Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and activity

Objectives Brown adipose tissue (BAT) is a potent thermogenic organ, activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT activity.

Methods Eight-week-old male Sprague Dawley rats received DVC stereotactic surgery to facilitate brain infusion for local administration of viruses that express mutated Drp1 genes. PET/CT scans were used to measure BAT glucose uptake using. Biochemical assays and immunohistochemistry determined altered levels of key signalling molecules and neural innervation of BAT.

Results We show that short-term HFD-feeding decreases the ability of BAT to uptake glucose and decreases catecholaminergic innervation of BAT, observed by altered intensities and pools of Tyrosine Hydroxylase (TH) labelling. HFD also increased the infiltration of enlarged white fat droplets in the BAT. We demonstrate that inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats can prevent the effects on BAT morphology and neural innervation, and increase BAT glucose uptake while lowering blood glucose and insulin levels. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduces BAT glucose uptake, TH and β3-adrenergic receptor levels.

Conclusions Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase energy expenditure and protect from developing obesity and diabetes.