Participation of toll-like receptor 9 (TLR9) in prostate dysfunctions of insulin resistance obese mice

Abstract

The worldwide incidence of obesity has increased dramatically in the past 25 years, and today is considered one of the major public health problems. Recent clinical studies indicate a strong correlation between obesity and genitourinary tract diseases, such as erectile dysfunction and overactive bladder syndrome. The benign prostatic hyperplasia (BPH), which is characterized by an increase in both physical size (static component) and prostate smooth muscle tone (dynamic component) has been also linked to obesity in humans and animals. Experimental studies demonstrated that prostates from obese rats show increased cell proliferation with consequent prostate overgrowth and hypercontractility, secondary to BPH. Furthermore, obese mice exhibited increases in prostatic levels of NF-kB and gp91phox, p22phox and p47phox protein expression (subunits of NADPH oxidase). A preliminary study in our group showed that high-fat diet (HFD) obese mice exhibit prostate hypercontractility associated with a significant increase (52%) in prostatic reactive oxygen species levels. Recent studies have been shown an important role for Toll-like receptors (TLR), particularly subtype 9 (TLR9), in the exacerbation of the chronic inflammatory condition associated with obesity, however the literature is scarce about the participation of TLR in prostatic disorders. Thus, this project aims to evaluate the role of TLR9 and its downstream signaling pathway in the pathogenesis of obesity-induced prostate dysfunctions. Our hypothesis is that the prostatic dysfunction in obese individuals have in common the activation of TLR9 with consequent increase in intracellular signaling and inflammatory factor production. Specifically, we hypothesize that prostatic TLR9 activation in obese animals leads to the production of pro-inflammatory cytokines and reactive-oxygen species resulting in prostatic hypercontractility and BPH development. If our hypothesis is correct, the pathway components involved in TLR9 activation will be ideal targets for new drugs to reduce prostate complications associated with obesity. (AU)