Dataset Information

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ER?/HGF/Met Pathway.

ABSTRACT: Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling is sufficient and necessary for such improvements. Hepatic gene and protein expression suggests that MRKO reduces hepatic lipogenesis and lipid storage. In the presence of estrogen, MRKO in macrophages decreases lipid accumulation and increases insulin sensitivity of hepatocytes through hepatocyte growth factor (HGF)/Met signaling. MR directly regulates estrogen receptor 1 (Esr1 [encoding ER?]) in macrophages. Knockdown of hepatic Met eliminates the beneficial effects of MRKO in female obese mice. These findings identify a novel MR/ER?/HGF/Met pathway that conveys metabolic signaling from macrophages to hepatocytes in hepatic steatosis and insulin resistance and provide potential new therapeutic strategies for NAFLD and T2DM.

SUBMITTER: Zhang YY

PROVIDER: S-EPMC5860190 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.

Zhang Yu-Yao YY Li Chao C Yao Gao-Feng GF Du Lin-Juan LJ Liu Yuan Y Zheng Xiao-Jun XJ Yan Shuai S Sun Jian-Yong JY Liu Yan Y Liu Ming-Zhu MZ Zhang Xiaoran X Wei Gang G Tong Wenxin W Chen Xiaobei X Wu Yong Y Sun Shuyang S Liu Suling S Ding Qiurong Q Yu Ying Y Yin Huiyong H Duan Sheng-Zhong SZ

Diabetes 20170321 6

Although the importance of macrophages in nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) has been recognized, how macrophages affect hepatocytes remains elusive. Mineralocorticoid receptor (MR) has been implicated to play important roles in NAFLD and T2DM. However, cellular and molecular mechanisms are largely unknown. We report that myeloid MR knockout (MRKO) improves glucose intolerance, insulin resistance, and hepatic steatosis in obese mice. Estrogen signaling i ...[more]

PMID: 28325853

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Project description:Background/objectivesVisceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice.Subjects/methodsFour adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4-5/group), cellular composition (FACS analysis, n = 5-6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6-10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5-11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8-10/group).ResultsWe found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many "non-adipocytes" such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05).ConclusionsPAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

Dataset Information

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ER?/HGF/Met Pathway.

Publications

Deletion of Macrophage Mineralocorticoid Receptor Protects Hepatic Steatosis and Insulin Resistance Through ERα/HGF/Met Pathway.

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