Obesity, Inflammation and BPH

This Planning Center proposal brings together a multidisciplinary team to determine the role of obesity in the development of benign prostatic hyperplasia (BPH). BPH is a major and costly healthcare issue in aging men. Many clinical and epidemiologic studies suggest that BPH progression is advanced by obesity and diabetes, both reaching epidemic proportions in the United States. The mechanisms by which obesity might drive hyperplastic growth of the prostate are not understood, however inflammation, insulin resistance, and consequent changes in oxidative stress may reasonably contribute to this phenomenon. The long term goal of this multi-disciplinary center is to determine how diet and obesity give rise to benign prostatic hyperplasia in humans.

Overall Hypothesis
The overall hypothesis is that benign hyperplastic growth of the prostate and associated inflammatory responses are influenced by obesity and diet. This proposal will explore links between food intake, inflammation and prostatic hyperplasia in mouse models. We will develop and fully characterize new mouse models in terms of histopathological changes and a full qualitative and quantitative analysis of immune/inflammatory cell infiltrate, to identify models which best replicate defined characteristics of the human disease. This addresses a critical research need for new in vivo models with which to investigate mechanisms underlying prostatic hyperplasia. We will investigate the consequences of caloric restriction on the resolution of hyperplasia and inflammation in these mice, and will determine whether different approaches to weight loss (restricted feeding versus bariatric surgery – a specialized technique available at only a limited number of centers for murine applications) influence the resolution of symptoms. To assess the effects of diet on systemic inflammation and insulin action we will examine four complimentary biomarkers representing oxidative stress (F2-isoprostane metabolite or F2iP-M), inflammation (prostaglandin E2 metabolite or PGE-M), and insulin activity and sensitivity (adiponectin and C-peptide). Both F2iP and PGE-M assays were developed and validated at Vanderbilt and this will be their first application in the study of benign prostate disease. These markers will be examined in the context of mouse models and the data will be correlated with a unique local human epidemiologic resource; the Nashville Men’s Health Study (NMHS). The epidemiologic component of the proposal will determine how these same systemic markers of inflammation, oxidative stress, and insulin activity, detectable in serum and urine, of human patients relate to histopathologically-determined prostatic inflammation as well as progression of lower-urinary tract symptoms (LUTS). Our conceptual framework is that obesity leads to systemic inflammation and insulin resistance, which in turn accelerates prostate inflammation and LUTS progression. This close integration of the human epidemiologic study of BPH/LUTS and the parallel development of mouse models of the same prostatic hyperplasia ensures the relevance of the mouse work.

Aim 1

Determine how of obesity and hyperlipidemia contribute to prostatic hyperplasia and inflammation in mice. This aim will test the hypothesis that changes in diet and consequent metabolic stress give rise to benign hyperplastic growth of the prostate epithelium and stroma with associated inflammation. We suggest that specific dietary components and/or genetic backgrounds may influence the expression of all or separate components of a hyperplastic/inflammatory response. This aim will use four models of obesity incorporating both dietary and genetic approaches to examine the role of fat, simple and complex carbohydrates as well as chronic overfeeding and hyperlipidemia in the pathogenesis of prostatic hyperplasia.

Aim 2

Determine the differential effects of varying weight loss strategies on obesity-induced prostatic hyperplasia and inflammation in the mouse. This aim will test the hypothesis that obesity-induced hyperplasia can be reversed by approaches which normalize weight. We will utilize two approaches (caloric restriction and bariatric surgery) and as a secondary endpoint will address whether the method of weight loss plays a role in symptom resolution.

Aim 3

Determine the relationship between obesity-related systemic biomarkers of inflammation and oxidative stress with prostate tissue inflammation and LUTS severity in humans. This aim will test the hypothesis that measures of obesity-related systemic biomarkers of inflammation, oxidative stress, or insulin activity will be associated with the extent and grade of chronic inflammation in prostate tissue, as well as progression of LUTS in human patients.