Metabolic syndrome (MetS) clusters cardiovascular and metabolic risk factors, along with hypogonadism (HG) and erectile dysfunction (ED). Lifestyle modifications, including physical exercise (PhyEx), are well-known treatments for this condition. We previously established a non-genomic, high-fat diet (HFD)-induced rabbit model of MetS that recapitulates the human phenotype, including HG and ED. We now report studies on the effect of PhyEx on hypothalamus-pituitary-testis (HPT) axis and penile relaxation (readout of erectile dysfunction). Rabbits fed a regular diet were used as controls (RD). RD and HFD rabbits were exercise-trained to run on a treadmill for 12 weeks (RD+PhyEx and HFD+PhyEx). HFD rabbits showed typical MetS features, hypogonadotropic HG (reduced testosterone, T, and LH) and a reduction of androgen-dependent tissue weights. GnRH immunostaining was reduced in the HFD hypothalamic preoptic area, and genes related to inflammation (COX2, IL6, CD68), glucose metabolism (GLUT1, GLUT4, IRS1), estrogen action (ERβ, GPR30) and GnRH inhibitory factors (NPY and PDYN) were increased in the HFD hypothalami. PhyEx completely restored T and LH plasma levels, prostate weight and GnRH immunostaining, doubling its gene expression. The HFD-induced increases in inflammation, estrogen signaling and glucose metabolism-related genes in the hypothalamus were all significantly reduced in HFD+PhyEx, along with a decrease in MCP-1 and its receptor (CCR2), TNFR and GLUT3. PhyEx increased Kiss1 and decreased orexigenic and GnRH-inhibiting factors (PDYN and its receptors OPRD1 and OPRK1), whereas increased anorexigenic ones (POMC). Kiss1 receptor immunostaining, decreased by HFD, was restored by PhyEx. In the testis, genes related to T formation (17βHSD3) and metabolism (5α-reductase) were increased by PhyEx. Accordingly, PhyEx increased the ratio of androstenedione to T concentration within the testis, which resulted downregulated by HFD, as demonstrated by mass-spectrometry analysis of testicular steroids. Corpora cavernosa (CC) strips from HFD rabbits showed hypo-responsiveness to acetylcholine and electrical field (EF) stimulation. In addition, sildenafil action on EF- or sodium nitroprusside-induced relaxation were also impaired. PhyEx reverted these alterations. In CC extracts, genes related to NO formation (DDAH1) and signaling (GCSA1, GCSB1, PDE5, PKG), smooth muscle differentiation (SM22, αSMA) and androgen action (AR, STAMP2) were upregulated by PhyEx. In conclusion, our results show that PhyEx may rescue erectile function, exert anti-inflammatory effects on hypothalamus and testis, and increase LH levels and T production, thus supporting a primary role for lifestyle modification to combat MetS-associated HG and ED.
18 - 21 May 2019
European Society of Endocrinology