Characterization of periprostatic adipose tissue in obese mice before and after treatment with beta-3-adrenergic agonist Mirabegron and the effect on prostate functional activity

Abstract

The Lower Urinary Tract Symptoms (LUTS) that consists of filing (incontinence and urinary frequency), storage and voiding symptoms have a high prevalence worldwide and affect both genders. Obesity predisposes glucose intolerance, insulin resistance, Dyslipidemia, Type 2 Diabetes Mellitus and cardiovascular disorders. Prospectives studies have been shown that obese men are more likely to develop LUTS when compared to lean men. Adipose tissue is an important source of pro-inflammatory, pro-contractile and pro-proliferative substances. In a recent study published by our group showed thatthe prostate weight and epididimal fat of obese mice are significantly greater when compared to lean mice tissues. Furthermore, obese mice present hypercontractility of the prostate and the bladder. In obese mice, that received the ²3-adrenoceptor, Mirabegron for 2 weeks, an approved drug to treating patients with overactive bladder, we observed an improvement in the overactive state of the bladder and a reduction of the epididymal fat mass and LDL levels. Yet, the ²3-adrenoceptor activation in adipose tissue is involved with lipolysis, mobilization of fatty acids in white adipose tissue and with brown adipose tissue thermogenesis. However, based on our previous findings we don't know whether the improvement in the bladder reactivity after Mirabegron treatment could be due to a direct effect on the smooth muscle and/or a lower release of pro-contractile, pro-proliferative and pro-inflammatory substances originates from periprostatic adipose tissue. Our preliminary results showed the adipocyte area of periprostatic adipose tissue is significantly greater in obese mice than in lean mice. Based on the presented above, we hypothesized that 1) the periprostatic adipose tissue can release pro-contractile, pro-inflammatory and pro-proliferative substances thus contributing to the hypercontractility and prostate hyperplasia; 2) the treatment with Mirabegron could interfere positively in the prostate reactivity by decreasing pro-inflammatory, pro-contractile and pro-proliferative substances production. Therefore, the aim of this project is to evaluate the periprostatic adipose tissue interference in the prostate reactivity in obese mice treated or not (control) with Mirabegron for 2 weeks through the histological and immunohistochemical assays (determination of proliferative and apoptotic indexes of the prostate), qRT-PCR (evaluate the gene expression of pro-inflammatory mediators and markers for White and brown adipose tissue), pro-inflammatory's citokines quantification in periprostatic adipose tissue, bioassay to evaluate whether the periprostatic adipose tissue presence interferes in prostate reactivity and whether the treatment with Mirabegron would improve these parameters, and finally the metabolic activity's determination in periprostatic adipose tissue by PET/CT in obese mice treated or not with Mirabegron. (AU)