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- Genetic background defines the regulation of postnatal cardiac growth by 17β-estradiol through a β-catenin mechanism. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 14.:en20132180.
Estrogen regulates several biological processes in health and disease. Specifically, estrogen exerts anti-hypertrophic effects in the diseased heart. However, its role in the healthy heart remains elusive. Our initial aim was to identify the effects of 17β-estradiol (E2) on cardiac morphology and global gene expression in the healthy mouse heart. Two-month-old C57BL/6J mice were ovariectomized and treated with E2 or vehicle for three months. We report that E2 induced physiological hypertrophic growth in the healthy C57BL/6J mouse heart characterized by an increase in nuclear β-catenin. Hypothesizing that β-catenin mediates these effects of E2, we employed a model of cardiac β-catenin deletion. Our surprising finding is that E2 had the opposite effects in wild-type littermates, which were actually on the C57BL/6N background. Notably, E2 exerted no significant effect in hearts of mice with depleted β-catenin. We further demonstrate an E2-dependent increase in glycogen synthase kinase 3β (GSK3β) phosphorylation and endosomal markers in C57BL/6J but not C57BL/6N mice. Together, these findings indicate an E2-driven inhibition of GSK3β and consequent activation of β-catenin in C57BL/6J mice, while the opposite occurs in C57BL/6N mice. In conclusion, E2 exerts divergent effects on postnatal cardiac growth in mice with distinct genetic backgrounds modulating members of the GSK3β/β-catenin cascade.
- A novel role for the thyroid hormone activating enzyme type 2 deiodinase in the inflammatory response of macrophages. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 14.:en20132066.
Deiodinase type 2 (D2) is a thyroid hormone activating enzyme converting the pro-hormone thyroxine (T4) into the active hormone triiodothyronine (T3). In the present study we show for the first time that D2 is upregulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine interleukin (IL)-1β and independently of serum T3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (MCT-10) and receptor (TRα1) stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the LPS-induced IL-1β and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T3, acting via the TRα, may be instrumental in this novel inflammatory response, as LPS-treated TRα(0/0) mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favours the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages.
- Essential roles of epithelial bone morphogenetic protein signaling during prostatic development. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 14.:en20132054.
Prostate is a male sex accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of pSmad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.
- Corticotropin-releasing hormone and the sympathoadrenal system are major mediators in the effects of peripherally administered exendin-4 on the hypothalamic-pituitary-adrenal axis of male rats. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 14.:en20131718.
Glucagon-like peptide-1 (GLP-1) and the GLP-1 receptor agonist, exendin-4 (Ex-4), potently stimulate hypothalamic-pituitary-adrenal (HPA) axis activity after either central or peripheral administration. Since several GLP-1 derivative drugs, including synthetic Ex-4, are currently in use to treat patients with type II diabetes mellitus, the characterization of Ex-4 effects on the HPA axis is highly relevant. Herein, the roles of CRH and AVP on these effects were investigated by administering the antagonists astressin and d(CH2)5Tyr(Me)AVP, respectively. The role of the sympathoadrenal system (SAS) was explored in bilateral adrenal enucleated and guanethidine-treated rats, whereas primary pituitary cell cultures were used to study direct effects on the corticotropes. Astressin completely abrogated (p<0.05) the effects of Ex-4 central administration on ACTH secretion but only slightly reduced (by 35%) the ACTH response to Ex-4 peripheral administration. Moreover, astressin significantly (p<0.05) decreased the corticosterone response to centrally but not peripherally administered Ex-4, suggesting different mechanisms depending on the route of administration. Pretreatment with d(CH2)5Tyr(Me)AVP failed to diminish either the ACTH and corticosterone response to Ex-4 and no direct effect of Ex-4 or GLP-1 was observed on pituitary cell cultures. In contrast, a significant (p<0.05) reduction in the corticosterone response elicited by Ex-4 peripheral administration was observed in enucleated and guanethidine-treated rats, indicating a role of the SAS in the glucocorticoid stimulatory effects of Ex-4. Our data demonstrate that the effects of Ex-4 on the HPA axis are partially mediated by CRH and the sympathoadrenal system, and stress the relevance of Ex-4 as a corticosterone secretagogue.
- Vanin-1 inactivation antagonizes the development of adrenocortical neoplasia in Sf-1 transgenic mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 8.:en20141088.
