Astrocyte fatty acid uptake and ketogenesis in the mediobasal hypothalamus coordinate adaptive metabolic responses against high-fat diet exposure in male rodents
The mediobasal hypothalamus (MBH) constitutes a central regulator of energy homeostasis; specialized neurons in this region integrate peripheral metabolic signals to coordinate processes like food intake, energy expenditure or glucose homeostasis. While MBH neuronal dysfunction has been linked to obesity, increasing evidence indicates that astrocytes in this region are also active participants in the modulation of energy balance. MBH astrocyte ketone body signaling, in particular, has been proposed as an adaptive mechanism aimed at regulating energy homeostasis during dietary challenge. Here, we investigated the effects of MBH astrocytic lipid metabolism on the control of energy balance. We targeted distinct components of this pathway, ablating fatty acid (FA) transporter FATP4 in mice and knocking down 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) in rats. MBH astrocyte FATP4 depletion markedly exacerbated high-fat diet (HFD)-induced obesity, increasing body weight and fat mass independently of food intake. Rather, this phenotype was driven by reduced energy expenditure and impaired brown adipose tissue oxidation. HMGCL knockdown in MBH astrocytes also promoted HFD-induced weight gain, not only through reduced energy expenditure but also through a transient hyperphagic response during early HFD exposure. In vitro studies in primary astrocyte cultures confirmed that disruption of FATP4 altered the expression of genes involved in mitochondrial lipid oxidation and ketogenesis. Similarly, HMGCL knockdown reduced the expression of monocarboxylate transporter MCT4, suggesting impaired astrocytic lactate and/or ketone body release. Together, these findings identify MBH astrocyte lipid metabolism as a critical component of the hypothalamic circuitry regulating energy balance, highlighting astrocytes as active contributors to the pathogenesis of obesity.