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K Eerola, S Virtanen, L Vähätalo, L Ailanen, M Cai, V Hruby, M Savontaus and E Savontaus

γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition. Lentiviral gene delivery was used to induce a continuous expression of γ-Msh only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The γ-MSH treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (−15% vs −6%) and fat mass (−37% vs −12%) and reduced cumulative food intake were observed in γ-MSH-treated animals. Fasting-induced feeding was increased on chow diet only; however, voluntary running wheel activity on Western diet was increased. The γ-MSH treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state-dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity.

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Tomoaki Hayakawa, Tomomi Minemura, Toshiharu Onodera, Jihoon Shin, Yosuke Okuno, Atsunori Fukuhara, Michio Otsuki and Iichiro Shimomura

Active glucocorticoid levels are elevated in the adipose tissue of obesity due to the enzyme 11 beta-hydroxysteroid dehydrogenase type 1. Glucocorticoids can bind and activate both glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), and pharmacological blockades of MR prevent high-fat diet-induced obesity and glucose intolerance. To determine the significance of MR in adipocytes, we generated adipocyte-specific MR-knockout mice (AdipoMR-KO) and fed them high-fat/high-sucrose diet. We found that adipocyte-specific deletion of MR did not affect the body weight, fat weight, glucose tolerance or insulin sensitivity. While liver weight was slightly reduced in AdipoMR-KO, there were no significant differences in the mRNA expression levels of genes associated with lipogenesis, lipolysis, adipocytokines and oxidative stress in adipose tissues between the control and AdipoMR-KO mice. The results indicated that MR in mature adipocytes plays a minor role in the regulation of insulin resistance and inflammation in high-fat/high-sucrose diet-induced obese mice.

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Edouard G A Mills, Waljit S Dhillo and Alexander N Comninos

Reproduction is fundamental for the survival of all species and requires meticulous synchronisation of a diverse complement of neural, endocrine and related behaviours. The reproductive hormone kisspeptin (encoded by the KISS1/Kiss1 gene) is now a well-established orchestrator of reproductive hormones, acting upstream of gonadotrophin-releasing hormone (GnRH) at the apex of the hypothalamic–pituitary–gonadal (HPG) reproductive axis. Beyond the hypothalamus, kisspeptin is also expressed in limbic and paralimbic brain regions, which are areas of the neurobiological network implicated in sexual and emotional behaviours. We are now forming a more comprehensive appreciation of extra-hypothalamic kisspeptin signalling and the complex role of kisspeptin as an upstream mediator of reproductive behaviours, including olfactory-driven partner preference, copulatory behaviour, audition, mood and emotion. An increasing body of research from zebrafish to humans has implicated kisspeptin in the integration of reproductive hormones with an overall positive influence on these reproductive behaviours. In this review, we critically appraise the current literature regarding kisspeptin and its control of reproductive behaviour. Collectively, these data significantly enhance our understanding of the integration of reproductive hormones and behaviour and provide the foundation for kisspeptin-based therapies to treat related disorders of body and mind.

Open access

Jin-Ran Chen, Oxana P Lazarenko, Haijun Zhao, Alexander W Alund and Kartik Shankar

Intrauterine or early postnatal high-fat diet (HFD) has substantial influences on adult offspring health; however, studies of HFD-induced maternal obesity on regulation of adult offspring bone formation are sparse. Here, we investigated the effects of HFD-induced maternal obesity on both fetal and adult offspring skeletal development. We found that HFD-induced maternal obesity significantly decreased fetal skeletal development, but enhanced fetal osteoblastic cell senescence signaling and significantly increased the expression of inflammatory factors of the senescence-associated secretory phenotype (SASP) in osteo-progenitors. It was found that p300/CBP activation led to H3K27 acetylation to increase the expression of senescence-related genes and PPARγ in embryonic mouse osteogenic calvarial cells from HFD obese dams. These results were recapitulated in human umbilical cord mesenchymal stem cells (UC MSCs) isolated from offspring of pregnant obese and lean mothers following delivery. Regardless of postnatal HFD challenge, adult offspring from HFD obese dams showed significantly suppressed bone formation. Such early involution of bone formation of adult offspring from HFD obese dams may at least in part due to histone acetylation, i.e., epigenetic regulation of genes involved in cell senescence signaling in pre-osteoblasts from prenatal development. These findings indicate fetal pre-osteoblastic cell senescence signaling is epigenetically regulated by maternal obesity to repress bone formation in adult offspring in rodents and suggest that at least some of these effects may also manifest in humans.

