Theophylline suppresses interleukin-6 expression by inhibiting glucocorticoid receptor signaling in pre-adipocytes

Adipose tissues in obese individuals are characterized by a state of chronic low-grade inflammation. Pre-adipocytes and adipocytes in this state secrete pro-inflammatory adipokines, such as interleukin 6 (IL-6), which induce insulin resistance and hyperglycemia. Theophylline (1,3-dimethylxanthine) exerts anti-inflammatory effects, but its effects on pro-inflammatory adipokine secretion by pre-adipocytes and adipocytes have not been examined. In this study, we found that theophylline decreased IL-6 secretion by 3T3-L1 pre-adipocytes and mouse-derived primary pre-adipocytes. The synthetic glucocorticoid dexamethasone (DEX) induced IL-6 expression in 3T3-L1 pre-adipocytes, and this effect was suppressed by theophylline at the mRNA level. Knockdown of CCAAT/enhancer binding protein (C/EBP) δ inhibited DEX-induced IL-6 expression, and theophylline suppressed C/EBPδ expression. Furthermore, theophylline suppressed transcriptional activity of the glucocorticoid receptor (GR) through suppression of nuclear localization of GR. In vivo, glucocorticoid corticosterone treatment (100 μg/mL) increased fasting blood glucose and plasma IL-6 levels in C57BL/6 N mice. Theophylline administration (0.1% diet) reduced corticosterone-increased fasting blood glucose, plasma IL-6 levels, and Il6 gene expression in adipose tissues. These results show that theophylline administration attenuated glucocorticoid-induced hyperglycemia and IL-6 production by inhibiting GR activity. The present findings indicate the potential of theophylline as a candidate therapeutic agent to treat insulin resistance and hyperglycemia.ArticleARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS.646:98-106(2018)journal articl

Competitive and compensatory effects of androgen signaling and glucocorticoid signaling

Androgens and glucocorticoids have competitive and compensatory effects in several physiological and pathophysiological processes.  Although blood androgen levels affect blood glucocorticoid levels and vice versa, it does not fully explain the relationship between the effects of androgens and glucocorticoids.  Androgens and glucocorticoids exert their functions through binding to androgen receptor (AR) and glucocorticoid receptor (GR), respectively.  AR homodimer and GR homodimer bind to the androgen response element (ARE) and glucocorticoid response element (GRE), respectively, where they positively or negatively regulate transcription.  AR/GR heterodimer can also form but whether it has a physiological role is unclear.  Notably, some ARE/GRE sites are recognized by both AR and GR.  This review focuses on the functional interventions between androgen signaling and glucocorticoid signaling in target cells that are involved in muscle atrophy, lipid metabolism in adipocytes and hepatocytes, and pancreatic β-cell death.  Androgens and glucocorticoids exert opposite effects by differentially regulating key genes (e.g., insulin-like growth factor-1, atrogin-1, and thioredoxin-interacting protein) involved in these physiological processes.  We also review functional compensation between these steroids in the development of castration-resistant prostate cancer in which glucocorticoids compensate for the castration-induced loss of AR function by activating key genes (e.g., serum/glucocorticoid-regulated kinase 1).  The gene expressions regulated by androgens and glucocorticoids are regulated through at least three different mechanisms in target cells: (i) regulation of applicable ligand levels by modulation of steroid metabolite enzyme levels, (ii) regulation of each other's receptor levels, and (iii) competitive binding between AR and GR on ARE/GRE sites.  Recent findings shed light on the complicated relationship between androgen signaling and glucocorticoid signaling in various cellular processes

Food texture affects glucose tolerance by altering pancreatic β-cell function in mice consuming high-fructose corn syrup.

The incidence of metabolic diseases, such as type 2 diabetes, has increased steadily worldwide. Diet, beverages, and food texture can all markedly influence these metabolic disorders. However, the combined effects of food texture and beverages on energy metabolism remains unclear. In the present study, we examined the effect of food texture on energy metabolism in mice administered high-fructose corn syrup (HFCS). Mice were fed a soft or hard diet along with 4.2% HFCS or tap water. Body weight and total caloric intake were not affected by food texture irrespective of HFCS consumption. However, caloric intake from HFCS (i.e., drinking volume) and diet were higher and lower, respectively, in the hard food group than in the soft food group. The hard food group's preference for HFCS was absent in case of mice treated with the μ-opioid receptor antagonist naltrexone. Despite increased HFCS consumption, blood glucose levels were lower in the hard-diet group than in the soft-diet group. In HFCS-fed mice, insulin levels after glucose stimulation and insulin content in the pancreas were higher in the hard food group than the soft food group, whereas insulin tolerance did not differ between the groups. These food texture-induced differences in glucose tolerance were not observed in mice fed tap water. Thus, food texture appears to affect glucose tolerance by influencing pancreatic β-cell function in HFCS-fed mice. These data shed light on the combined effects of eating habits and food texture on human health