👤 Gema Frühbeck

Periprostatic adipose tissue (PPAT) has been recognized to associate with prostate cancer (PCa) aggressiveness and progression. Here, we sought to investigate whether excess adiposity modulates the methylome of PPAT in PCa patients. DNA methylation profiling was performed in PPAT from obese/overweight (OB/OW, BMI > 25 kg m Five thousand five hundred twenty-six differentially methylated CpGs were identified between OB/OW and NW PCa patients with 90.2% hypermethylated. Four hundred eighty-three of these CpGs were found to be located at both promoters and CpG islands, whereas the representing 412 genes were found to be involved in pluripotency of stem cells, fatty acid metabolism, and many other biological processes; 14 of these genes, particularly Results showed that the whole epigenome methylation profiles of PPAT were significantly different in OB/OW compared to normal weight PCa patients. The epigenetic variation associated with excess adiposity likely resulted in altered lipid metabolism and immune dysregulation, contributing towards unfavorable PCa microenvironment, thus warranting further validation studies in larger samples. Show less

Studies associate specific fatty-acids (FA) with the pathophysiology of inflammation. We aimed to analyze the impact of exercise on adipose tissue FA profile in response to a high-fat diet (HFD) and to ascertain whether these exercise-induced changes in specific FA have repercussions on obesity-related inflammation. Sprague-Dawley rats were assigned into sedentary, voluntary physical-activity (VPA) and endurance training (ET) groups fed a standard (S, 35kcal% fat) or high-fat (71kcal% fat) diets. VPA-animals had unrestricted access to wheel-running. After 9-wks, ET-animals engaged a running protocol for 8-wks, while maintained dietary treatments. The FA content in epididymal white-adipose tissue (eWAT) triglycerides was analyzed by gas-chromatography and the expression of inflammatory markers was determined using RT-qPCR, Western and slot blotting. Eight-wks of ET reversed obesity-related anatomical features. HFD increased plasma tumor necrosis factor (TNF)-α content and eWAT monocyte chemoattractant protein (MCP)-1 protein expression. HFD decreased eWAT content of saturated FA and monounsaturated FA, while increased linoleic acid and prostaglandin E2 (PGE2) levels in eWAT. VPA decreased visceral adiposity, adipocyte size and MCP-1 in HFD-fed animals. The VPA and ET interventions diminished palmitoleic acid and increased linoleic acid in HFD-fed groups. Moreover, both interventions increased PGE2 levels in standard diet-fed groups and decreased in HFD. ET increased eWAT fatty acid desaturase 1 (FADS1) and elongase 5 (ELOVL5) protein content in both diet types. ET reduced eWAT inflammatory markers (TNF-α, IL-6), macrophage recruitment (MCP-1 and F4/80) and increased IL-10/TNF-α ratio in plasma and in eWAT in both diet types. Exercise induced FA-specific changes independently of dietary FA composition, but only ET attenuated the inflammatory response in VAT of HFD-fed rats. Moreover, the exercise-induced FA changes did not correlate with the inflammatory response in VAT of rats submitted to HFD. Show less

Periprostatic (PP) adipose tissue surrounds the prostate, an organ with a high predisposition to become malignant. Frequently, growing prostatic tumor cells extend beyond the prostatic organ towards this fat depot. This study aimed to determine the genome-wide expression of genes in PP adipose tissue in obesity/overweight (OB/OW) and prostate cancer patients. Differentially expressed genes in human PP adipose tissue were identified using microarrays. Analyses were conducted according to the donors' body mass index characteristics (OB/OW versus lean) and prostate disease (extra prostatic cancer versus organ confined prostate cancer versus benign prostatic hyperplasia). Selected genes with altered expression were validated by real-time PCR. Ingenuity Pathway Analysis (IPA) was used to investigate gene ontology, canonical pathways and functional networks. In the PP adipose tissue of OB/OW subjects, we found altered expression of genes encoding molecules involved in adipogenic/anti-lipolytic, proliferative/anti-apoptotic, and mild immunoinflammatory processes (for example, FADS1, down-regulated, and LEP and ANGPT1, both up-regulated). Conversely, in the PP adipose tissue of subjects with prostate cancer, altered genes were related to adipose tissue cellular activity (increased cell proliferation/differentiation, cell cycle activation and anti-apoptosis), whereas a downward impact on immunity and inflammation was also observed, mostly related to the complement (down-regulation of CFH). Interestingly, we found that the microRNA MIRLET7A2 was overexpressed in the PP adipose tissue of prostate cancer patients. Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression. Show less