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- Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 24.:en20141393.
Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic β-cell. Complications of pregnancy such as diabetes and intrauterine growth restriction are associated with changes in fetal insulin concentrations, secretion and β-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and β-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose-stimulated insulin secretion (GSIS) and β-cell mass in the ovine fetus. Singleton ovine fetuses were infused with intravenous insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133±1 days gestation, was significantly attenuated in the hyperinsulinemic fetuses (P<0.05). There was no change in β-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P<0.05) and higher norepinephrine (1160±438 vs. 522±106 pg/ml, P<0.005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.
- Galectin-3 Activates PPARγ and Supports White Adipose Tissue Formation and High-Fat Diet-Induced Obesity. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 24.:en20141374.
Galectin-3, a β-galactoside-binding lectin, is elevated in obesity and type 2 diabetes mellitus, and metformin treatment reduces galectin-3 levels. However, the role of galectin-3 in adipogenesis remains controversial. We found that 17-month-old galectin-3-deficient (lgals3(-/-)) mice had decreased body size and epididymal white adipose tissue (eWAT) without related inflammatory diseases when fed normal chow. Galectin-3 knock-down significantly reduced adipocyte differentiation in 3T3-L1 cells and also decreased expression of PPARγ, C/EBPα, and C/EBPβ. Endogenous galectin-3 directly interacted with PPARγ, and galectin-3 ablation reduced nuclear accumulation and transcriptional activation of PPARγ. After a 12-week high-fat diet (60% fat), lgals3(-/-) mice had lower body weight and eWAT mass than lgals3(+/+) mice. Moreover, the expression of PPARγ and other lipogenic genes was drastically decreased in the eWAT and liver of lgals3(-/-) mice. We suggest that galectin-3 directly activates PPARγ and leads to adipocyte differentiation in vitro and in vivo. Furthermore, galectin-3 might be a potential therapeutic target in metabolic syndromes as a PPARγ regulator.
- β-catenin stabilization in gonadotropes impairs follicle-stimulating hormone synthesis in male mice in vivo. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 24.:en20141296.
Though classically considered a WNT signaling intermediary, CTNNB1 (β-catenin) can also mediate GnRH induction of gonadotropin β subunit (Fshb and Lhb) transcription in the murine gonadotrope-like cell line LβT2. Here, we assessed CTNNB1's role in gonadotropin synthesis in vivo. We used a Cre/lox approach to introduce both gain- and loss-of-function mutations in the murine Ctnnb1 gene in gonadotrope cells. Gonadotropin production and fertility were normal in Ctnnb1 knockout mice. Similarly, females harboring a deletion of exon 3 of Ctnnb1, which stabilizes the resulting CTNNB1 protein, showed normal fertility and gonadotropin synthesis. Interestingly, males with the activating CTNNB1-Δexon 3 mutation exhibited 50% reductions in FSH synthesis and secretion, without a corresponding change in LH. This selective regulation of FSH suggested an alteration in the activin/inhibin/follistatin system. Indeed, CTNNB1-Δexon 3 males showed a 60% increase in serum inhibin B levels and, in culture, their pituitaries exhibited a greater sensitivity to exogenous inhibin than controls. At the same time, pituitary, but not testicular, follistatin (Fst) expression was increased significantly in these mice. Castration normalized FSH levels in CTNNB1-Δexon 3 males to those seen in castrated controls. Paradoxically, pituitaries from CTNNB1-Δexon 3 males exhibited greater basal and activin-stimulated FSH synthesis in vitro. Similarly, CTNNB1-Δexon 3 overexpression potentiated activin A-induced murine Fshb promoter activity in LβT2 cells. Together, these results indicate that CTNNB1 is dispensable for gonadotropin synthesis in vivo. However, sustained CTNNB1 signaling potentiates activin-induced Fshb expression in gonadotropes, but this effect is overcome in vivo by enhanced inhibin feedback sensitivity and Fst expression.
- Cdc42 is critical for cartilage development during endochondral ossification. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 24.:en20141032.
