Efeito da inibição da histona deacetilase 3 em um modelo de obesidade em camundongos

Abstract

Epigenetics is the study of hereditary changes related to gene expression without involving changes in DNA. Among the epigenetic mechanisms, histone deacetylase-catalyzed histone deacetylation (HDACs) represses the transcription. Dietary factors influence the histones, being important to interconnect obesity and epigenetic aspects. HDAC3 is still poorly reported in metabolic studies and may be inhibited by RGFP966, a selective inhibitor of the type benzamide. The objective of present study was to investigate the role of HDAC3 in mice induced to obesity via a hyperlipid diet. This is an experimental study conducted with 32 C57BJ / 6 adult mice (n = 8), where normal pellet diet (NPD) or high fat diet (HFD) were administred for 120 days. During the day 91 to day 120 was administered the RGFP966 (50 mg/kg; subcutaneously via) to cause hyperacetylation. Body weight was measured weekly and on day 120 animals were euthanized with pentobarbital (180 mg/kg; intraperitoneal via) and the blood and the hippocampus were collected for biochemical analysis. The following blood parameters were analyzed: glucose, insulin, lipid profile, leptin and adiponectin. In the hippocampus were analyzed: interleukin 6 (IL-6), interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α). The results of the present study demonstrated that HFD increased body weight, plasma glucose, insulin, triglycerides, total cholesterol and low density lipoprotein (LDL) levels compared to control, while RGFP966 (50 mg / kg) reduced these levels. Plasma high densitiy lipoprotein (HDL) had lower values in HFD mice, however the use of RGFP966 led to a significant increase of this lipoprotein. The interleukins IL-6, IL-1β and TNF-α in the hippocampus increased significantly in the HFD group compared to the NPD group. In contrast, the inhibitor RGFP966 reduced interleukins, attenuating the inflammatory process caused by HFD. As for adipokine levels, HFD dramatically increased leptin levels and reduced plasma adiponectin levels. The use of the inhibitor attenuated these changes, since its administration in the HFD group avoided the reduction of adiponectin and the increase of leptin, acting in the regularization of food intake signaling and energetic homeostasis. It was found that the selective inhibition of HDAC3 by RGFP966 modulated changes in body weight, biochemical parameters, blood adipokines and proinflammatory cytokines in the hippocampus even with HFD administration, evidencing that the HDAC3 enzyme is involved in the alterations resulting to obesity. Thus, the inhibition of HDAC3 may protect against weight gain, metabolic and inflammatory changes proving to be an important therapeutic target for studies related to obesity.