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

Abstract

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.

Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism

“…Emerging evidence has now revealed that a number of hepatokines possess a metabolic capacity to regulate a myriad of biological processes in multiple extrahepatic tissues. In addition, hepatokines mediate the physiological benefit and/or influence in certain circumstances, such as exercise [ 238 ] and fasting/refeeding transition [ 239 , 240 ], suggesting that hepatokines can be attractive and important targets for the maintenance of metabolic homeostasis. Hepatokine dysregulation is implicated in the development of NAFLD and insulin resistance.…”

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

“…Indeed, a majority of genes altered by WD were equivalently up- or down-regulated across genotypes (Figure 5A-B; Figure S13). Top down-regulated genes included those previously associated with diabetes and obesity, such as Manf 28 and Creld2 29 that facilitate protein folding (Figure 5C), and Igfbp3 and Igfbp7 , two structurally similar proteins that regulate the bioavailability of IGFs and insulin. As noted for WD-fed MR-Intact mice, WD also down-regulated genes associated with extracellular matrix in SMC-MR-KO mice (Figure 5C, Table S13 and 14) and top up-regulated genes also included those implicated in diabetes and obesity, such as Cd36, Txnip, Angptl4, Cyp1a1 , and Fabp4 (Figure 5D).…”

P2X7 Activation Enhances Lipid Accumulation During Adipocytes Differentiation Through Suppressing the Expression of Sirtuin-3, Sirtuin-5, and Browning Genes

“…Obesogenic stimuli and HFD may also increase BAT thermogenic capacity to maintain body weight ( García-Ruiz et al, 2015 ). The feeding-induced mesencephalic astrocyte-derived neurotrophic factor was recently shown to ameliorate diet-induced obesity by promoting adipose browning ( Wu et al, 2021 ). A study detected an increased gene expression of P2X7 not only in WAT but also in whitened BAT of diet-induced obesity and ob/ob mice.…”