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- Intraperitoneal CCK and fourth-intraventricular Apo AIV require both peripheral and NTS CCK1R to reduce food intake in male rats. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 24.:en20131846.
Apolipoprotein AIV (Apo AIV) and cholecystokinin (CCK) are secreted in response to fat consumption, and both cause satiation via CCK 1 receptor (CCK-1R)-containing vagal afferent nerves to the NTS where Apo AIV is also synthesized. Fasted male Long-Evans rats received ip CCK-8 or fourth-ventricular (i4vt) Apo AIV alone or in combination. Food intake and c-Fos proteins were assessed. I4vt Apo AIV and/or ip CCK at effective doses reduced food intake and activated c-Fos proteins in the NTS and hypothalamic ARC and PVN. Blockade of the CCK-1R by i4vt lorglumide adjacent to the NTS attenuated the satiating and c-Fos-stimulating effects of CCK and Apo AIV, alone or in combination. Maintenance on a high-fat diet (HFD) for 10 weeks resulted in weight gain and attenuation of both the behavioral and c-Fos responses to a greater extent than occurred in LFD-fed and pair-fed HFD animals. These observations suggest that NTS Apo AIV or/and peripheral CCK requires vagal CCK-1R signaling to elicit satiation and that maintenance on a HFD reduces the satiating capacity of these two signals.
- Assessment of the metabolic pathways associated with glucose-stimulated biphasic insulin secretion. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 24.:en20131805.
Biphasic glucose-stimulated insulin secretion involves a rapid first-phase followed by a prolonged second-phase of insulin secretion. The biochemical pathways that control these two phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy (GC-MS) based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, TCA, pentose phosphate pathway and several amino acids are strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with L-valine, trans-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, DL-3-aminoisobutyric acid, L-glutamine, sarcosine, L-lysine and thymine and positively with L-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5'-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid and palmitoleic acid. TCA cycle intermediates pyruvate, α-ketoglutarate and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, DL-3-aminobutyric acid and L-norleucine were negatively associated metabolites with the second-phase insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively and positively associated with biphasic insulin. The insights provided by this data set creates a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.
- Programming of the Hypothalamic-Pituitary-Adrenal Axis by Neonatal Intermittent Hypoxia: Effects on Adult Male ACTH and Corticosterone Responses are Stress-Specific. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 24.:en20131736.
Intermittent hypoxia (IH) is an animal model of apnea-induced hypoxia, a common stressor in the premature neonate. Neonatal stressors may have long-term programming effects in the adult. We hypothesized that neonatal exposure to IH leads to significant changes in basal and stress-induced hypothalamic-pituitary-adrenal (HPA) axis function in the adult male rat. Rat pups were exposed to normoxia (control) or 6@30-sec cycles of IH (5% or 10% inspired O2) daily on postnatal days 2 to 6. At approximately 100 days of age, we assessed the diurnal rhythm of plasma corticosterone and stress-induced plasma ACTH and corticosterone responses, as well as mRNA expression of pertinent genes within the HPA-axis. Basal diurnal rhythm of plasma corticosterone and fecal corticosterone concentrations in the adult rat were not affected by prior exposure to neonatal IH. Adults exposed to 10% IH as neonates exhibited an augmented peak ACTH response and a prolonged corticosterone response to restraint stress; however, HPA axis responses to insulin-induced hypoglycemia were not augmented in adults exposed to neonatal IH. Pituitary Pomc, Crhr1, Nr3c1, Nr3c2, Avpr1b, and Hif1a mRNA expression was decreased in adults exposed to neonatal 10% IH. Expression of pertinent hypothalamic and adrenal mRNAs was not affected by neonatal IH. We conclude that exposure to neonatal 10% IH programs the adult HPA axis to hyper-respond to acute stimuli in a stressor-specific manner.
- Central Adiponectin Acutely Improves Glucose Tolerance in Male Mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 24.:en20131734.
Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also anti-inflammatory. During obesity, adiponectin levels and sensitivity are reduced. While the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the two adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1μg) was injected intracerebroventricularly (ICV) and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signalling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated while AdipoR1 was up-regulated in the arcuate nucleus (ARC) of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin deficient mice acute ICV adiponectin improved glucose tolerance 60 min after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased pAMPK and did not change pSTAT3 immunoreactivity. In HF fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of pGSK-3β(Ser9) and pJNK(Thr183/Tyr185) immunoreactive cells in the ARC and ventromedial hypothalamus. This study demonstrates that the insulin sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.
- Metabolic influences on reproduction: Adiponectin attenuates gonadotropin-releasing hormone-1 neuronal activity in female mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 24.:en20131677.
Metabolic dysfunctions are often linked to reproductive abnormalities. Adiponectin, a peripheral hormone secreted by white adipose tissue, is important in energy homeostasis and appetite regulation. Gonadotropin-releasing hormone-1 (GnRH) neurons are integral components of the reproductive axis, controlling synthesis and release of gonadotropins. This report examined whether adiponectin can directly act on GnRH neurons. Double-label immunofluorescence on brain sections from adult female mice revealed that a subpopulation of GnRH neurons express AdipoR2. GnRH/AdipoR2+ cells were distributed throughout the forebrain. To determine the influence of adiponectin on GnRH neuronal activity and the signal transduction pathway of AdipoR2, GnRH neurons maintained in explants were assayed using whole cell patch clamping and calcium imaging. This mouse model system circumvents the dispersed distribution of GnRH neurons within the forebrain, making analysis of large numbers of GnRH cells possible. Single cell PCR analysis and immunocytochemistry confirmed the presence of AdipoR2 in GnRH neurons in explants. Functional analysis revealed 20% of the total GnRH population responded to adiponectin, exhibiting hyperpolarization or decreased calcium oscillations. Pertubation studies revealed that adiponection activates AMP-Kinase via the PKCζ/LKB1 pathway. The modulation of GnRH neuronal activity by adiponectin demonstrated in this report, directly links energy balance to neurons controlling reproduction.
- Molecular Basis for the Activation of Gonadotropin-Inhibitory Hormone Gene Transcription by Corticosterone. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 19.:en20132076.
The inhibitory effect of stress on reproductive function is potentially mediated by high concentrations of circulating glucocorticoids (GC) acting via the GC receptor (GR). Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion. GnIH may mediate stress-induced reproductive dysfunction. However, it is not yet known whether GC-bound GR is directly involved in GnIH transcription. Herein, we demonstrated the localization of GR mRNA in GnIH neurons in the paraventricular nucleus of quail, suggesting that GC can directly regulate GnIH transcription. We next showed that 24 h treatment with corticosterone (CORT) increases GnIH mRNA expression in the quail diencephalon. We further investigated the mechanism of activation of GnIH transcription by CORT using a GnIH-expressing neuronal cell line, rHypoE-23, derived from rat hypothalamus. We found the expression of GR mRNA in rHypoE-23 cells and increased GnIH mRNA expression by 24 h CORT treatment. We finally characterized the promoter activity of rat GnIH gene stimulated by CORT. Through DNA deletion analysis, we identified a CORT responsive region at 2000 to 1501 bp upstream of GnIH precursor coding region. This region included two glucocorticoid response elements (GREs) at -1665 and -1530 bp. Mutation of -1530 GRE abolished CORT responsiveness. We also found CORT-stimulated GR recruitment at the GnIH promoter region containing the -1530 GRE. These results provide a putative molecular basis for transcriptional activation of GnIH under stress by demonstrating that CORT directly induces GnIH transcription by recruitment of GR to its promoter.
- The Orphan Nuclear Receptor Nr5a2 is Essential for Luteinization in the Female Mouse Ovary. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 19.:en20131765.
