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Min Joo Kim, Se Hee Min, Seon Young Shin, Mi Na Kim, Hakmo Lee, Jin Young Jang, Sun-Whe Kim, Kyong Soo Park and Hye Seung Jung

PERK is a pancreatic endoplasmic reticulum (ER) kinase. Its complete deletion in pancreatic β cells induces insulin deficiency; however, the effects of partial Perk suppression are unclear. We investigated the effect of partial PERK suppression using the specific PERK inhibitors GSK2606414 and GSK2656157. Low-dose GSK2606414 treatment for 24 h enhanced glucose-stimulated insulin secretion (GSIS), islet insulin content and calcium transit in mouse (at 40 nM) and human (at 50–100 nM) pancreatic islets. GSK2606414 also induced the expression of the ER chaperone BiP and the release of calcium from the ER. When Bip expression was inhibited using a Bip siRNA, the GSK2606414-induced augmentation of the ER calcium level, islet insulin contents, glucose-stimulated cytosolic calcium transit and GSIS were abrogated. In both wild-type and insulin-deficient Atg7-knockout mice, 8 weeks of GSK2656157 treatment enhanced GSIS and improved hyperglycemia without affecting body weight. In conclusion, partial PERK inhibition induced BiP expression in islets, increased glucose-stimulated calcium transit and islet insulin contents and enhanced GSIS, suggesting that low-dose PERK inhibitors could potentially be used to treat insulin deficiency.

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Min Kyong Moon, In-Kyong Jeong, Tae Jung Oh, Hwa Young Ahn, Hwan Hee Kim, Young Joo Park, Hak Chul Jang and Kyong Soo Park

Bisphenol A (BPA) is a widely used endocrine disruptor. Recent epidemiologic results have suggested an association between exposure to BPA and cardiovascular disease, type 2 diabetes, and obesity. We investigated the in vivo effects of long-term oral exposure to BPA on insulin resistance and glucose intolerance. In the present study, 4- to 6-week-old male mice on a high-fat diet (HFD) were treated with 50 μg/kg body weight per day of BPA orally for 12 weeks. Long-term oral exposure to BPA along with an HFD for 12 weeks induced glucose intolerance in growing male mice. Intraperitoneal glucose tolerance tests showed that the mice that received an HFD and BPA exhibited a significantly larger area under the curve than did those that received an HFD only (119.9±16.8 vs 97.9±18.2 mM/min, P=0.027). Body weight, percentage of white adipose tissue, and percentage of body fat did not differ between the two groups of mice. However, treatment with BPA reduced Akt phosphorylation at position Thr308 and GSK3β phosphorylation at position Ser9 in skeletal muscle. BPA tended to decrease serum adiponectin levels and to increase serum interleukin 6 and tumor necrosis factor α, although these findings were not statistically significant. Treatment with BPA did not induce any detrimental changes in the islet area or morphology or the insulin content of β cells. In conclusion, long-term oral exposure to BPA induced glucose intolerance and insulin resistance in growing mice. Decreased Akt phosphorylation in skeletal muscle by way of altered serum adipocytokine levels might be one mechanism by which BPA induces glucose intolerance.

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Jay W Porter, Joe L Rowles III, Justin A Fletcher, Terese M Zidon, Nathan C Winn, Leighton T McCabe, Young-Min Park, James W Perfield II, John P Thyfault, R Scott Rector, Jaume Padilla and Victoria J Vieira-Potter

Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21-knockout (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n = 9–15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR) and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects.

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Jin-Bong Lee, Sung-Jin Yoon, Sang-Hyun Lee, Moo-Seung Lee, Haiyoung Jung, Tae-Don Kim, Suk Ran Yoon, Inpyo Choi, Ik-Soo Kim, Su Wol Chung, Hee Gu Lee, Jeong-Ki Min and Young-Jun Park

Healthy expansion of adipose tissue maintains metabolic homeostasis by storing excess chemical energy in increased fat mass. The STAT5-PPAR gamma pathway reportedly regulates adipocyte differentiation, lipid metabolism and adipogenesis. Ginsenoside Rg3 is one of the diverse groups of steroidal saponins, the major active components of ginseng, which have demonstrated pharmacological properties. In this study, we evaluated the therapeutic effects of ginsenoside Rg3 under pathological conditions in vitro and in vivo. We examined the effects of ginsenoside Rg3 on glucose level, insulin sensitivity and lipogenesis in high-fat diet-fed C57BL/6 mice. Ginsenoside Rg3 was also applied to the pre-adipocyte cell line 3T3-L1 to assess the impact on lipogenesis. Ginsenoside Rg3 reduced epididymal white adipose tissue (eWAT) size and hepatic steatosis, and the amount of triglycerides (TGs) in both eWAT and liver. Similar to the murine model, Rg3-treated 3T3-L1 cells showed a reduction in lipid accumulation and amount of total TGs. Ginsenoside Rg3 regulates the expression of PPAR gamma though STAT5 in vitro and in vivo. According to our results, lipid metabolism-related genes were downregulated in the high-fat mice and 3T3-L1 cell line. Rg3 shows potential for the amelioration of obesity-induced pathology, acting though STAT5-PPAR gamma to facilitate the healthy functioning of adipose tissue. This is the first report of evidence that obesity-induced insulin resistance and lipotoxicity can be treated with ginsenoside Rg3, which acts though the STAT5-PPAR gamma pathway in vivo and in vitro.

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Terese M Zidon, Jaume Padilla, Kevin L Fritsche, Rebecca J. Welly, Leighton T. McCabe, Olivia E. Stricklin, Aaron P. Frank, Young-Min Park, Deborah J. Clegg, Dennis Lubahn, Jill Kanaley and Victoria Vieira-Potter

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ). We examined ovariectomized (OVX) and ovary-intact wildtype (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n=7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all p<0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (p<0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.