Losartan Attenuates Insulin Resistance and Regulates Browning Phenomenon of White Adipose Tissue in ob/ob Mice.

Hsuan-Miao Liu,Tse-Hung Huang,Cheng-Hui Wang,Tzung-Yan Lee,Zi-Yu Chang

doi:10.3390/cimb43030128

Abstract

Insulin resistance (IR) is a villain role to the pathology of fatty liver diseases implicated in adipose tissue dysfunction, which is characterized by lipid droplets (LDs) accumulation and hypoxia-inducible factor 1α (HIF1α) related macrophage infiltration. HIF1α is required for its lipogenic actions in adipocytes, while and it regulates M1 and M2 polarization features of macrophages. Losartan has been shown to be an insulin sensitizer in obese states, actions involving in HIF1α signaling. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, GTT, ITT, and HOMA-IR were identified losartan alleviated IR signaling in obese mice. This alleviation may through inhibits HIF1α by suppressing STAT3-NF-κB signaling, which, in turn, revealed HIF1α-dependent decreases the angiogenesis pathway in adipose tissue, including regulation of VEGF and TGFβR2 levels. In white adipose tissue, a set of lipogenesis-related genes, Srebp1, Fas, and Scd-1 were markedly downregulated after losartan intervention, as well as reduced LDs size and LD-associated proteins, perilipin family proteins (PLINs) compared with obese mice. Losartan abolished macrophage infiltration with upregulation of M2 and inhibition of M1 macrophage markers in obese mice. Our data suggest that losartan attenuated obese-induced fatty liver, linked to alleviating inflammation in adipose tissues and a shift in M1/M2 macrophage balance. Furthermore, losartan might improve mitochondria biogenesis by upregulating SIRT1, PGC1α, UCP1, and mRNA of Tfam, Cd137, Tmem26, Ucp1 expression in white adipose tissue compared with the obese group. Taken together, losartan may improve IR and adipose dysfunction by inhibiting lipotoxicity and HIF1α pathways.

Highlights

Adipose dysfunction may influence glucose homeostasis, including increased adipose energy storage in obesity results in increased free fatty acid (FFA) flux to other tissues, which promote insulin resistance (IR) and potential adverse effects, referred to by some as “lipotoxicity” [1]
We found that losartan (i) improved glucose tolerance test (GTT), insulin tolerance test (ITT), and homeostasis model assessment of insulin resistance (HOMA-IR); (ii) ameliorated Lipid droplets (LDs) accumulation in liver and epididymis white adipose tissue (WAT) (EWAT); (iii) suppressed M1/M2 macrophage ratio and inflammation in ob/ob mice; (iv) promoted mitochondrial biogenesis and homeostasis model assessment of insulin resistance (HOMA-IR); (ii) ameliorated LDs accumulation in liver and epididymis WAT (EWAT); (iii) suppressed M1/M2 macrophage
The variation of the endocrine functions and metabolic of adipose tissue is constantly The variation of the endocrine functions and metabolic of adipose tissue is constantly associated with type 2 diabetes and IR

Summary

Introduction

Adipose dysfunction may influence glucose homeostasis, including increased adipose energy storage in obesity results in increased free fatty acid (FFA) flux to other tissues, which promote insulin resistance (IR) and potential adverse effects, referred to by some as “lipotoxicity” [1]. Both lipotoxicity and inflammation play a major role in adipose tissue dysfunction in development of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and IR [2]. In adipose tissue, impaired insulin action allows for increased lipolysis, which will contribute to re-esterification of lipids in other tissues (such as liver) and further exacerbates IR [4]. Lipid droplets (LDs)-associated proteins, such as perilipins (PLINs), and the cell death-inducing DNA fragmentation factor-alpha-like effector (CIDE)

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