title: PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.
abstract: Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARγ isoforms in PPARγ knockout prostate epithelial cells. Expression and activation of either PPARγ 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. Differential effects of PPARγ isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPARγ1. In contrast, PPARγ2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPARγ agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARγ agonization increased prostatic differentiation markers, whereas HFD downregulated PPARγ-regulated genes and decreased prostate differentiation. These data provide a rationale for pursuing a fundamental metabolic understanding of changes to glucose and fatty acid metabolism in benign and malignant prostatic diseases associated with systemic metabolic stress.
authors.affiliation: Department of Urologic Surgery, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Engineering, and Vanderbilt University Medical Center, Nashville, TN 37232-2765, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Strand
authors.forename: M
authors.initials: M
authors.lastname: Jiang
authors.forename: T A
authors.initials: TA
authors.lastname: Murphy
authors.forename: Y
authors.initials: Y
authors.lastname: Yi
authors.forename: K C
authors.initials: KC
authors.lastname: Konvinse
authors.forename: O E
authors.initials: OE
authors.lastname: Franco
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J D
authors.initials: JD
authors.lastname: Young
authors.forename: S W
authors.initials: SW
authors.lastname: Hayward
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D059305:Diet, High-Fat; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055786:Gene Knockout Techniques; D005947:Glucose / Q000378:metabolism; D050155:Lipogenesis; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D018384:Oxidative Stress; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000166:cytology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D005227:Fatty Acids; D047495:PPAR gamma; D020033:Protein Isoforms; D045162:Thiazolidinediones; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase; D005947:Glucose