SF-1 (NR5A1) overexpression can induce adrenocortical tumor formation in transgenic mice and is associated with more severe prognosis in patients with adrenocortical cancer. In this study we have identified Vanin-1 (Vnn1), an SF-1 target gene, as a novel modulator of the tumorigenic effect of Sf-1 overexpression in the adrenal cortex. Vanin-1 is endowed with pantetheinase activity, releasing cysteamine in tissues and regulating cell response to oxidative stress by modulating the production of glutathione. Sf-1 transgenic mice developed adrenocortical neoplastic lesions (both dysplastic and nodular) with a frequency increasing with age. Genetic ablation of the Vnn1 gene in Sf-1 transgenic mice significantly reduced the severity of neoplastic lesions in the adrenal cortex. This effect could be reversed by treatment of Sf-1 transgenic / Vnn1 null mice with cysteamine. These data show that alteration of the mechanisms controlling intracellular redox and detoxification mechanisms is relevant to the pathogenesis of adrenocortical neoplasia induced by SF-1 overexpression.
- Effects of the antitumor drug OSI-906, a dual inhibitor of IGF-1 receptor and insulin receptor, on the glycemic control, β cell functions, and β cell proliferation in male mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 8.:en20132032.
The IGF-1 receptor (IGF1R) has become a therapeutic target for the cancer. The efficacy of OSI-906 (Linstinib), a dual inhibitor of IGF1R and insulin receptor, for solid cancers has been examined in clinical trials. The effects of OSI-906, however, on the blood glucose levels and pancreatic β cell functions have not yet been reported. We investigated the impact of OSI-906 on the glycemic control, insulin secretion, β cell mass, and β cell proliferation in male mice. Oral administration of OSI-906 worsened glucose tolerance in a dose-dependent manner in the wild-type mice. OSI-906 at a dose equivalent to the clinical daily dose (7.5 mg/kg) transiently evoked glucose intolerance and hyperinsulinemia. IRS-2-deficient mice and mice with diet-induced obesity, both models of peripheral insulin resistance, exhibited more severe glucose intolerance after OSI-906 administration than glucokinase-haploinsufficient mice, a model of impaired insulin secretion. Phloridzin improved the hyperglycemia induced by OSI-906 in mice. In vitro, OSI-906 showed no effect on the insulin secretion from isolated islets. After daily administration of OSI-906 for a week to mice, the β cell mass and β cell proliferation rate were significantly increased. The insulin signals in the β cells were apparently unaffected in those mice. Taken together, the results suggest that OSI-906 could exacerbate diabetes, especially in patients with insulin resistance. On the other hand the results suggest that the β cell mass may expand in response to chemotherapy with this drug.
- Sweet Taste Receptors Regulate Basal Insulin Secretion and Contribute to Compensatory Insulin Hypersecretion During the Development of Diabetes in Male Mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 8.:en20132015.
β-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage β-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on β-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2(-/-) knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2(-/-) mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.
- Prevention of obesity induced renal injury in male mice by DPP4 inhibition. [JOURNAL ARTICLE]
- Endocrinology 2014 Apr 8.:en20131920.
Therapies to prevent renal injury in obese hypertensive individuals are being actively sought due to the obesity epidemic arising from the western diet (WD) which is high in fructose and fat. Recently, activation of the immune system and hyperuricemia, observed with high fructose intake, have been linked to the pathophysiology of hypertension and renal injury. Since dipeptidyl peptidase 4 (DPP4) is a driver of maladaptive T-cell/ macrophage responses, renal protective benefits of DPP4 inhibition in the WD-fed mice were examined. Mice fed a WD for 16 weeks were given a DPP4 inhibitor MK0626 in their diet beginning at 4 weeks of age. WD-fed mice were obese, hypertensive, insulin resistant and manifested proteinuria, increased plasma DPP4 activity and uric acid levels. WD fed mice also had elevated kidney DPP4 activity, MCP1 and IL12 levels and suppressed IL10 levels in the kidney suggesting macrophage driven inflammation, glomerular and tubulointerstitial injury. WD-induced increases in DPP4 activation in the plasma and kidney and proteinuria in WD mice were abrogated by MK0626 although blood pressure and systemic insulin sensitivity were not improved. Contemporaneously, MK0626 reduced serum uric acid levels and renal oxidative stress, IL12 levels and increased IL10 levels suggesting that suppression of DPP4 activity leads to suppression of renal immune/inflammatory injury responses to a WD. Taken together, these results demonstrate that DPP4 inhibition prevents high fructose/high fat diet-induced glomerular and tubular injury independent of blood pressure/insulin sensitivity and offers a potentially novel therapy for diabetic and obesity related kidney disease.
- Growth and development: Bone dysplasia-a frequent cause of short stature in children. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Apr 8.