Exacerbation by knocking-out metallothionein gene of obesity-induced cardiac remodeling is associated with the activation of CARD9 signaling.

in International journal of biological sciences by Haina Zhang, Wenqian Zhou, Xiang Wang, Hongbo Men, Jiqun Wang, Jianxiang Xu, Shanshan Zhou, Quan Liu, Lu Cai

TLDR

  • The study found that metallothionein (MT) knockout mice developed more severe obesity and metabolic disorder compared to wild-type mice, and that MT may play a protective role in preventing obesity-induced metabolic syndrome and cardiovascular disease.
  • Key Insights: MT-KO mice had increased cardiac macrophages, proinflammatory cytokines, and oxidative stress, but decreased MT expression, the mechanism of which needs further investigation.

Abstract

Obesity increases the risk of metabolic syndrome including insulin resistance, dyslipidemia, and cardiovascular disease. We demonstrated insulin resistance, cardiac hypertrophy, and cardiac inflammation in an obese mouse model induced by a high-fat diet (HFD). Caspase recruitment domain-containing protein 9 (CARD9) and B-cell lymphoma/leukemia 10 (BCL10) were upregulated, and p38 MAPK was activated in these mice. Zinc supplementation prevented these changes with upregulation of metallothionein (MT). Deletion ofexacerbated palmitate-triggered expression of BCL10 and p38 MAPK activation and eliminated the protective benefits of zinc in palmitate-treated cardiomyocytes. Here we further investigated the mechanisms by which endogenous MT expression affects HFD-induced cardiac remodeling and the CARD9/BCL10/p38 MAPK pathway. Maleknockout and 129S wild-type mice were assigned to receive either a normal diet or a HFD from 8-week-age for 18 weeks.knockout (KO) aggravated HFD-induced obesity and systemic metabolic disorder, reflected by increased body weight, perirenal white adipose tissue, and plasma cholesterol, and cardiac hypertrophy and fibrosis. Obese-KO mice had abundant cardiac macrophages, upregulated cardiac proinflammatory cytokines, chemokines, adhesion molecules, CARD9, and BCL10 and activated NF-κB.-KO exacerbated HFD-induced trace metal dyshomeostasis and oxidative stress.-KO combined with HFD-induced obesity synergistically promotes cardiac remodeling, possibly via trace metal dyshomeostasis-induced oxidative stress to trigger CARD9/BCL10-mediated NF-κB activation.

Overview

  • The study investigated the effects of obesity on metabolic syndrome and cardiovascular disease in mice.
  • The researchers found that caspase recruitment domain-containing protein 9 (CARD9) and B-cell lymphoma/leukemia 10 (BCL10) were upregulated, and p38 MAPK was activated in obese mice.
  • Zinc supplementation prevented these changes and upregulated metallothionein (MT).

Comparative Analysis & Findings

  • The study compared the effects of high-fat diet (HFD) on wild-type and metallothionein (MT) knockout (KO) mice.
  • The researchers found that MT-KO mice developed more severe obesity and metabolic disorder compared to wild-type mice.
  • The study also found that MT-KO mice had increased cardiac macrophages, proinflammatory cytokines, and oxidative stress, but decreased metallothionein (MT) expression.

Implications and Future Directions

  • The study suggests that metallothionein (MT) may play a protective role in preventing obesity-induced metabolic syndrome and cardiovascular disease.
  • Future studies should investigate the mechanisms by which MT regulates the CARD9/BCL10/p38 MAPK pathway and its potential therapeutic applications.
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