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Overexpression of C-type Natriuretic Peptide in Endothelial Cells Protects against Insulin Resistance and Inflammation during Diet-induced Obesity.

ABSTRACT: The endogenous peptide C-type natriuretic peptide (CNP) binds its receptor, guanylyl cyclase B (GCB), and is expressed by endothelial cells in diverse tissues. Because the endothelial cells of visceral adipose tissue have recently been reported to play a role in lipid metabolism and inflammation, we investigated the effects of CNP on features of obesity by using transgenic (Tg) mice in which CNP was placed under the control of the Tie2 promoter and was thus overexpressed in endothelial cells (E-CNP). Here we show that increased brown adipose tissue thermogenesis in E-CNP Tg mice increased energy expenditure, decreased mesenteric white adipose tissue (MesWAT) fat weight and adipocyte hypertrophy, and prevented the development of fatty liver. Furthermore, CNP overexpression improved glucose tolerance, decreased insulin resistance, and inhibited macrophage infiltration in MesWAT, thus suppressing pro-inflammation during high-fat diet-induced obesity. Our findings indicate an important role for the CNP produced by the endothelial cells in the regulation of MesWAT hypertrophy, insulin resistance, and inflammation during high-fat diet-induced obesity.

SUBMITTER: Bae CR

PROVIDER: S-EPMC5574992 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance.

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Myeloid cell-restricted insulin receptor deficiency protects against obesity-induced inflammation and systemic insulin resistance.

Project description:A major component of obesity-related insulin resistance is the establishment of a chronic inflammatory state with invasion of white adipose tissue by mononuclear cells. This results in the release of pro-inflammatory cytokines, which in turn leads to insulin resistance in target tissues such as skeletal muscle and liver. To determine the role of insulin action in macrophages and monocytes in obesity-associated insulin resistance, we conditionally inactivated the insulin receptor (IR) gene in myeloid lineage cells in mice (IR(Deltamyel)-mice). While these animals exhibit unaltered glucose metabolism on a normal diet, they are protected from the development of obesity-associated insulin resistance upon high fat feeding. Euglycemic, hyperinsulinemic clamp studies demonstrate that this results from decreased basal hepatic glucose production and from increased insulin-stimulated glucose disposal in skeletal muscle. Furthermore, IR(Deltamyel)-mice exhibit decreased concentrations of circulating tumor necrosis factor (TNF) alpha and thus reduced c-Jun N-terminal kinase (JNK) activity in skeletal muscle upon high fat feeding, reflecting a dramatic reduction of the chronic and systemic low-grade inflammatory state associated with obesity. This is paralleled by a reduced accumulation of macrophages in white adipose tissue due to a pronounced impairment of matrix metalloproteinase (MMP) 9 expression and activity in these cells. These data indicate that insulin action in myeloid cells plays an unexpected, critical role in the regulation of macrophage invasion into white adipose tissue and in the development of obesity-associated insulin resistance.

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Project description:Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13(+/-)) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13(-/-)) are embryonic lethal. Male and female ubc13(+/-) mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13(+/-) mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13(+/-) mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions.

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