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The cytokine-like protein FAM19A5 is highly expressed in the brain, but little is known about its functions there. Here, we found that FAM19A5 was expressed in mouse hypothalamic cells expressing proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP), and in the microglia. Tumor necrosis factor-α (TNF-α), which induces inflammatory sickness responses, greatly increased hypothalamic expression of FAM19A5. Knockdown of FAM19A5 expression resulted in decreased TNF-α-induced anorexia, body weight loss and TNF-α-induced expression of inflammatory factors. In contrast, intracerebroventricular administration of FAM19A5 induced anorexia, body weight loss and hyperthermia, together with increased expression of inflammatory factors. FAM19A5 injection also induced increases in c-fos activation and POMC mRNA level in hypothalamic POMC neurons. Together, these results suggest that FAM19A5 plays an important role in hypothalamic inflammatory responses. • FAM19A5 is expressed in hypothalamic proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. • FAM19A5 is involved in tumor necrosis factor-α-induced hypothalamic inflammatory responses. • FAM19A5 induces anorexia, body weight loss and hyperthermia and increases mRNA expression of inflammatory factors and POMC. [ABSTRACT FROM AUTHOR]