Pomolic acid in persimmon peel suppresses the increase in glycerol-3 phosphate dehydrogenase activity in 3T3-L1 adipocytes.

Persimmon peels, though usually discarded, are useful sources of nutraceuticals. In this study, persimmon peel-derived pomolic acid was found to suppress the increase in the activity of glycerol-3 phosphate dehydrogenase, a neutral fat synthesis-related enzyme, in 3T3-L1 adipocytes, whereas oleanolic and ursolic acids did not exert this effect. Therefore, persimmon peel may be an effective functional food material.

Fetal androgen signaling defects affect pancreatic ß-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats.

We previously demonstrated that androgen signaling expands pancreatic ß-cell mass in the sexual maturation period (Am J Physiol Endocrinol Metab 314: E274-E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in ß-cell mass development and ß-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive ß-cell precursor cells but was markedly reduced in insulin-positive ß-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced ß-cell mass and Ki67-positive proliferating ß-cells at birth in a male-specific manner without affecting body weight. The decrease of ß-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to ß-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic ß-cell function.

Androgen signaling expands ß-cell mass in male rats and ß-cell androgen receptor is degraded under high-glucose conditions.

A deficient pancreatic ß-cell mass increases the risk of type 2 diabetes mellitus. Here, we investigated the effects of testosterone on the development of pancreatic ß-cell mass in male rats. The ß-cell mass of male rats castrated at 6 wk of age was reduced to ~30% of that of control rats at 16 wk of age, and castration caused glucose intolerance. Loss of ß-cell mass occurred because of decreases in islet density per pancreas and ß-cell cluster size. Castration was negatively associated with the number of Ki-67-positive ß-cells and positively associated with the number of TUNEL-positive ß-cells. These ß-cell changes could be prevented by testosterone treatment. In contrast, castration did not affect ß-cell mass in male mice. Androgen receptor (AR) localized differently in mouse and rat ß-cells. Testosterone enhanced the viability of INS-1 and INS-1 #6, which expresses high levels of AR, in rat ß-cell lines. siRNA-mediated AR knockdown or AR antagonism with hydroxyflutamide attenuated this enhancement. Moreover, testosterone did not stimulate INS-1 ß-cell viability under high d-glucose conditions. In INS-1 ß-cells, d-glucose dose dependently (5.5-22.2 mM) downregulated AR protein levels both in the presence and absence of testosterone. The intracellular calcium chelator (BAPTA-AM) could prevent this decrease in AR expression. AR levels were also reduced by a calcium ionophore (A23187), but not by insulin, in the absence of the proteasome inhibitor MG132. Our results indicate that testosterone regulates ß-cell mass, at least in part, by AR activation in the ß-cells of male rats and that the ß-cell AR is degraded under hyperglycemic conditions.

Androgen receptor silences thioredoxin-interacting protein and competitively inhibits glucocorticoid receptor-mediated apoptosis in pancreatic ß-Cells.

Androgen receptor (AR) is known to bind to the same cis-element that glucocorticoid receptor (GR) binds to. However, the effects of androgen signaling on glucocorticoid signaling have not yet been elucidated. Here, we investigated the effects of testosterone on dexamethasone (DEX, a synthetic glucocorticoid)-induced apoptosis of pancreatic ß-cells, which might be involved in the pathogenesis of type 2 diabetes mellitus in males. We used INS-1 #6 cells, which were isolated from the INS-1 pancreatic ß-cell line and which express high levels of AR. Testosterone and dihydrotestosterone inhibited apoptosis induced by DEX in INS-1 #6 cells. AR knockdown and the AR antagonist hydroxyflutamide each diminished the anti-apoptotic effects of testosterone. AR was localized in the nucleus of both INS-1 #6 cells and pancreatic ß-cells of male rats. Induction of thioredoxin-interacting protein (TXNIP) is known to cause pro-apoptotic effects in ß-cells. Testosterone suppressed the DEX-induced increase of TXNIP at the transcriptional level. A Chromatin immunoprecipitation assays showed that both AR and GR competitively bound to the TXNIP promoter in ligand-dependent manners. Recombinant DNA-binding domain of AR bound to the same cis-element of the TXNIP promoter that GR binds to. Our results show that AR and GR competitively bind to the same cis-element of TXNIP promoter as a silencer and enhancer, respectively. These results indicate that androgen signaling functionally competes with glucocorticoid signaling in pancreatic ß-cell apoptosis.