Astrocytic lipid metabolism determines susceptibility to diet-induced obesity

Hypothalamic astrocytes play pivotal roles in both nutrient sensing and the modulation of synaptic plasticity of hypothalamic neuronal circuits in control of feeding and systemic glucose and energy metabolism. Here, we show the relevance of astrocytic fatty acid (FA) homeostasis under the opposing control of angiopoietin-like 4 (ANGPTL-4) and peroxisome proliferator–activated receptor gamma (PPARγ) in the cellular adaptations of hypothalamic astrocytes and neurons to the changing metabolic milieu. We observed that increased availability of FA in astrocytes induced by cell- and time-selective knockdown of Angptl4 protected against diet-induced obesity, while cell- and time-selective knockdown of Angptl4-regulated Pparγ lead to elevated susceptibility to obesity. Overall, our results unravel a previously unidentified role for astrocytic FA metabolism in central control of body weight and glucose homeostasis.