Journal of Pharmacy and Pharmacology 7 (2019)133-147 doi: 10.17265/2328-2150/2019.04.001 Agnuside Reduces Visceral Adipocyte Size, Improves Insulin Sensitivity and Reverses Hepatic Steatosis in Ovariectomized Rats Franciele Neves Moreno 1,2 , Eduardo Hideo Gilglioni 1,2 , Rosângela Fernandes Garcia 3 , Naiara Cristina Lucredi 4 , Sandra Mara Ferreira 5 , Nilton Almeida Brito 3 , Marcia do Nascimento Brito 3 , Emy Luiza Ishii-Iwamoto 1,2 and Clairce Luzia Salgueiro-Pagadigorria 3 1. Laboratory of Experimental Steatosis, Department of Biochemistry, State University of Maringa, Maringa 87020-900, PR, Brazil 2. Laboratory of Biological Oxidations, Department of Biochemistry, State University of Maringa, Maringa 87020-900, PR, Brazil 3. Department of Physiological Sciences, State University of Maringa, Maringa 87020-900, PR, Brazil 4. Laboratory of Biological oxidations, Department of Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, SC, Brazil 5. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Campinas 13083-970, SP, Brazil Abstract: This study aimed to investigate the effects of agnuside (AGN), a phytoestrogen in Vitex agnus-castus, on cellular and metabolic alterations induced by ovariectomy in rats. Ovariectomized (OVX) Wistar rats were used as an animal model of postmenopausal metabolic syndrome. The visceral and subcutaneous adipocyte sizes, the peripheral insulin sensitivity and the occurrence of nonalcoholic fatty liver disease (NAFLD) and liver oxidative damage were evaluated. The results were compared with those obtained from control rats (sham-operated) and OVX rats treated daily with AGN. Obese OVX rats exhibited visceral adipocyte hypertrophy and developed glucose intolerance, hyperinsulinemia, NAFLD and dyslipidemia. AGN exerted beneficial effects on several metabolic parameters in OVX rats, including the improvement in glucose intolerance, hyperinsulinemia and NAFLD. Besides, AGN promoted a general improvement in the liver redox state. Although the reduction of the mesenteric adipocyte size is very likely to be an important mode of action of AGN, some actions of AGN could also involve the interaction with estrogen receptors. Key words: Metabolic syndrome, ovariectomized rats, adipocyte size, NAFLD, agnuside. 1. Introduction Epidemiological data show that an estimated 1.1 billion women worldwide will be menopausal by 2025 [1]. Postmenopausal women are prone to fat metabolism disorders and obesity, with a central pattern of fat distribution and adipocyte hypertrophy [2], which are both predisposing factors for insulin resistance (IR) [3] and nonalcoholic fatty liver disease Correspondence: Clairce Luzia Salgueiro-Pagadigorria, Ph.D., professor, research fields: liver, sub cellular fractions, metabolic syndrome, estrogen deficiency and energy metabolism. (NAFLD) [4, 5]. These features occur because hypertrophic adipocytes exhibit increased lipolysis, releasing fatty acids (FA) directly in the portal venous system. This release overloads the liver and leads to the accumulation of triacylglycerols (TAG) in the cytosol of hepatocytes [6, 7]. Liver lipid metabolism is regulated by estrogens through genomic actions; thus, under conditions of estrogen deficiency, the incidence of NAFLD increases considerably [8]. The fat accumulation in the liver, in turn, leads to oxidative cell damage [9-12]. Hormone replacement therapy has been considered D DAVID PUBLISHING