Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-g Expression in Pulmonary Artery Any Elisa de Souza Schmidt Gonc ¸ alves 1† , Guilherme Zweig Rocha 1† , Rodrigo Marin 1 , Rafael Ludemann Camargo 1 , Andrey dos Santos 1 , Helison do Carmo 1 , Dioze Guadagnini 1 , Orlando Petrucci 1 , Zenaide Providello Moyse ´ s 3 , Vera Maria Cury Salemi 3 , Alexandre Gabarra Oliveira 2† and Mario Jose ´ Abdalla Saad 1 * 1 Department of Internal Medicine, Faculty of Medicine, State University of Campinas, Campinas, Brazil, 2 Department of Physical Education, São Paulo State University (UNESP), Rio Claro, Brazil, 3 Heart Institute (InCor) do Hospital das Clı ´nicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil Obesity and insulin resistance (IR) are well-studied risk factors for systemic cardiovascular disease, but their impact on pulmonary hypertension (PH) is not well clarified. This study aims to investigate if diet-induced obesity induces PH and if peroxisome-proliferator- activated receptor (PPAR-g) and/or endoplasmic reticulum (ER) stress are involved in this process. Mice were maintained on a high-fat diet (HFD) for 4 months, and IR and PH were confirmed. In a separate group, after 4 months of HFD, mice were treated with pioglitazone (PIO) or 4-phenylbutyric acid for the last month. The results demonstrated that HFD for at least 4 months is able to increase pulmonary artery pressure, which is maintained, and this animal model can be used to investigate the link between IR and PH, without changes in ER stress in the pulmonary artery. There was also a reduction in circulating adiponectin and in perivascular adiponectin expression in the pulmonary artery, associated with a reduction in PPAR-g expression. Treatment with PIO improved IR and PH and reversed the lower expression of adiponectin and PPAR-g in the pulmonary artery, highlighting this drug as potential benefit for this poorly recognized complication of obesity. Keywords: obesity, insulin resistance, pioglitazone, PPAR-g, high-fat (HF) diet INTRODUCTION Pulmonary hypertension (PH) is a disease of the pulmonary circulation associated with an excessive proliferation of vascular cells that may induce alterations in the resistance of the pulmonary arteries (PAs), but systemic vessels are spared (1, 2). It may be idiopathic or familial, which are rare forms, but most often, PH is associated with more common diseases such as left heart failure, collagen vascular diseases, congenital heart disease, and AIDS, among others (1, 3). PH is defined by mean pulmonary artery pressure ≥25 mmHg at rest or 30 mmHg during exercise, measured invasively Frontiers in Endocrinology | www.frontiersin.org September 2021 | Volume 12 | Article 701994 1 Edited by: Rosalia Rodriguez-Rodriguez, International University of Catalonia, Spain Reviewed by: Sawsan A. Zaitone, Suez Canal University, Egypt Zhu Huijuan, Peking Union Medical College Hospital (CAMS), China Liang Xu, Wenzhou Medical University, China *Correspondence: Mario Jose ´ Abdalla Saad msaad@unicamp.br † These authors have contributed equally to this work Specialty section: This article was submitted to Obesity, a section of the journal Frontiers in Endocrinology Received: 28 April 2021 Accepted: 16 August 2021 Published: 06 September 2021 Citation: Gonc ¸ alves AEdSS, Rocha GZ, Marin R, Camargo RL, Santos Ad, Carmo Hd, Guadagnini D, Petrucci O, Moyse ´ s ZP, Salemi VMC, Oliveira AG and Saad MJA (2021) Pulmonary Hypertension in Obese Mice Is Accompanied by a Reduction in PPAR-g Expression in Pulmonary Artery. Front. Endocrinol. 12:701994. doi: 10.3389/fendo.2021.701994 ORIGINAL RESEARCH published: 06 September 2021 doi: 10.3389/fendo.2021.701994