Menopause: The Journal of The North American Menopause Society Vol. 20, No. 12, pp. 1264/1274 DOI: 10.1097/gme.0b013e31828f5e3c * 2013 by The North American Menopause Society Adverse association between obesity and menopause in mice treated with bezafibrate, a pan peroxisome proliferatorYactivated receptor agonist Tatiane da Silva Faria, BSc, PhD, Antonio Ludgero Correia-Junior, BSc, MSc, Thabata Lessa dos Anjos, MD, Marcia Barbosa Aguila, RD, PhD, and Carlos Alberto Mandarim-de-Lacerda, MD, PhD Abstract Objective: The goal of this study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HF) on insulin sensitivity and pancreatic remodeling in C57BL/6 mice treated with bezafibrate. Methods: Female C57BL/6 mice were subjected to OVX or surgical procedure without removal of the ovary (SHAM). Animals received standard chow (SC; 10% lipids) or HF (60% lipids). After 13 weeks on the diets, the animals were subdivided into six groups based on diet, bezafibrate treatment, or both: SHAM-SC, SHAM-HF, SHAM-HFBz, OVX-SC, OVX-HF, and OVX-HFBz. After treatment for 5 weeks, the pancreas was removed and analyzed using morphometry, stereological tools, immunostaining, and multiplex assay kits. Results: SHAM-HF and OVX-HF mice showed increased fasting glucose levels, plasma insulin levels, ho- meostasis model of assessment for insulin resistance index, body mass, islet hypertrophy, A-cell mass, and insulin immunostaining, but decreased GLUT2 immunostaining. Bezafibrate treatment prevented islet hypertrophy and reduced body mass, plasma insulin levels, and homeostasis model of assessment for insulin resistance index. Conclusions: OVX combined with HF accentuates the effects of menopause, leading to the development of insulin resistance. Bezafibrate treatment reduces body mass, plasma insulin levels, and pancreatic islet hypertrophy in mice fed HF. Key Words: Ovariectomy Y High-fat diet Y Insulin resistance Y Islet hypertrophy Y GLUT2. O besity, a serious public health problem in the 21st century, leads to fatty infiltration and organ dys- function of the heart, kidney, and liver. 1 More re- cently, a similar condition has been shown to occur in the pancreas in the form of nonalcoholic fatty pancreas disease. 2<4 This condition is significant because visceral obesity is as- sociated with many diseases, particularly hypertension, hy- perlipidemia, impaired glucose tolerance, pancreatic A-cell failure, and insulin resistance (IR). 5,6 As a consequence, in women with type II diabetes mellitus (T2DM) and in rodent models of diabetes and obesity, A-cells compensate for IR by increasing their mass before failure. 7 Menopause is a transition period characterized by a pro- gressive reduction of estrogens levels, which is associated with increased visceral adiposity, IR, T2DM, cardiovascular disease (CVD), and inflammatory markers. 8<10 Today, women can expect to spend nearly a third of their lives in the meno- pausal state. Therefore, the individual and public health im- pact of menopause-associated diseases is significant. 11 One approach to modeling menopause in rodents is ovariectomy (OVX; surgically induced menopause), which promotes obe- sity and metabolic complications, particularly IR. 12 Peroxisome proliferatorYactivated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR>, PPARC/ss, and PPARF are ligand-activated nuclear transcription factors that modulate the expression of genes regulating glucose, lipid, and cholesterol metabolism; an imbalance in these factors can lead to obesity, T2DM, and CVD. These receptors are also drug targets; currently, PPAR> (fibrates) and PPARF (thiazolidinediones) agonists are used clinically for the treatment of dyslipidemia and T2DM, respectively. 13 Bezafibrate is a known activator of PPARs that can activate PPAR subtypes and is considered a pan-PPAR agonist. 14 Received December 5, 2012; revised and accepted February 26, 2013. From the Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, Rio de Janeiro, Brazil. Funding/support: This study was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (www.cnpq.br) and Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (www.faperj.br). Financial disclosure/conflicts of interest: None reported. Address correspondence to: Carlos Alberto Mandarim-de-Lacerda, MD, PhD, Laboratorio de Morfometria, Metabolismo e Doen0a Cardiovascular, Centro Biomedico, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Av. 28 de Setembro, 87, fds, Rio de Janeiro 20551-030, RJ, Brazil. E-mail: mandarim@uerj.br 1264 Menopause, Vol. 20, No. 12, 2013 Copyright © 2013 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.