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- Autoimmunity: A new mechanism underlying thyroid autoimmunity revealed. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Sep 2.
- Dyslipidaemia: Cardiovascular prevention-end of the road for niacin? [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Sep 2.
- Diabetes: Reprogrammed pancreatic δ-cells restore insulin production. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Sep 2.
- Blocking Ligand Occupancy of the αVβ3 Integrin Inhibits the Development of Nephropathy in Diabetic Pigs. [JOURNAL ARTICLE]
- Endocrinology 2014 Aug 29.:en20141318.
Hyperglycemia stimulates secretion of αVβ3 ligands from vascular cells including endothelial cells resulting in activation of the αVβ3 integrin. This study determined if blocking ligand occupancy of αVβ3 would inhibit the development of diabetic nephropathy. Ten diabetic pigs received an F(ab)2 fragment of an antibody directed against the extracellular domain of the β3 subunit and ten received a control IgG F(ab)2 for 18 weeks. Non-diabetic pigs excreted 115 ± 50 μg of protein/mg creatinine compared to control F(ab)2 treated diabetic animals (218± 57 μg/mg) whereas diabetic animals treated with the anti-β3 F(ab)2 excreted 119 ± 55 μg/mg (p<0.05). Mesangial volume/glomerular volume increased to 21 ± 2.4 in control treated diabetic animals compared to 14 ± 2.8% (p<0.01) in animals treated with active antibody. Diabetic animals treated with control F(ab)2 had significantly less glomerular podocin staining compared to nondiabetic animals and this decrease was attenuated by treatment with anti-β3 F(ab)2. Glomerular basement membrane thickness was increased in the control, F(ab)2 treated diabetic animals (212±14 nm) compared to nondiabetic animals (170 ± 8.8 nm) but it was unchanged (159.9 ± 16.4 nm) in animals receiving anti-β3 F(ab)2. Podocyte foot process width was greater in control, F(ab)2 treated, animals (502± 34 nm) compared to animals treated with the anti-β3 F(ab)2 (357±47 nm, p<0.05). Renal β3 tyrosine phosphorylation decreased from 13,934 ± 6437 to 6730 ± 1524 (p<0.01) scanning units in the anti-β3 treated group. We conclude that administration of an antibody that inhibits activation of the β3 subunit of αVβ3 that is induced by hyperglycemia attenuates proteinuria and early histologic changes of diabetic nephropathy suggesting that it may have utility in preventing the progression of this disease complication.
- GPER-1 and Estrogen Receptor-β Ligands Modulate Aldosterone Synthesis. [JOURNAL ARTICLE]
- Endocrinology 2014 Aug 28.:en20141416.
Fertile women have lower blood pressure (BP) and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 β-estradiol blunts aldosterone secretion, and thereby affects the gender dimorphism of BP, is unknown. We therefore sought for the estrogen receptor subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of 17 β-estradiol on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosterone-producing adenoma cells the most expressed estrogen receptors were the estrogen receptor β (ERβ) and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ERβ blockade 17 β-estradiol (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (+ 5-to7-fold vs baseline, p <0.001). Under the same condition the GPER-1 receptor agonist G-1 (10 nmol/L) mimicked this effect, which was abrogated by co-treatment with either the GPER-1 receptor antagonist G15, or a selective protein kinase A (PKA) inhibitor (Rp-8-Br-MB-cAMPS). Silencing of the ERβ significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered CYP11B2 gene and protein expression. Moreover, it blunted the stimulatory effect of 17 β-estradiol on CYP11B2 that was seen during ERβ blockade. These results support the conclusion that in humans 17 β-estradiol inhibits aldosterone synthesis by acting via ERβ. Pharmacologic disinhibition of ERβ unmasks a potent secretagogue effect of 17 β-estradiol that involves GPER-1 and PKA signaling.
- Divergent Effects of Oxytocin Treatment of Obese Diabetic Mice on Adiposity and Diabetes. [JOURNAL ARTICLE]
- Endocrinology 2014 Aug 26.:en20141466.
Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined.
- APELIN COUNTERACTS VASOPRESSIN-INDUCED WATER REABSORPTION VIA CROSSTALK BETWEEN APELIN AND VASOPRESSIN RECEPTOR SIGNALING PATHWAYS IN THE RAT COLLECTING DUCT. [JOURNAL ARTICLE]
- Endocrinology 2014 Aug 26.:en20141257.
Apelin receptors (ApelinR) are expressed along an increasing cortico-medullary gradient in collecting ducts (CD). We showed here, that intravenous injection of apelin 17 (K17F) in lactating rats characterized by increases in both synthesis and release of vasopressin (AVP), increased diuresis concomitantly with a significant decrease in urine osmolality and no change in Na(+) and K(+) excretion. Under these conditions, we also observed a significant decrease in apical aquaporin-2 immunolabeling in CD, with a cortico-medullary gradient, suggesting that K17F-induced diuresis could be linked to a direct action of apelin on CD. We then examined the potential crosstalk between V1a (V1aR), V2 (V2R) AVP receptors and ApelinR signaling pathways in outer (OMCD) and inner medullary (IMCD) microdissected rat CD. In OMCD, expressing the three receptors, K17F inhibited cAMP production and Ca(2+) influx induced by dDAVP, a V2R agonist. Similar effects were observed in IMCD expressing only V2R and ApelinR. In contrast in OMCD, K17F increased by 51 the Ca(2+) influx induced by the stimulation of V1aR by AVP in the presence of the V2R antagonist SR121463B, possibly enhancing the physiological antagonist effect of V1aR on V2R. Thus, the diuretic effect of apelin is not only due to a central effect by inhibiting AVP release in the blood circulation as previously shown, but also to a direct action of apelin on CD, by counteracting the antidiuretic effect of AVP occurring via V2R.
- A dopamine D2-receptor agonist attenuates the ability of stress to alter sleep in mice. [JOURNAL ARTICLE]
- Endocrinology 2014 Aug 26.:en20141134.
Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin, a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between prolactin secretion and REM sleep following restraint stress to determine whether: 1) the ability of stress to increase REM sleep is prolactin-dependent, and 2) fluctuating prolactin levels underlie sex differences in sleep responses to stress. Since dopamine D2-receptors in the pituitary gland are the primary regulator of prolactin secretion, D2-receptor agonist, cabergoline, was used to attenuate prolactin levels in mice prior to one-hour of restraint stress. Mice were implanted with EEG/EMG recording electrodes and received an intraperitoneal injection of either 0.3 mg/kg cabergoline or vehicle prior to a control procedure of one hour of sleep deprivation by gentle handling during the light phase. Six days following the control procedure, mice received cabergoline or vehicle 15-mins prior to one-hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males, but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on prolactin and that sex differences in REM sleep amount may be driven by prolactin.
- Genetics: Vitamin D and blood pressure-a preliminary verdict. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Aug 26.
- Diabetes: Saturated fatty acids-not all bad news. [JOURNAL ARTICLE]
- Nat Rev Endocrinol 2014 Aug 26.