Objective Elevation of energy expenditure through an increase of brown adipose tissue (BAT) thermogenesis is regarded as one of the most promising ways to prevent obesity development. The preoptic area (POA) of the hypothalamus is a critical area for control of BAT thermogenesis. However, the intracellular signaling cascades in the POA for regulation of BAT thermogenesis are poorly understood. Methods Phosphorylation proteomics (phosphoproteomics) and bioinformatics approaches were used to disclose numerous hypothalamic signaling pathways involved in the regulation of BAT thermogenesis. Conditional manipulation of the p38α gene in mouse POA was performed by stereotaxic injection of adeno‐associated virus 9 vector to explore the role of p38α in BAT thermogenesis. Results Multiple hypothalamic signaling pathways were triggered by cold exposure, especially the mitogen‐activated protein kinase (MAPK) signaling pathway. The p38α activation, but not extracellular signal‐regulated kinase 1/2 (ERK1/2) and c‐Jun NH2‐terminal kinase (JNK), in the hypothalamus was significantly decreased during cold exposure. p38α deficiency in the POA dramatically elevated energy expenditure owing to a marked increase in BAT thermogenesis, resulting in significantly decreased body weight gain and fat mass. Overexpression of p38α in the POA led to a dramatic increase in weight gain. Conclusions These results demonstrate that p38α in the POA exacerbates obesity development, at least in part owing to a decrease in BAT thermogenesis.

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