Dax1 in AgRP neurons regulates thermogenesis via GR-HDAC3-mediated CRFR1 suppression

The arcuate nucleus of the hypothalamus plays a pivotal role in metabolic homeostasis by integrating the functions of AgRP and POMC neurons. Dax1, a nuclear receptor-like transcription factor, is highly enriched in AgRP neurons; however, its role in energy balance regulation remains largely unexplored. Here, we demonstrate the function of Dax1 in hypothalamic AgRP neurons and its contribution to systemic energy homeostasis and thermogenesis in mice.

We generated AgRP neuron-specific Dax1 conditional knockout mice and assessed their physiological and metabolic responses under high-fat diet feeding and cold exposure. Energy expenditure, brown adipose tissue (BAT) thermogenesis, neuronal activation, and neuropeptide expression were evaluated. Molecular mechanisms were investigated by gene expression analysis, chromatin immunoprecipitation, and biochemical assays.

We show that conditional deletion of Dax1 in AgRP neurons enhances energy expenditure, stimulates BAT thermogenesis, and confers resistance to diet-induced obesity in female mice. Notably, these mice exhibit blunted AgRP neuron activation upon cold challenge. Mechanistically, corticotropin-releasing factor receptor type 1 (CRFR1), a key regulator of AgRP neuronal excitability, was upregulated in Dax1-deficient AgRP neurons. We further identified that Dax1 recruits the HDAC3 corepressor complex to the glucocorticoid receptor at the glucocorticoid response element within the Crfr1 promoter, thereby repressing Crfr1 transcription in response to glucocorticoid signaling.

Our findings establish Dax1 as a critical transcriptional repressor of Crfr1 in AgRP neurons, linking hypothalamic steroid signaling to the regulation of adaptive thermogenesis and systemic energy balance.