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E Y Faraoni, A I Abeledo Machado, P A Pérez, C A Marcial López, M A Camilletti, M Peña-Zanoni, S B Rulli, S Gutiérrez and G Díaz-Torga

Among all the hormone-secreting pituitary tumours, prolactinomas are the most frequently found in the clinic. Since dopamine is the primary inhibitor of lactotroph function, dopamine agonists represent the first-line therapy. However, a subset of patients exhibits resistance to these drugs, and therefore, alternative treatments are desired. As activins inhibit prolactin gene expression through the inhibition of Pit-1 involving the p38MAPK pathway, in the present work, we studied the local activin system as an alternative inhibitory system for lactotroph hyperplasia treatment. We used two different mouse models of prolactinoma: transgenic mice with overexpression of the human chorionic gonadotropin β-subunit (hCGβ) and mice lacking dopamine receptor type 2. In both models, females, but not males, develop lactotroph hyperplasia from the fourth month of life. We found reduced expression of pituitary activin subunits and activin receptors in hyperplastic pituitaries from both models compared with wild-type counterparts. Consequently, hyperplastic pituitaries presented a reduced activin-inhibitory action on prolactin secretion. Additionally, while female wild-type lactotrophs presented high levels of phospho-p38MAPK, it was lost in prolactinomas, concomitant with decreased activin expression, increased Pit-1 expression and tumour development. In contrast, male pituitaries express higher mRNA levels of activin subunits βA and βB, which would suggest a stronger activin inhibitory function on lactotrophs, protecting this sex from tumour development, despite genotype. The present results highlight the importance of the activin inhibitory action on lactotroph function and place the local activin system as a new target for the treatment of dopamine agonist-resistant prolactinomas.

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Zahida Yesmin Roly, Andrew T Major, Alex Fulcher, Martin A Estermann, Claire E Hirst and Craig A Smith

The embryonic Müllerian ducts give rise to the female reproductive tract (fallopian tubes, uterus and upper vagina in humans, the oviducts in birds). Embryonic Müllerian ducts initially develop in both sexes, but later regress in males under the influence of anti-Müllerian hormone. While the molecular and endocrine control of duct regression in males have been well studied, early development of the ducts in both sexes is less well understood. Here, we describe a novel role for the adhesion G protein-coupled receptor, GPR56, in development of the Müllerian ducts in the chicken embryo. GPR56 is expressed in the ducts of both sexes from early stages. The mRNA is present during the elongation phase of duct formation, and it is restricted to the inner Müllerian duct epithelium. The putative ligand, Collagen III, is abundantly expressed in the Müllerian duct at the same developmental stages. Knockdown of GPR56 expression using in ovo electroporation results in variably truncated ducts, with a loss of expression of both epithelial and mesenchymal markers of duct development. Over-expression of GPR56 in vitro results in enhanced cell proliferation and cell migration. These results show that GPR56 plays an essential role in avian Müllerian duct development through the regulation of duct elongation.

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Baiyang You, Yaoshan Dun, Wenliang Zhang, Lingjun Jiang, Hui Li, Murong Xie, Yuan Liu and Suixin Liu

Mitochondrial quality control (MQC) and function are determinants for cellular energy metabolism, and their disorders are reported to play an important role in the development of insulin resistance (IR). Salidroside was reported to have beneficial effects on MQC through AMPK pathway; however, it is unknown whether salidroside exerts anti-IR effect with this action. This study sought to investigate the effects of salidroside on IR with an exploration of the mechanisms of its action. Experimental IR models were adopted in high-fat-diet (HFD)-fed mice and palmitate-treated C2C12 myotubes, respectively. Blood levels of glucose and insulin as well as cellular glucose uptake were determined, and mitochondrial function and MQC-associated parameters and reactive oxygen species (ROS) production were analyzed based on treatments with the activator (AICAR), inhibitors (compound C and EX-527) or specific siRNA of Ampk/Sirt1 and mitochondrial ROS scavenger (mito-TEMPO). Protein expression level was determined by Western blot, cellular observation by transmission electron microscope and ROS production by functional analysis kits. Salidroside reduced IR and activated insulin signaling along with the stimulation of AMPK/SIRT1 signaling and downstream regulation of MQC and ROS production. These salidroside effects were comparable to those of AICAR and could be prevented by AMPK/SIRT1 inhibitors or siRNAs, respectively. Salidroside reduces IR and regulates MQC and ROS production by activating AMPK/SIRT1 signaling pathway. Since IR is a critical issue for public health, to explore a potent agent against IR is of high interest. The anti-IR effects of salidroside warrant further experimental and clinical studies.

