Involvement of the glutamine RF­amide peptide and its cognate receptor GPR103 in prostate cancer.

Glutamine RF­amide peptide (QRFP) belongs to the RFamide neuropeptide family, which is involved in a wide spectrum of biological activities, ranging from food intake and cardiovascular functioning to analgesia, aldosterone secretion, locomotor activity and reproduction. Recently, QRFP has been demonstrated to exert its effects by activating the G protein­coupled receptor GPR103. QRFP is expressed in the brain and peripherally in the adipose tissue, bladder, colon, testis, parathyroid and thyroid gland, as well as in the prostate gland. Following lung cancer, prostate cancer constitutes the second most frequently diagnosed cancer among men, whilst obesity appears to be a contributing factor for aggressive prostate cancer. In the present study, we sought to investigate the role of QRFP in prostate cancer, using two androgen­independent human prostate cancer cell lines (PC3 and DU145) as in vitro experimental models and clinical human prostate cancer samples. The expression of both QRFP and GPR103 at the gene and protein level was higher in human prostate cancer tissue samples compared to control and benign prostatic hyperplasia (BHP) samples. Furthermore, in both prostate cancer cell lines used in the present study, QRFP treatment induced the phosphorylation of ERK1/2, p38, JNK and Akt. In addition, QRFP increased cell migration and invasion in these in vitro models, with the increased expression of MMP2. Furthermore, we demonstrated that the pleiotropic adipokine, leptin, increased the expression of QRFP and GPR103 in PC3 prostate cancer cells via a PI3K­ and MAPK­dependent mechanism, indicating a novel potential link between adiposity and prostate cancer. Our findings expand the existing evidence and provide novel insight into the implication of QRFP in prostate cancer.

Short-Chain Fatty Acid Acetate Stimulates Adipogenesis and Mitochondrial Biogenesis via GPR43 in Brown Adipocytes.

Short-chain fatty acids play crucial roles in a range of physiological functions. However, the effects of short-chain fatty acids on brown adipose tissue have not been fully investigated. We examined the role of acetate, a short-chain fatty acid formed by fermentation in the gut, in the regulation of brown adipocyte metabolism. Our results show that acetate up-regulates adipocyte protein 2, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 expression and affects the morphological changes of brown adipocytes during adipogenesis. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and cAMP response element-binding protein, and these responses were sensitive to G(i/o)-type G protein inactivator, Gßγ-subunit inhibitor, phospholipase C inhibitor, and MAPK kinase inhibitor, indicating a role for the G(i/o)ßγ/phospholipase C/protein kinase C/MAPK kinase signaling pathway in these responses. These effects of acetate were mimicked by treatment with 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide, a synthetic G protein-coupled receptor 43 (GPR43) agonist and were impaired in GPR43 knockdown cells. Taken together, our results indicate that acetate may have important physiological roles in brown adipocytes through the activation of GPR43.

Nesfatin-1 inhibits proliferation and enhances apoptosis of human adrenocortical H295R cells.

NUCB2/nesfatin and its proteolytically cleaved product nesfatin-1 are recently discovered anorexigenic hypothalamic neuroproteins involved in energy homeostasis. It is expressed both centrally and in peripheral tissues, and appears to have potent metabolic actions. NUCB2/nesfatin neurons are activated in response to stress. Central nesfatin-1 administration elevates circulating ACTH and corticosterone levels. Bilateral adrenalectomy increased NUCB2/nesfatin mRNA levels in rat paraventricular nuclei. To date, studies have not assessed the effects of nesfatin-1 stimulation on human adrenocortical cells. Therefore, we investigated the expression and effects of nesfatin-1 in a human adrenocortical cell model (H295R). Our findings demonstrate that NUCB2 and nesfatin-1 are expressed in human adrenal gland and human adrenocortical cells (H295R). Stimulation with nesfatin-1 inhibits the growth of H295R cells and promotes apoptosis, potentially via the involvement of Bax, BCL-XL and BCL-2 genes as well as ERK1/2, p38 and JNK1/2 signalling cascades. This has implications for understanding the role of NUCB2/nesfatin in adrenal zonal development. NUCB2/nesfatin may also be a therapeutic target for adrenal cancer. However, further studies using in vivo models are needed to clarify these concepts.