OBESITÀ ED EFFETTI BENEFICI DELL'EMEOSSIGENASI

Obesity is nowadays a growing global health pandemic disease requiring an urgent intervention. High dietary fat intake promotes the development of obesity in humans and animal models as a result of an imbalance between energy intake and energy expenditure that is determinant for the excessive energy storage in the form of fat and so redundant accumulation of adipose tissue. When the energy balance is positive, the adipose tissue prevalently undergoes an increment of white adipocytes, that become at first hypertrophic and then, due to a close relationship between one adipocyte and its neighbor, hyperplastic. Adipose tissue is a major endocrine organ, releasing signaling and mediator proteins, defined adipokines, via which adipose tissue is strictly linked with other organs. An excessive accumulation of fat tissue during obesity alters adipokines secretion: this imbalance in adipose tissue homeostasis lead to the development of both cardiovascular and renal dysfunctions linking obesity with hypertension, atherosclerosis and nephropathy. Numerous studies have investigated the prevention and treatment of obesity and its associated dysfunctions using naturally-occurring antioxidants. We focused our attention on the inducible isoform of heme oxygenase (HO-1). HO-1 catalyzes the breakdown of heme, a potentially harmful pro-oxidant, into its products biliverdin and carbon monoxide, with a concomitant release of iron. HO-1 acts as a protective system against oxidative stress and inflammation. Moreover, it is considered to have a role in the regulation of vascular tone and it may provide renal cytoprotection. The epoxyeicosatrienoic acid (EET), derived from the metabolism of arachidonic acid by cytochrome P450 epoxygenase enzyme, induces HO-1 expression and activity and so it plays various biological activities. It is also considered a cytoprotective mediator because its function in activating AMPK, LKB1 and Akt, kinases that play a pivotal role in the regulation of energy metabolism. Moreover, EET could upregulate endothelial nitric oxide synthase (eNOS) and so increase the release of nitric oxide (NO), modulating vascular tone and homeostasis. In this study we at first analyzed the consequences of high fat diet on adipose tissue, aorta and kidney and then we hypothesized that the induction of HO-1, through EET administration would ameliorate fat accumulation and the resulting dysfunctions in a mice model of obesity. C57BL/6 mice were divided into four groups: lean, lean fed with a high fat diet (HF), lean fed with a high fat diet and treated with EET (HF EET), lean fed with a high fat diet and treated with EET and MSPPOH, an inhibitor of EET (HF EET MSPPOH). Food intake, body weight, blood levels of glucose, adiponectin and pro-inflammatory cytokines, along with HO-1, AMPKα1/pAMPKα1, LKB1/pLKB1, Akt/pAkt and eNOS expression were analyzed. We demonstrated that adipose tissue plays a focal role in the pathogenesis of obesity: we observed in fact white hypertrophic and hyperplastic adipocytes and an imbalance of adipokine secretion in the HF group. The HF mice showed low level of HO-1 and adiponectin and high systemic levels of the pro-inflammatory TNF-α and IL-6. The intraperitoneally EET administration prevented weight gain, decreased subcutaneous fat content, increased adiponectin and decreased TNF-α and IL-6. The HO-1 expression in adipose tissue, aorta and kidney consequently increased pAMPKα1, pLKB1, pAkt, and eNOS. The co-treatment with EET and MSPPOH countered the beneficial effects of EET, underling its capability of inhibitor of EET synthesis. In conclusion, this study provides strong evidence confirming the fundamental endocrinal function of the adipose tissue and its pivotal role in the pathogenesis of obesity. Moreover, HO-1 has important anti-obesity effects, manifested by a decrease of fat content, an increased number of low size adipocytes and with reciprocal increases in adiponectin, pAMPKα1, pLKB1, pAkt and eNOS, all effects that ameliorate both energy metabolism and vascular tone and so the deleterious effect of a high dietary fat intake.