Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway

Activating beige adipocytes in white adipose tissue (WAT) to increase energy expenditure is a promising strategy to combat obesity. We identified that mesencephalic astrocyte-derived neurotrophic factor (Manf) is a feeding-induced hepatokine. Liver-specific Manf overexpression protected mice against high-fat diet-induced obesity and promoted browning of inguinal subcutaneous WAT (iWAT). Manf overexpression in liver was also associated with decreased adipose inflammation and improved insulin sensitivity and hepatic steatosis. Mechanistically, Manf could directly promote browning of white adipocytes via the p38 MAPK pathway. Blockade of p38 MAPK abolished Manf-induced browning. Consistently, liver-specific Manf knockout mice showed impaired iWAT browning and exacerbated diet-induced obesity, insulin resistance, and hepatic steatosis. Recombinant Manf reduced obesity and improved insulin resistance in both diet-induced and genetic obese mouse models. Finally, we showed that circulating Manf level was positively correlated with BMI in humans. This study reveals the crucial role of Manf in regulating thermogenesis in adipose tissue, representing a potential therapeutic target for obesity and related metabolic disorders.