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Samuel M Lee Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Jose Muratalla Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Marta Sierra-Cruz Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Jose Cordoba-Chacon Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA

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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.

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Abigail Wolf Greenstein Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Biologic Resources Laboratory, University of Illinois at Chicago, Chicago, Illinois, USA

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Neena Majumdar Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Peng Yang Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Papasani V Subbaiah Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Rhonda D Kineman Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Jose Cordoba-Chacon Research and Development Division, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA
Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Peroxisome proliferator-activated receptor γ (PPARγ) is the target for thiazolidinones (TZDs), drugs that improve insulin sensitivity and fatty liver in humans and rodent models, related to a reduction in hepatic de novo lipogenesis (DNL). The systemic effects of TZDs are in contrast to reports suggesting hepatocyte-specific activation of PPARγ promotes DNL, triacylglycerol (TAG) uptake and fatty acid (FA) esterification. As these hepatocyte-specific effects of PPARγ could counterbalance the positive therapeutic actions of systemic delivery of TZDs, the current study used a mouse model of adult-onset, liver (hepatocyte)-specific PPARγ knockdown (aLivPPARγkd). This model has advantages over existing congenital knockout models, by avoiding compensatory changes related to embryonic knockdown, thus better modeling the impact of altering PPARγ on adult physiology, where metabolic diseases most frequently develop. The impact of aLivPPARγkd on hepatic gene expression and endpoints in lipid metabolism was examined after 1 or 18 weeks (Chow-fed) or after 14 weeks of low- or high-fat (HF) diet. aLivPPARγkd reduced hepatic TAG content but did not impact endpoints in DNL or TAG uptake. However, aLivPPARγkd reduced the expression of the FA translocase (Cd36), in 18-week Chow- and HF-fed mice, associated with increased NEFA after HF feeding. Also, aLivPPARγkd dramatically reduced Mogat1 expression, that was reflected by an increase in hepatic monoacylglycerol (MAG) levels, indicative of reduced MOGAT activity. These results, coupled with previous reports, suggest that Cd36-mediated FA uptake and MAG pathway-mediated FA esterification are major targets of hepatocyte PPARγ, where loss of this control explains in part the protection against steatosis observed after aLivPPARγkd.

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Ellen R Lubbers Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Edward O List Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Adam Jara Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine
Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Lucila Sackman-Sala Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Jose Cordoba-Chacon Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Manuel D Gahete Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Rhonda D Kineman Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Ravneet Boparai Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Andrzej Bartke Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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John J Kopchick Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine
Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Darlene E Berryman Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine
Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine
Edison Biotechnology Institute, Department of Biomedical Sciences, School of Applied Health Sciences and Wellness, Jesse Brown VA Medical Center, Southern Illinois University School of Medicine

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Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high-molecular-weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered GH signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH vs IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying that the effects of GH on adiponectin are depot specific. Interestingly, rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity.

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Kristen R Lednovich Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Sophie Gough Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Medha Priyadarshini Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Nupur Pandya Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Chioma Nnyamah Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Kai Xu Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Barton Wicksteed Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Sidharth Mishra USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida, USA

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Shalini Jain USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida, USA

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Joseph L Zapater Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA

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Jose Cordoba-Chacon Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA

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Hariom Yadav USF Center for Microbiome Research, University of South Florida Morsani College of Medicine, Tampa, Florida, USA

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Brian T Layden Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA

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Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar ‘Western diet’ (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.

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Andre Sarmento-Cabral Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mercedes del Rio-Moreno Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mari C Vazquez-Borrego Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Mariyah Mahmood Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Elena Gutierrez-Casado Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Natalie Pelke Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Grace Guzman Department of Pathology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA

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Papasani V Subbaiah Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Jose Cordoba-Chacon Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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Shoshana Yakar Department of Molecular Pathobiology, New York University College of Dentistry, New York, New York, USA

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Rhonda D Kineman Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA

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A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

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