FAM237B, a conserved orexigenic neuropeptide, is regulated by fasting, insulin, and neuroinflammation in mouse...

Agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons in the arcuate nucleus integrate metabolic and inflammatory signals to control food intake. FAM237B (Gm8773/NPGM) is a putative orexigenic peptide enriched in a subset of AgRP neurons, yet misannotated as a long non-coding RNA in mice that has since been recognized as a 139 aa microprotein. Here, we combine evolutionary, transcriptomic, and physiological approaches to define FAM237B as an ancient, metabolically regulated neuropeptide within NPY/AgRP neurons. Comparative genomics and synteny analysis show that the Fam237b gene is conserved from jawless vertebrates to mammals and likely predates AgRP, with a highly conserved C-terminal region and sequence consistent with prohormone processing. Single-cell and bulk RNA sequencing reveal that Fam237b is enriched in mouse arcuate AgRP neurons and present at lower levels in the human hypothalamus. In NPY/AgRP hypothalamic cell models and in mice, Fam237b expression rises with fasting or serum withdrawal and is suppressed by insulin in parallel with Agrp. Insulin-mediated repression of Fam237b requires PI3K, but not MEK, signaling. Finally, pro-inflammatory stimuli (LPS, IL-6, and TNF-α) robustly increase Fam237b mRNA in primary hypothalamic cultures and NPY/AgRP cell models. These findings position FAM237B as an evolutionarily conserved micropeptide with a role in hypothalamic regulation of food intake and energy homeostasis, whose expression is jointly tuned by energy status, insulin signaling, and neuroinflammation.