Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through five cognate G protein-coupled receptors (S1P1–S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and a S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist SEW-2871, VPC23019, or their combination act on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased mRNA levels of tumor necrosis factor-α and CD11c, whereas increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor gamma and its regulated genes. By contrast, VPC23019 did not cause all such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.
Despite extensive investigation, the mechanisms underlying adipogenesis are not fully understood. We previously identified proliferative cells in adipose tissue expressing adipocyte-specific genes, which were named small proliferative adipocytes (SPA). In this study, we investigated the characteristics and roles of SPA in adipose tissue. Epididymal and inguinal fat was digested by collagenase, and then SPA were separated by centrifugation from stromal vascular cells (SVC) and mature white adipocytes. To clarify the feature of gene expression in SPA, microarray and real-time PCR were performed. The expression of adipocyte-specific genes and several neuronal genes was increased in the order of SVC < SPA < mature white adipocytes. In addition, proliferin was detected only in SPA. SPA differentiated more effectively into lipid-laden cells than SVC. Moreover, differentiated SPA expressed uncoupling protein 1 and mitochondria-related genes more than differentiated SVC. Treatment of SPA with pioglitazone and CL316243, a specific β3-adrenergic receptor agonist, differentiated SPA into beige-like cells. Therefore, SPA are able to differentiate into beige cells. SPA isolated from epididymal fat (epididymal SPA), but not SPA from inguinal fat (inguinal SPA), expressed a marker of visceral adipocyte precursor, WT1. However, no significant differences were detected in the expression levels of adipocyte-specific genes or neuronal genes between epididymal and inguinal SPA. The ability to differentiate into lipid-laden cells in epididymal SPA was a little superior to that in inguinal SPA, whereas the ability to differentiate into beige-like cells was greater in inguinal SPA than epididymal SPA. In conclusion, SPA may be progenitors of beige cells.
We have reported that several neuronal genes, glutamate receptor 7 and synuclein γ, are expressed in adipocytes. Since the individual roles of these neuronal genes are different, it is unlikely that these genes carry out any common functions together. Numerous neuronal genes are negatively regulated by REST. Therefore, we generated the mice lacking REST in adipocytes to investigate the role of these genes. Rest2lox/2lox mice were mated with Adipoq-Cre mice, and the resultant Adipoq-Cre/Rest2lox/2lox mice were compared with Adipoq-Cre mice. Male Adipoq-Cre/Rest2lox/2lox mice exceeding 10 weeks of age showed increased body weight and fat mass. There was no difference in food consumption, glucose tolerance evaluated by intraperitoneal GTT (ip-GTT) and adipocyte size. However, glucose tolerance was deteriorated in Adipoq-Cre/Rest2lox/2lox mice after treated with high fat diet (HFD) for 8 weeks. The characteristics of gene expression in epididymal fat isolated from Adipoq-Cre/Rest2lox/2lox mice was examined with microarray with Adipoq-Cre/Rest2lox/2lox mice as a control. Significant increased mRNA levels were detected numerous neuronal genes such as Gdap1, Nrxn1, Nrsn1 and Syn1, in Adipoq-Cre/Rest2lox/2lox mice. In addition, expression of several oncogenes, including Srrm3, Lhfpl5, Stmn3 and Chga (a marker of neuro-endocrine tumor such as pheochromocytoma) were increased in these mice. On the other hand, brown adipose tissue (BAT) in Adipoq-Cre/Rest2lox/2lox mice showed white adipose tissue (WAT)-like appearance. These results suggested that REST might regulate adipocyte differentiation and function in both WAT and BAT. Disclosure M. Fuwa: None. K. Kajita: None. K. Taguchi: None. Y. Kitada: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.
RE1-silencing transcription factor (REST) is a transcriptional factor which negatively regulates the expression of numerous neuronal genes. In this study, model mice lacking REST in adipocytes were generated to investigate the role of REST in adipocytes. This was achieved by mating Rest2lox/2lox mice with Adipoq-Cre mice, and the resultant Adipoq-Cre/Rest2lox/2lox mice were compared with Adipoq-Cre mice. Adipoq-Cre/Rest2lox/2lox mice exceeding 10 weeks of age showed increased body weight, fat mass, and adipocyte size; however no difference was observed in food intake. Glucose tolerance deteriorated under a high fat diet, but not under normal diets in Adipoq-Cre/Rest2lox/2lox mice. Oxygen consumption decreased in Adipoq-Cre/Rest2lox/2lox mice. The characteristics of gene expression in epididymal fat, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT), isolated from Adipoq-Cre/Rest2lox/2lox mice, were compared by microarray with those from Adipoq-Cre mice. Although expression of numerous neuronal genes increased in Adipoq-Cre/Rest2lox/2lox mice, there were no differences in adipocyte-specific genes. Gene analyses utilizing a cluster one program detected a significant decrease in the mitochondrial translation gene group in WAT, but not BAT. There was no difference in the amount of mitochondrial DNA, whereas the expression of cytochrome C protein was reduced in WAT but not BAT, which was isolated from Adipoq-Cre/Rest2lox/2lox mice. These results indicate that obesity in Adipoq-Cre/Rest2lox/2lox mice is due to a mitochondrial dysfunction in WAT. It is also suggested that REST might regulate the mitochondrial function in WAT. Disclosure M. Fuwa: None. K. Kajita: None. K. Taguchi: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.
A 73-year-old man visited our hospital with chief complaints of fever of unknown origin and bilateral shoulder and hip joint pain. He was initially diagnosed with polymyalgia rheumatica (PMR). Although the patient was treated with prednisolone 15 mg/day, his PMR-related symptoms did not improve. Further examination was performed as the patient was suspected of having paraneoplastic syndrome. Assessment results showed prostate cancer without metastases. After undergoing robot-assisted radical prostatectomy, the patient’s PMR-related symptoms dramatically improved. Hence, the prednisolone dose was decreased to 4 mg/day. PCa may have triggered the development of PMR through the activation of immune-mediated systemic inflammatory responses.
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