Abstract
BackgroundBeige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice.MethodsMale Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content.ResultsGQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT.ConclusionThis study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT.General SignificanceThese findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity.
Highlights
Obesity and type 2 diabetes are currently major health problems worldwide
This study suggests for the first time that a partial peroxisome proliferator-activated receptor-γ (PPARγ) agonist may increase brown adipose tissue (BAT) activity and induce the expression of thermogenesis-related genes in visceral white adipose tissue (WAT)
These findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity
Summary
Obesity and type 2 diabetes are currently major health problems worldwide. The rate at which new cases are emerging and the significant risk of both morbidity and mortality stemming from its long-term vascular complications pose great health, social and economic challenges worldwide. A third type of adipocyte, so-called “beige” or “brite”, was described in rodents as an inducible cell type in WAT depots, in a process named browning of white fat These cells share morphological features with brown adipocytes, express markers of thermogenesis, such as UCP-1, and display full thermogenic capacity upon stimuli such as cold and β3-adrenergic signaling [5]. Beige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice
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