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Jiali Liu, Yue Li, Xiaoyan Zhou, Xi Zhang, Hao Meng, Sanyuan Liu, Lei Zhang, Juntao He, Qian He and Yan Geng

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

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Olena A Fedorenko, Pawitra Pulbutr, Elin Banke, Nneoma E Akaniro-Ejim, Donna C Bentley, Charlotta S Olofsson, Sue Chan and Paul A Smith

L-type channel antagonists are of therapeutic benefit in the treatment of hyperlipidaemia and insulin resistance. Our aim was to identify L-type voltage-gated Ca2+ channels in white fat adipocytes, and determine if they affect intracellular Ca2+, lipolysis and lipogenesis. We used a multidisciplinary approach of molecular biology, confocal microscopy, Ca2+ imaging and metabolic assays to explore this problem using adipocytes isolated from adult rat epididymal fat pads. CaV1.2, CaV1.3 and CaV1.1 alpha1, beta and alpha2delta subunits were detected at the gene expression level. The CaV1.2 and CaV1.3 alpha1 subunits were identified in the plasma membrane at the protein level. Confocal microscopy with fluorescent antibodies labelled CaV1.2 in the plasma membrane. Ca2+ imaging revealed that the intracellular Ca2+ concentration, [Ca2 +]i was reversibly decreased by removal of extracellular Ca2+, an effect mimicked by verapamil, nifedipine and Co2+, all blockers of L-type channels, whereas the Ca2+ channel agonist BAY-K8644 increased [Ca2+]i. The finding that the magnitude of these effects correlated with basal [Ca2+]i suggests that adipocyte [Ca2+]i is controlled by L-type Ca2+ channels that are constitutively active at the adipocyte depolarized membrane potential. Pharmacological manipulation of L-type channel activity modulated both basal and catecholamine-stimulated lipolysis but not insulin-induced glucose uptake or lipogenesis. We conclude that white adipocytes have constitutively active L-type Ca2+ channels which explains their sensitivity of lipolysis to Ca2+ channel modulators. Our data suggest CaV1.2 as a potential novel therapeutic target in the treatment of obesity.

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Bernadette M Trojanowski, Heba H Salem, Heike Neubauer, Eric Simon, Martin Wagner, Rajkumar Dorajoo, Bernhard O Boehm, Leticia Labriola, Thomas Wirth and Bernd Baumann

Maturity-onset diabetes of the young (MODY) is a group of monogenetic forms of diabetes mellitus caused by mutations in genes regulating β-cell development and function. MODY represents a heterogeneous group of non-insulin-dependent diabetes arising in childhood or adult life. Interestingly, clinical heterogeneity in MODY patients like variable disease onset and severity is observed even among individual family members sharing the same mutation, an issue that is not well understood. As high blood glucose levels are a well-known factor promoting β-cell stress and ultimately leading to cell death, we asked whether additional β-cell stress might account for the occurrence of disease heterogeneity in mice carrying a MODY4 mutation. In order to challenge β-cells, we established a MODY4 animal model based on Pdx1 (pancreatic and duodenal homeobox 1) haploinsufficiency, which allows conditional modulation of cell stress by genetic inhibition of the stress-responsive IKK/NF-κB signalling pathway. While Pdx1+/− mice were found glucose intolerant without progressing to diabetes, additional challenge of β-cell function by IKK/NF-κB inhibition promoted rapid diabetes development showing hyperglycaemia, hypoinsulinemia and loss of β-cell mass. Disease pathogenesis was characterized by deregulation of genes controlling β-cell homeostasis and function. Importantly, restoration of normal IKK/NF-κB signalling reverted the diabetic phenotype including normalization of glycaemia and β-cell mass. Our findings implicate that the avoidance of additional β-cell stress can delay a detrimental disease progression in MODY4 diabetes. Remarkably, an already present diabetic phenotype can be reversed when β-cell stress is normalized.

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Michal Silber, Irit Miller, Hadas Bar-Joseph, Ido Ben-Ami and Ruth Shalgi

PCOS is the most common endocrinopathy in women; associated with obesity and insulin resistance (IR). IR leads to accumulation of advanced-glycation-end-products (AGEs) and their receptor, RAGE. PCOS patients have increased levels of vascular endothelial growth factor (VEGF), interleukin 6/8 (IL-6/8) and anti-Mϋllerian-hormone (AMH). PEDF is a secreted-glycoprotein known for its anti-angiogenic and anti-inflammatory properties. We aimed to elucidate the role of PEDF in the pathogenesis and treatment of PCOS. We used a prenatal PCOS mouse model and fed the female offspring a high-fat diet, inducing metabolic PCOS (met.PCOS) characteristics. Female offspring were divided into three groups: control; met.PCOS; met.PCOS + recombinant PEDF (rPEDF). Met.PCOS mice gained more weight, had elevated serum IL-6 and higher mRNA levels of AMH, PEDF and RAGE in their granulosa cells (GCs) than met.PCOS + rPEDF mice. An in vitro Met.PCOS model in human GCs (KGN) line was induced by prolonged incubation with insulin/AGEs, causing development of IR. Under the same conditions, we observed an elevation of VEGF, IL-6/8 mRNAs, concomitantly with an increase in PEDF mRNA, intracellular protein levels, and an elevation of PEDF receptors (PEDF-Rs) mRNA and protein. Simultaneously, a reduction in the secretion of PEDF from GCs, was measured in the medium. The addition of rPEDF (5 nM) activated P38 signaling, implying that PEDF-Rs maintained functionality, and negated AGE-induced elevation of IL-6/8 and VEGF mRNAs. Decreased PEDF secretion may be a major contributor to hyperangiogenesis and chronic inflammation, which lie at the core of PCOS pathogenesis. rPEDF treatment may restore physiological angiogenesis inflammatory balance, thus suggesting a potential therapeutic role in PCOS.

