The potential role of hypothalamic POMC^TRPM2 in interscapular BAT thermogenesis

The major function of primary order neurons in the arcuate nucleus of the hypothalamus is control of energy homeostasis. Among these neurons, proopiomelanocortin (POMC) neurons play a significant role in controlling anorexigenic feeding behavior and upregulating energy expenditure. In addition, transient receptor potential melastatin 2 (TRPM2) is a well-established temperature sensor, but no evidence of regulation of brown adipose tissue (BAT) thermogenesis via POMC^TRPM2 neurons in the arcuate nucleus has been reported so far. Here, through single-cell reverse-transcription and immunohistochemistry analyses, we confirmed that a subset of POMC neurons express TRPM2. Also, we confirmed the neuronal connection between POMC and BAT using cholera toxin subunit B. The chemogenetic stimulation of POMC neurons induced BAT thermogenesis, and this thermogenic effect was inhibited by a TRPM2 blocker. These results indicate that TRPM2 could modulate POMC neuronal activity and play a role in regulating BAT activity through neuronal connections. Adenosine diphosphoribose (ADPR), a TRPM2 agonist, depolarized POMC neurons, and this effect was suppressed by TRP and TRPM2 antagonists. In addition, intracerebrovascular injection of ADPR increased c-Fos expression of a subset of POMC neurons, BAT and core body temperature and expression of IRF-4, but not uncoupling protein 1, in normal chow diet- and high-fat diet-fed mice. TRPM2 antagonists blocked this increase. Our findings offer new insights into the physiological mechanism of IRF-4-mediated BAT thermogenesis, which is regulated by acute activation of hypothalamic POMC^TRPM2 neurons. Consequently, these approaches to promoting BAT thermogenesis can provide novel basic concepts to establish therapeutic strategies and precautions to combat metabolic disorders.