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摄食诱导的肝激素 Manf 通过 p38MAPK 通路促进脂肪褐变来改善饮食诱导的肥胖。

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

机构信息

Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

出版信息

J Exp Med. 2021 Jun 7;218(6). doi: 10.1084/jem.20201203.

DOI:10.1084/jem.20201203
PMID:33856409
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8054200/
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.

摘要

激活白色脂肪组织（WAT）中的米色脂肪细胞以增加能量消耗是对抗肥胖的一种有前途的策略。我们发现中脑神经胶质细胞衍生神经营养因子（Manf）是一种进食诱导的肝源激素。肝脏特异性 Manf 过表达可保护小鼠免受高脂肪饮食诱导的肥胖，并促进腹股沟皮下 WAT（iWAT）的棕色化。肝脏中 Manf 的过表达还与脂肪炎症减少以及胰岛素敏感性和肝脂肪变性改善有关。从机制上讲，Manf 可以通过 p38 MAPK 途径直接促进白色脂肪细胞的棕色化。p38 MAPK 的阻断消除了 Manf 诱导的棕色化。一致地，肝脏特异性 Manf 敲除小鼠表现出腹股沟 iWAT 棕色化受损，并加剧了饮食诱导的肥胖、胰岛素抵抗和肝脂肪变性。重组 Manf 可减轻两种饮食诱导和遗传肥胖小鼠模型的肥胖并改善胰岛素抵抗。最后，我们表明循环 Manf 水平与人的 BMI 呈正相关。这项研究揭示了 Manf 在调节脂肪组织产热中的关键作用，代表了肥胖和相关代谢紊乱的潜在治疗靶点。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bd3f/8054200/deefbf925f4d/JEM_20201203_Fig1.jpg
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