The prevalence of obesity worldwide is increasing sharply, and while surgical and behavioural interventions are largely employed, their efficacy is scarce on the long-term. Alternative approaches, targeting the brown adipose tissue (BAT) are being investigated due to the potent thermogenic effects of this organ. BAT activation is driven by direct adrenergic sympathetic discharge from the central nervous system (CNS) and circulating glucose and fatty acids. The nucleus of the tractus solitarius (NTS) in the brainstem is an important relay centre for information related to nutritional status, provided by the visceral vagal afferents; astrocytes are the most abundant cells in the brain and their role in regulating systemic metabolism is of growing interest, and evidence show their involvement in BAT thermogenesis (Manaserh et al., 2020).
 
Previous studies within our group have shown that inhibition of mitochondria fission in astrocytes- using an adenoviral vector expressing a dominant negative form of Drp1 in astrocytes of the NTS (GFAP:Drp1-K38A)-was sufficient to reduce food intake and prevent weight gain in HFD-fed rats (Patel et al., 2021).
Our main aim is to investigate whether targeting NTS astrocytes with GFAP:Drp1-K38A could affect the thermogenic profile of BAT and increase adrenergic discharge to the organ, which associates with enhanced metabolic demand. The experimental protocol was approved by the ethical committee for the use of animals in research of the University of Leeds. Male SD rats were subjected to stereotactic surgery followed by an injection of either GFAP:Drp1-K38A or GFAP:GFP in the NTS. Animals were fed HFD (5.51 kcal/g) diet for 15 days and sacrificed by pentobarbital overdose (60 mg/kg).Values are mean ±SEM and analysed with one-way ANOVA.
 
Noradrenaline precursor Tyrosine Hydroxylase (TH) levels in BAT of HFD-fed animals that received GFAP:Drp1K38-A in the NTS are increased 144% when compared to GFAP:GFP controls (p<0.001) (n=4). The mRNA levels of Collagen Type I (CD36) are significantly increased, and the lipolytic markers adipose trygliceride lipase (PNPLA2) and hormone sensitive lipase (HSL) are significantly downregulated in animals that received GFAP:Drp1K38-A in the NTS when compared to controls (p<0.0001, p<0.0001 and p<0.0001 respectively).Uncoupling protein 1 (UCP1) mRNA transcript were unchanged between the two groups (n=12).
Our treatment does not seem to impact-UCP1 dependent thermogenesis, however, our results suggest that inhibition of mitochondria fission in NTS astrocytes restored TH reservoirs in BAT-essential for beta adrenergic-driven thermogenesis, and appears to induce a preferential uptake for fatty acids (FA) rather than triglycerides in BAT as suggested by increased mRNA transcripts of fatty acid transporter CD36 and decreased lipolytic markers ATGL and HSL. These findings support previous findings by (Shin et al., 2018) which suggest that BAT lipolysis in brown adipose tissue is not required for non-shivering thermogenesis. and that FA are uptake in BAT following lipolysis mediated liberation of FA in white adipose tissue (WAT). In this scenario NTS astrocytes may be able to mediate a centrally driven shift in BAT metabolic demand to maximise uptake and combustion of excess nutrients derived from diet and/or WAT lipolysis during high-fat diet.