Cdc42 is a widely expressed protein that belongs to the family of Rho GTPases and controls a broad variety of signal transduction pathways in a variety of cell types. To investigate the physiological functions of Cdc42 during cartilage development, we generated chondrocyte-specific inactivated Cdc42 mutant mice (Cdc42(fl/fl); Col2-Cre). The gross morphology of mutant neonates showed shorter limbs and body as compared to the control mice (Cdc42(fl/fl)). Skeletal preparations stained with alcian blue and alizarin red also revealed that the body and the long bone length of the mutants were shorter than those of the control mice. Furthermore, severe defects were found in growth plate chondrocytes in the femur sections of mutant mice, characterized by a reduced proliferating zone height, wider hypertrophic zone, and loss of columnar organization in proliferating chondrocytes. The expression levels of chondrocyte marker genes, such as Col2, Col10, and Mmp13, in mutant mice were decreased as compared to the control mice. Mineralization of trabecular bones in femur sections was also decreased in the mutants as compared to control mice, whereas osteoid volume was increased. Together, these results suggested that chondrocyte proliferation and differentiation in growth plates in the present mutant mice were not normally organized, which contributed to abnormal bone formation. We concluded that Cdc42 is essential for cartilage development during endochondral bone formation.
- Partial blockade of Kv2.1 channel potentiates GLP-1's insulinotropic effects in islets and reduces its dose required for improving glucose tolerance in type 2 diabetic male mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 22.:en20141728.
Glucagon-like peptide-1 (GLP-1)-based medicines have recently been widely used to treat type 2 diabetic patients, while adverse effects of nausea and vomiting have been documented. Inhibition of voltage-gated K(+) channel subtype Kv2.1 in pancreatic β-cells has been suggested to contribute to mild depolarization and promotion of insulin release. This study aimed to determine whether blockade of Kv2.1 channels potentiates insulinotropic effect of GLP-1 agonists. Kv2.1 channel blocker guangxitoxin-1E (GxTx) and GLP-1 agonist exendin-4 at sub-threshold concentrations, when combined, markedly increased insulin release and cytosolic Ca(2+) concentration ([Ca(2+)]i) in a glucose-dependent manner in mouse islets and β-cells. Exendin-4 at sub-threshold concentration alone increased islet insulin release and β-cell [Ca(2+)]i in Kv2.1(+/-) mice. The [Ca(2+)]i response to sub-threshold exendin-4 and GxTx in combination was attenuated by pretreatment with protein kinase-A (PKA) inhibitor H-89, indicating PKA-dependency of the cooperative effect. Furthermore, sub-threshold doses of GxTx and GLP-1 agonist liraglutide in combination markedly increased plasma insulin and improved glucose tolerance in diabetic db/db mice and NSY mice. These results demonstrate that a modest suppression of Kv2.1 channels dramatically raises insulinotropic potency of GLP-1-based drugs, which opens a new avenue to reduce their doses and associated adverse effects, while achieving the same glycemic control in type 2 diabetes.
- Specialized subpopulations of kisspeptin neurons communicate with GnRH neurons in female mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 22.:en20141671.
The neuropeptide kisspeptin is a potent stimulator of GnRH neurons and has been implicated as a major regulator of the hypothalamus-pituitary-gonadal (hpg) axis. There are mainly two anatomically segregated populations of neurons that express kisspeptin in the female hypothalamus; one in the anteroventral periventricular nucleus (AVPV) and the other in the arcuate nucleus (ARC). Distinct roles have been proposed for AVPV and ARC kisspeptin neurons during reproductive maturation and in mediating estrogen feedback on the hpg axis in adults. Despite their pivotal role in the regulation of reproductive physiology, little is known about kisspeptin neuron connectivity. While previous data suggest heterogeneity within the AVPV and ARC kisspeptin neuron populations, how many and which of these potential kisspeptin neuron subpopulations are actually communicating with GnRH neurons is not known. Here we used a combinatorial genetic transsynaptic tracing strategy to start to analyze the connectivity of individual kisspeptin neurons with the GnRH neuron population in female mice with a single cell resolution. We find that only subsets of AVPV and ARC kisspeptin neurons are synaptically connected with GnRH neurons. We demonstrate that the majority of kisspeptin neurons within the AVPV and ARC does not communicate with GnRH neurons. Furthermore, we show that all kisspeptin neurons within the AVPV connected to GnRH neurons are estrogen-sensitive and that most of these express tyrosine hydroxylase. Our data demonstrate functional specialization within the two kisspeptin neuron populations.
- Ghrelin protects alveolar macrophages against lipopolysaccharide-induced apoptosis through growth hormone secretagogue receptor 1a-dependent c-Jun N-terminal kinase and Wnt/β-catenin signaling and suppresses lung inflammation. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 22.:en20141539.
