Effects of lobeglitazone on insulin resistance and hepatic steatosis in high-fat diet-fed mice

PLoS One. 2018 Jul 6;13(7):e0200336. doi: 10.1371/journal.pone.0200336. eCollection 2018.

Abstract

Lobeglitazone (Lobe) is a novel thiazolidinedione antidiabetic drug that reduces insulin resistance by activating peroxisome proliferator-activated receptor-gamma (PPARγ). However, the exact mechanisms of antidiabetic effects of Lobe have not been established in an animal model. The aim of this study was to evaluate the hypoglycemic effects of Lobe and investigate possible factors involved in Lobe-enhanced hepatic steatosis in high-fat diet (HFD)-fed mice. Mice were fed an HFD for 15 weeks. Lobe was administrated orally during the last 9 weeks. Lobe treatment significantly reduced insulin resistance and increased expression of hepatic glucose transporter 4 (GLUT4) and PPARs in HFD-fed mice. However, increased body weight and hepatic steatosis were not reduced by Lobe in these mice. Metabolomics fingerprinting showed that several lipogenesis-related hepatic and serum metabolites in HFD-fed mice had positive or negative correlations with Lobe administration. In particular, increased leptin levels during HFD were further increased by Lobe. HFD-induced signaling transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus was increased by Lobe. In addition, immunohistochemical analysis showed more proopiomelanocortin (POMC)-positive neurons in the hypothalamus of HFD-fed mice (with or without Lobe) compared with normal diet-fed mice. Despite improving leptin signaling in the hypothalamus and enhancing insulin sensitivity in HFD-fed mice, Lobe increased body weight and steatosis. Further research is necessary regarding other factors affecting Lobe-enhanced hepatic steatosis and hyperphagia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Diet, High-Fat
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Glucose Transporter Type 4 / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / physiology*
  • Lipogenesis / drug effects
  • Liver / drug effects*
  • Liver / metabolism
  • Mice
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use

Substances

  • Glucose Transporter Type 4
  • Hypoglycemic Agents
  • PPAR gamma
  • Pyrimidines
  • STAT3 Transcription Factor
  • Thiazolidinediones
  • AMP-Activated Protein Kinases
  • lobeglitazone

Grant support

This study (GSR) was supported by the Basic Science Research Program through the National Research Foundation (NRF) of Korea (No. 2015R1A5A2008833). Author Hyun-Jin Kim is affiliated to EZmass Co., Ltd., which is a Personal Venture Company of Dr. Hyun-Jin Kim’s lab at Gyeongsang National University. EZmass Co., Ltd. provided support in the form of salary for author H-JK, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.