A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice

Objective: Nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries h...

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Autores principales:	Dan Wu, Venkateswararao Eeda, Ram Babu Undi, Shivani Mann, Michael Stout, Hui-Ying Lim, Weidong Wang
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Insulin resistance Type 2 diabetes Obesity PPARγ PPARγ agonist White-to-brown conversion Internal medicine RC31-1245
Acceso en línea:	https://doaj.org/article/7719d52b396d4a2699204719731d6da7
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spelling	oai:doaj.org-article:7719d52b396d4a2699204719731d6da72021-11-24T04:29:00ZA novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice2212-877810.1016/j.molmet.2021.101363https://doaj.org/article/7719d52b396d4a2699204719731d6da72021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2212877821002106https://doaj.org/toc/2212-8778Objective: Nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice. Methods: A novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated. Results: WO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis. Conclusions: WO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.Dan WuVenkateswararao EedaRam Babu UndiShivani MannMichael StoutHui-Ying LimWeidong WangElsevierarticleInsulin resistanceType 2 diabetesObesityPPARγPPARγ agonistWhite-to-brown conversionInternal medicineRC31-1245ENMolecular Metabolism, Vol 54, Iss , Pp 101363- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Insulin resistance Type 2 diabetes Obesity PPARγ PPARγ agonist White-to-brown conversion Internal medicine RC31-1245
spellingShingle	Insulin resistance Type 2 diabetes Obesity PPARγ PPARγ agonist White-to-brown conversion Internal medicine RC31-1245 Dan Wu Venkateswararao Eeda Ram Babu Undi Shivani Mann Michael Stout Hui-Ying Lim Weidong Wang A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
description	Objective: Nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice. Methods: A novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated. Results: WO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis. Conclusions: WO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.
format	article
author	Dan Wu Venkateswararao Eeda Ram Babu Undi Shivani Mann Michael Stout Hui-Ying Lim Weidong Wang
author_facet	Dan Wu Venkateswararao Eeda Ram Babu Undi Shivani Mann Michael Stout Hui-Ying Lim Weidong Wang
author_sort	Dan Wu
title	A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
title_short	A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
title_full	A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
title_fullStr	A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
title_full_unstemmed	A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
title_sort	novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/7719d52b396d4a2699204719731d6da7
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A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice

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