Alveolar macrophages (AMs) undergo increased apoptosis during sepsis-induced acute respiratory distress syndrome (ARDS). Ghrelin exhibits an antiapoptotic effect in several cell types and protects against sepsis-induced ARDS in rats; however, the molecular mechanisms underlying this antiapoptotic effect remain poorly understood. In this study, we first examined the antiapoptotic effect of ghrelin on lipopolysaccharide (LPS)-stimulated AMs in vitro. In AMs, growth hormone secretagogue receptor 1a (GHSR-1a), the ghrelin receptor, was expressed, and treatment of AMs with ghrelin markedly reduced LPS-induced apoptosis, mitochondrial transmembrane potential (ΔΨm) decrease and cytochrome c release. These effects of ghrelin were mediated by GHSR-1a, because a GHSR1-a-targeting siRNA abolished the antiapoptotic action of ghrelin. LPS treatment activated the c-Jun N-terminal kinase (JNK) signaling pathway but inhibited the Wnt/β-catenin pathway. Interestingly, combined LPS-ghrelin treatment reduced JNK activation and increased Wnt/β-catenin activation. Furthermore, like ghrelin treatment, the addition of the JNK inhibitor SP600125 or the GSK-3β inhibitor SB216763 rescued AMs from apoptosis. We also demonstrated that ghrelin altered the balance of Bcl-2-family proteins and inhibited caspase-3 activity. Next, we investigated whether ghrelin protected against septic ARDS in vivo. Sepsis was induced in male rats by performing cecal ligation and puncture; administration of ghrelin reduced sepsis-induced AM apoptosis, pulmonary injury, protein concentrations in the bronchoalveolar lavage fluid, the lung neutrophil infiltration and wet-to-dry weight ratio. However, administration of a specific ghrelin-receptor antagonist, [D-Lys-3]-GHRP-6, abolished the beneficial effects of ghrelin. Collectively, our results suggest that ghrelin exerts anantiapoptotic effect on AMs at least partly by inhibiting JNK and activating the Wnt/β-catenin pathway, and thereby helps alleviate septic ARDS in rats.
- COL6A3 is regulated by leptin in human adipose tissue and reduced in obesity. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 22.:en20141042.
Fibrosis of adipose tissue (AT) increases AT rigidity, reduces its expandability and contributes to metabolic dysfunction. Collagen type VI, alpha3 (COL6A3) encodes one subunit of a fibrotic extracellular matrix (ECM) protein highly expressed in rodent AT. Knock-out of collagen VI in rodent AT led to a significant improvement in metabolic health in obese, diabetic (ob/ob) mice however, it is unknown whether this collagen has the same metabolic significance in human AT. We therefore aimed to undertake a comprehensive assessment of COL6A3 in relation to human AT and obesity. Characterisation of COL6A3 in human AT showed 5 fold higher expression in the stromalvascular fraction compared with adipocyte expression and significantly higher expression in subcutaneous than omental AT. In both depots COL6A3 expression appeared to be lowered in obesity, whilst diet and surgery-induced weight loss increased COL6A3 expression in subcutaneous AT. Leptin treatment caused a dose dependent decrease in COL6A3 expression although no effect was seen with insulin or glucose treatment and no difference observed in subjects with diabetes. In addition, we found that the collagen expression profile in humans differs significantly from rodents as COL6A3 does not appear to be the predominant collagen in adipose, muscle or liver. Our findings oppose those initially seen in rodent studies and most importantly, demonstrate a direct regulation of COL6A3 by leptin. This highlights the importance of a paracrine leptin signalling pathway in human AT and suggests an additional mechanism by which leptin can regulate ECM composition and with it AT expandability.
- Functional Characterization of GH-Like Homolog in Amphioxus Reveals an Ancient Origin of GH/GH Receptor System. [JOURNAL ARTICLE]
- Endocrinology 2014 Oct 21.:en20141377.
Amphioxus belongs to the subphylum cephalochordata, an extant representative of the most basal chordates. Despite many studies on the endocrine system of amphioxus, no evidence showed the presence of pituitary hormones. In this study, we clearly demonstrated the existence of a functional GH-like hormone in amphioxus, which is able to bind purified GH receptors, stimulate IGF-I expression, promote growth rate of fish, and rescue embryonic defects caused by a shortage of GH. We also showed the presence of a GH/prolactin-like-binding protein containing the entire hormone binding domain of GH/prolactin receptors in amphioxus, which is widely expressed among tissues, and interacts with the GH-like hormone. It is clear from these results that the GH/GH receptor-like system is present in amphioxus and, hence, in all classes of chordates. Notably, the GH-like hormone appears to be the only member of the vertebrate pituitary hormones family in amphioxus, suggesting that the hormone is the ancestral peptide that originated first in the molecular evolution of the pituitary hormones family in chordates. These data collectively suggest that a vertebrate-like neuroendocrine axis setting has already emerged in amphioxus, which lays a foundation for subsequent formation of hypothalamic-pituitary system in vertebrates.
- Diabetes: Antihelminthic drug for T2DM therapy? [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Oct 21.