity, obesity, and Type two Diabetes Mellitus (T2DM). High-fat diet (HFD) increases mitochondrial fission in the NTS, triggering weight gain, hyperphagia and insulin resistance. In this work we hypothesised that changes in mitochondrial dynamics in the NTS are associated with alterations in BAT glucose metabolism and hepatic lipid metabolism, and particularly, that inhibiting mitochondrial fission in the NTS protects rats from HFD by augmenting BAT glucose uptake and preventing lipid accumulation in the liver.

Here we show that short-term HFD-feeding decreases BAT glucose uptake and alters catecholaminergic innervation to BAT, by decreasing the availability of noradrenaline precursor tyrosine hydroxylase (TH) within BAT. Additionally, we report white lipid droplet infiltration in the BAT tissue. The inhibition of mitochondrial fission in astrocytes of the NTS of HFD-fed rats is sufficient to increase BAT glucose uptake and prevent the effects of HFD on BAT innervation and morphology. We also report that 2-weeks of HFD are sufficient to increase hepatic triglycerides (TG) and induce signs of steatosis in the liver, and this was prevented by the inhibition of mitochondrial fission in astrocytes of the NTS. The inhibition of mitochondrial fission in the astrocytes of the NTS of HFD-fed rats was also associated with a decrease in circulating blood glucose and insulin levels. In regular chow-fed (RC) rats, the activation of mitochondrial fragmentation in astrocytes of the NTS is sufficient to reduce BAT glucose uptake and TH immunoreactivity without affecting BAT morphology and to induce insulin resistance in the NTS and systemic hyperinsulinemia. Moreover, an increase in hepatic TG content is observed, but no effects on the hepatic cytoarchitecture were observed. In summary, mitochondrial dynamics in the astrocytes of the NTS appear to be important regulators of BAT thermogenesis and hepatic lipid content, and they could constitute a novel therapeutic target to protect from the development of obesity and diabetes.