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Akiko Mizokami, Satoru Mukai, Jing Gao, Tomoyo Kawakubo-Yasukochi, Takahito Otani, Hiroshi Takeuchi, Eijiro Jimi and Masato Hirata

Osteocalcin is a bone-derived hormone that in its uncarboxylated form (GluOC) plays an important role in glucose and energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation through its putative receptor GPRC6A. We previously showed that the effect of GluOC on insulin secretion is mediated predominantly by glucagon-like peptide-1 (GLP-1) released from intestinal endocrine cells in response to GluOC stimulation. Moreover, oral administration of GluOC was found to reduce the fasting blood glucose level, to improve glucose tolerance, and to increase the fasting serum insulin concentration and β-cell area in the pancreas in wild-type mice. We have now examined the effects of oral GluOC administration for at least 4 weeks in GLP-1 receptor-knockout mice. Such administration of GluOC in the mutant mice triggered glucose intolerance, enhanced gluconeogenesis and promoted both lipid accumulation in the liver as well as adipocyte hypertrophy and inflammation in adipose tissue. Furthermore, inactivation of GLP-1 receptor signaling in association with GluOC administration induced activation of the transcription factor FoxO1 and expression of its transcriptional coactivator PGC1α in the liver, likely accounting for the observed upregulation of gluconeogenic gene expression. Our results thus indicate that the beneficial metabolic effects of GluOC are dependent on GLP-1 receptor signaling.

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Erin Faught and Mathilakath M Vijayan

During early development, stress or exogenous glucocorticoid (GC) administration reduces body mass in vertebrates, and this is associated with the glucocorticoid receptor (GR) activation. Although GCs also activate the mineralocorticoid receptor (MR), the physiological significance of MR activation on early developmental growth is unknown. We tested the hypothesis that activation of both GR and MR are required for postnatal growth suppression by GCs. Differential regulation of GR and MR activation was achieved by using ubiquitous GR- (GRKO) and MR- (MRKO) knockout zebrafish (Danio rerio) in combination with exogenous cortisol treatment. MR activation increased protein deposition in zebrafish larvae and also upregulated lepa and downregulated lepr transcript abundance. Cortisol treatment reduced body mass and protein content in the WT, and this corresponded with the upregulation of muscle proteolytic markers, including murf1 and redd1 by GR activation. The combined activation of MR and GR by cortisol also upregulated the gh and igf1 transcript abundance, and insulin expression compared to the WT. However, cortisol-mediated reduction in body mass and protein content required the activation of both MR and GR, as activation by GR alone (MRKO + cortisol) did not reduce the larval protein content. Collectively, our results indicate that MR activation favors protein deposition and GR activation stimulates proteolysis, while their combined activation is involved in cortisol-mediated growth suppression. Overall, this work provides insight into the physiological significance of MR activation in regulating protein deposition during early development at a systems level.

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Umberto Simeoni, Clive Osmond, Ricardo Garay, Christophe Buffat, Farid Boubred, Christophe Chagnaud, Elisabeth Jouve, Christine Audebert, Jean-Michel Antoine and Kent Thornburg

Low weight in early infancy is a known risk factor for cardio-metabolic syndrome in adult life. However, little is known either about developmental programming in subjects of normal birthweight or about events between the ages which separate early programming and the occurrence of disease at late adulthood. We tested the hypothesis that circulating concentrations of leptin, adiponectin and insulin in young, healthy adults, born with a birth size within the normal range, are influenced by early life growth patterns. In an observational study of 188 healthy volunteers aged 18–25 years (97 males, 91 females) we investigated the association of metabolic function with their birth size, their growth during childhood and their body composition. High plasma leptin in early adulthood, a risk factor for cardio-metabolic syndrome, was associated with low weight at age 2 years (correlation coefficient controlled for adult weight = −0.21, P < 0.01). It was also positively associated with pre-prandial insulin and with HOMA (Homeostasis Model Assessment) insulin resistance. Leptin, leptin-adiponectin ratio and insulin correlated with lean mass, fat mass and percent fat (P < 0.0001). In conclusion, high leptin in early adulthood was associated with both low weight at age 2 years and insulin resistance. We speculate that high leptin is developmentally programmed and can contribute to the association between low weight in early infancy and increased cardio-metabolic risk in adulthood in healthy subjects.