In the ovary, the follicular granulosa cells express the nuclear receptor, Nr5a2, and following ovulation, Nr5a2 expression persists in the corpus luteum. Previous studies demonstrated that Nr5a2 is required for both ovulation and luteal steroid synthesis. Our objectives were to analyze the temporal sequence in the regulatory effects of Nr5a2 in the ovary, with focus on its contribution to luteal function. We developed a female mouse model of granulosa-specific targeted disruption from the formation of the antral follicles forward (genotype Nr5a2(Cyp19-/-)). Mice lacking Nr5a2 in granulosa cells of antral follicles are infertile. Although their cumulus cells undergo expansion after gonadotropin stimulation, ovulation is disrupted in those mice, at least in part, due to the downregulation of the progesterone receptor (Pgr) gene. The depletion of Nr5a2 in antral follicles permits formation of luteal-like structures, but not functional corpora lutea as evidenced by reduced progesterone levels and failure to support pseudopregnancy. Progesterone synthesis is affected by depletion of Nr5a2 due to, among others, defects in the transport of cholesterol, evidenced by downregulation of Scarb1, Ldlr and Star. Comparison of this mouse line with the models in which Nr5a2 is depleted from the primary follicle forward (genotype Nr5a2(Amhr2-/-)) and following the ovulatory signal (genotype Nr5a2(Pgr-/-)) demonstrates that Nr5a2 differentially regulates female fertility across the trajectory of follicular development.
- IGF-I stimulates CCN5/WISP2 gene expression in pancreatic β-cells, which promotes cell proliferation and survival against streptozotocin. [JOURNAL ARTICLE]
- Endocrinology 2014 Feb 19.:en20131735.
Insulin-like growth factor (IGF)-I is normally produced from hepatocytes and other sources, stimulates protein synthesis, cell survival and proliferation through receptor-mediated activation of PI3K and MAPK and targets specific molecules within the pancreatic islet cells. The current study was designed to identify novel targets that may mediate its pro-islet actions. Whole-genome cDNA microarray analysis in IGF-I overexpressing islets identified 82 genes specifically up- or down-regulated. Prominent among them was CCN5/WISP2 whose expression was increased 3- and 2-fold at the mRNA and protein levels. Dual-labeled immunofluorescence revealed that CCN5 expression was low in the β-cells of wild-type islets but was significantly induced in response to IGF-I overexpression. In vitro treatment of mouse islets with IGF-I increased both CCN5 mRNA and protein levels significantly. To define the role of CCN5 in islet cell biology, we stably overexpressed its cDNA in insulinoma MIN6 cells and detected a 2-fold increase in the proliferation of MIN6-CCN5 compared to control cells that correlated with significant elevations in the levels of cyclin D1 and the phosphorylation of Akt and Erk2. Moreover, MIN6-CCN5 cells were found to be resistant to streptozotocin-induced cell death. Using confocal microscopy and subcellular fractionation overexpressed CCN5 exhibited cytoplasmic accumulation upon stimulation by high glucose. Our results indicate that CCN5, which is minimally expressed in islet β-cells, is strongly and directly induced by IGF-I. CCN5 overexpression stimulates the proliferation of insulinoma cells, activates Akt kinase, and inhibits streptozotocin-induced apoptosis, suggesting that increased CCN5 expression contributes to IGF-I-stimulated islet cell growth and/or survival.
- Medical oncology: Cardiovascular events linked to levels of cortisol production. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Feb 18.
- Achieving glycaemic targets with basal insulin in T2DM by individualizing treatment. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Feb 18.
Insulin therapy is an effective method for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM), and most patients with T2DM eventually require insulin replacement to attain and preserve satisfactory glycaemic control. All patients with T2DM should be considered as potential candidates for intensive insulin treatment; however, there are certain considerations regarding replacement therapy for different types of people and special populations, such as patients with multiple comorbidities, adolescents, pregnant women and the elderly. Lowering HbA1c levels in isolation without assessing the patient as a whole is becoming redundant. HbA1c targets should be individualized to the specific patient, and insulin treatment ought to be customized accordingly. There are several questions that need to be taken into account when considering adding insulin therapy to other oral antidiabetic agents, for example, for whom and when insulin therapy is indicated and which basal insulin should be utilized. Potential barriers exist related to patients, providers and health-care systems that can delay the start of insulin therapy, and every effort should be made to identify and address these obstacles.