Erectile dysfunction induced by high fat diet: the role of TNF-alpha

• Grant number: 19/19749-8
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2020
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Fernando Silva Carneiro
• Grantee: Fernando Silva Carneiro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Obese men are at high risk for the development of erectile dysfunction (ED). The prevalence of obesity in men reporting ED symptoms may be as high as 79%. Abdominal adiposity, determined by waist circumference, is implicated as a risk factor for ED. In addition, the severity of ED correlates positively with increased abdominal adiposity. A common mechanism between obesity and ED is endothelial dysfunction. The main characteristic of endothelial dysfunction is the reduction in NO bioavailability, which results in diminished corpus cavernous (CC) smooth muscle relaxation. Obesity is characterized by a chronic low-grade inflammatory state, where adipose tissue increases the secretion of proinflammatory adipokines and reduces the secretion of anti-inflammatory adipokines. This adipokine production imbalance results in increased generation of reactive oxygen species (ROS) and endothelial dysfunction. TNF-± is the major cytokine produced by hypertrophied adipocytes. TNF-± role on erectile function has been described previously by our research group. TNF-± knockout animals showed increased CC relaxation and decreased contraction induced by sympathetic stimulation and phenylephrine. The expression of key enzymes for erection such as eNOS and nNOS also increased in the CC of TNF-± knockout animals. On the other hand, systemic infusion of TNF-± caused increased contraction mediated by sympathetic stimulation, phenylephrine, and endothelin-1 (ET-1) in CC. Therefore, our data suggest that TNF-± plays a detrimental role on erectile function. Although the association between obesity and ED is clear, the mechanisms that contribute to ED associated with obesity is unknown. Therefore, the present project will test the hypothesis that obesity increases TNF-±, which promotes changes in the reactivity of CC and contributes to the development of ED. Furthermore, we will determine if oxidative stress mediates the changes induced by TNF-±. The present study will investigate two central axes of the present hypothesis: 1) To test the hypothesis that TNF-± plays an important role in CC reactivity changes and erectile function in vivo in the model of obesity induced by a high fat diet. In this step we will determine the in vivo erectile function and the reactivity of CC in TNF-± knockout animals submitted to the obesity protocol. The other axis of the present hypothesis aims to: 2) To test the hypothesis that oxidative stress mediates the changes induced by TNF-± in CC and erectile function of obese animals. In this stage of the project, we will determine the generation of reactive oxygen species (ROS), the expression and activity of pro-oxidant and antioxidant enzymes in the CC of control and obese animals. In addition, mice submitted to obesity will be treated with apocynin or vehicle, and we will again evaluate the reactivity of CC and erectile function in vivo. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

SOBRANO FAIS, RAFAEL; MENEZES DA COSTA, RAFAEL; CARVALHO MENDES, ALLAN; MESTRINER, FABIOLA; COMERMA-STEFFENSEN, SIMON GABRIEL; TOSTES, RITA C.; SIMONSEN, ULF; SILVA CARNEIRO, FERNANDO. NLRP3 activation contributes to endothelin-1-induced erectile dysfunction. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, v. 27, n. 1, p. 14-pg., 2022-12-14. (16/07641-0, 18/05638-7, 16/11988-5, 19/19749-8)

BRESSAN, ALECSANDER F.; MAIA, VICTORIA OLIVEIRA; RODRIGUES, BEATRIZ DE SOUZA; BERTOZI, GIULIANA; BATAH, SABRINA S.; FABRO, ALEXANDRE T.; PELIZZO, GLORIA; PIERUCCI, UGO MARIA; TOSTES, RITA C.; SBRAGIA, LOURENCO; et al. Congenital diaphragmatic hernia increases the sensitivity of pulmonary arteries to nitric oxide. PHARMACOLOGICAL RESEARCH, v. 191, p. 8-pg., 2023-05-01. (19/19749-8)