Chronic Urotensin-II Administration Improves Whole-Body Glucose Tolerance in High-Fat Diet-Fed Mice.

Li Zhang,Xi Chen,Guan-Hua Du,Lin Yin,Chun-Yang Xu,Wei-Hua Jia,Xiu-Ying Yang,Na Li,Nuo-Qi Wang,Gui-Fen Qiang,Bi-Yu Hou

doi:10.3389/fendo.2019.00453

Abstract

Urotensin-II (U-II) is an endogenous peptide agonist of a G protein-coupled receptor—urotensin receptor. There are many conflicting findings about the effects of U-II on blood glucose. This study aims to explore the effects of U-II on glucose metabolism in high-fat diet-fed mice. Male C57BL/6J mice were fed a 45% high-fat diet or chow diet and were administered U-II intraperitoneally for in vivo study. Skeletal muscle C2C12 cells were used to determine the effects of U-II on glucose and fatty acid metabolism as well as mitochondrial respiratory function. In this study, we found that chronic U-II administration (more than 7 days) ameliorated glucose tolerance in high-fat diet-fed mice. In addition, chronic U-II administration reduced the weight gain and the adipose tissue weight, including visceral, subcutaneous, and brown adipose tissue, without a significant change in blood lipid levels. These were accompanied by the increased mRNA expression of the mitochondrial thermogenesis gene Ucp3 in skeletal muscle. Furthermore, in vitro treatment with U-II directly enhanced glucose and free fatty acid consumption in C2C12 cells with increased aerobic respiration. Taken together, chronic U-II stimulation leads to improvement on glucose tolerance in high-fat diet-fed mice and this effect maybe closely related to the reduction in adipose tissue weights and enhancement on energy substrate utilization in skeletal muscle.

Highlights

Urotensin-II (U-II) was first isolated from the neurosecretory system of the goby fish (Gillichthys mirabilis) [1] and later cloned from humans [2]
Single administration of 100 nmol/kg U-II reduced α subunit of peroxisome proliferators activated receptor γ coactivator-1(Pgc1α) expression (Figure 1D) but induced uncoupling protein 3 (Ucp3) expression in skeletal muscle (Figure 1E)
Our results showed that the weights of several types of adipose tissue were significantly reduced in the U-II treatment group after 3 weeks of U-II treatments (Figures 4A–D), including epididymal adipose (Figure 4A), retroperitoneal adipose (Figure 4B), subcutaneous white adipose tissue (Figure 4C), and brown adipose tissue (BAT) (Figure 4D)

Summary

Introduction

Urotensin-II (U-II) was first isolated from the neurosecretory system of the goby fish (Gillichthys mirabilis) [1] and later cloned from humans [2]. U-II isopeptides have a cyclical structure and are 11–15 amino acids in length. The human U-II (hU-II) having been identified in the spinal cord is 11 amino acids long. The mRNA transcripts for the U-II precursor (UTS2) and UT receptor gene (UTS2R) are widely expressed in the central nervous system and in peripheral tissues, including the brain, kidney, liver, lung, pancreas, skeletal muscle, and other tissues and vascular and cardiac cells [5, 6]. Consistent with the wide distribution of U-II and UT receptors, the urotensinergic system has been linked with numerous pathological states, including atherosclerosis, heart failure, hypertension, renal disease, and diabetes [7]

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