Fatty Acid Synthase regulates glucose and energy homeostasis via POMC neurons and adrenergic signals.

OBJECTIVES: Hypothalamic Fatty Acid Synthase (FASN) plays a critical role in regulating energy balance by influencing food intake and body weight. This study aimed to investigate the neuronal mechanisms by which FASN impacts metabolism, focusing on its role in Pro-Opiomelanocortin (POMC) neurons. METHODS: We used transgenic mouse models with pre- or postnatal deletion of FASN specifically in POMC neurons in male mice. We evaluated changes in adiposity, glucose metabolism and metabolic parameters including food intake, energy expenditure and substrate utilization using metabolic chambers. Changes in neuronal activity were assessed using electrophysiology and further validated by optogenetic stimulation of POMC neurons. Additionally, the role of adrenergic signaling was examined using pharmacological approaches and gene expression analyses. RESULTS: FASN deletion in POMC neurons reduced food intake, decreased adiposity, and altered glucose metabolism. FASN-deficient POMC neurons exhibited increased baseline activity. The developmental stage of FASN deletion influenced its effects on energy expenditure and body weight regulation. Additionally, FASN in POMC neurons was found to be essential for maintaining glucose homeostasis and insulin release via adrenergic signaling. CONCLUSIONS: FASN in POMC neurons plays an age- and neuron-specific role in regulating feeding, energy expenditure, and glucose homeostasis through mechanisms including the sympathetic nervous system. These findings highlight FASN as a potential therapeutic target for metabolic diseases by improving energy expenditure and insulinemia. Given the developmental programming of metabolic outcomes, interventions aimed at modulating FASN activity may have long-lasting benefits in managing metabolic diseases.