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Sujith Rajan, Ganesh Panzade, Ankita Srivastava, Kripa Shankar, Rajesh Pandey, Durgesh Kumar, Sanchita Gupta, Abhishek Gupta, Salil Varshney, Muheeb Beg, Raj Kumar Mishra, Ravi Shankar and Anil Gaikwad

miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3′UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high-fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome.

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V Squicciarini, R Riquelme, K Wilsterman, G E Bentley and H E Lara

RFamide-related peptide (RFRP-3) is a regulator of GnRH secretion from the brain, but it can also act in human ovary to influence steroidogenesis. We aimed to study the putative local role of RFRP-3 in the ovary and its potential participation in the development of a polycystic ovary phenotype induced by chronic sympathetic stress (cold stress). We used adult Sprague–Dawley rats divided into control and stressed groups. In both groups, we studied the effect of intraovarian exposure to RFRP-3 on follicular development and plasma ovarian steroid concentrations. We also tested the effect of RFRP-3 on ovarian steroid production in vitro. Chronic in vivo intraovarian exposure to RFRP-3 decreased basal testosterone concentrations and cold stress-induced progesterone production by the ovary. In vitro, RFRP-3 decreased hCG-induced ovarian progesterone and testosterone secretion. Immunohistochemistry and mRNA expression analysis showed a decrease in Rfrp and expression of its receptor in the ovary of stressed rats, a result which is in line with the increased testosterone levels found in stressed rats. In vivo application of RFRP-3 recovered the low levels of secondary and healthy antral follicles found in stressed rats. Taken together, our data indicate a previously unknown response of hypothalamic and ovarian RFRP-3 to chronic cold stress, influencing ovarian steroidogenesis and follicular dynamics. Thus, it is likely that RFRP-3 modulation in the ovary is a key component of development of the polycystic ovary phenotype.

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Marta Toral, Rosario Jimenez, Sebastián Montoro-Molina, Miguel Romero, Rosemary Wangensteen, Juan Duarte and Félix Vargas

Thyroid hormone activity is associated with L-arginine metabolism and nitric oxide (NO) production, which participate in the cardiovascular manifestations of thyroid disorders. L-arginine transporters play an important role in activating L-arginine uptake and NO production. However, the effects of thyroid hormones on L-arginine transporters in endothelial cells have not yet been evaluated. The following methods were used. We measured L-arginine uptake, mRNA expression of L-arginine transporters, endothelial nitric oxide synthase (eNOS) mRNA and NO generation after the administration of T3, T4 and the T3 analog, 3,3′,5-triiodothyroacetic acid TRIAC in human umbilical vein endothelial cells (HUVECs). We also analyzed the role of αvβ3 integrin and of phosphatidyl-inositol-3 kinase (PI3K), mitogen-activated protein kinases (MAPKs: ERK1/2, p38 and SAPK-JNK) and intracellular calcium signaling pathways as underlying mechanisms. To this end, αvβ3 integrin was pharmacologically inhibited by tetraiodothyroacetic acid (TETRAC) or genetically blocked by silencing αv mRNA and PI3K, MAPKs and intracellular calcium by selective inhibitors. The following results were obtained. Thyroid hormones and the T3 analog TRIAC increased L-arginine uptake in HUVECs, the sodium-independent y+/CAT isoforms, except CAT2b, sodium-dependent y+L system and sodium-independent system b0,+L-arginine transporters, eNOS mRNA and NO production. These effects were suppressed by αvβ3 integrin inhibition with TETRAC or αv integrin downregulation or by PI3K, MAPK or intracellular Ca2+ signaling inhibitors. In conclusion, we report for the first time that activation of L-arginine uptake by thyroid hormones is related to an upregulation of L-arginine transporters. This effect seems to be mediated by activation of αvβ3 integrin receptor and subsequent PI3K, MAPK and intracellular Ca2+ signaling pathways.

Free access

Sara S Ellingwood and Alan Cheng

The synthesis of glycogen represents a key pathway for the disposal of excess glucose while its degradation is crucial for providing energy during exercise and times of need. The importance of glycogen metabolism is also highlighted by human genetic disorders that are caused by mutations in the enzymes involved. In this review, we provide a basic summary on glycogen metabolism and some of the clinical aspects of the classical glycogen storage diseases. Disruptions in glycogen metabolism usually result in some level of dysfunction in the liver, muscle, heart, kidney and/or brain. Furthermore, the spectrum of symptoms observed is very broad, depending on the affected enzyme. Finally, we briefly discuss an aspect of glycogen metabolism related to the maintenance of its structure that seems to be gaining more recent attention. For example, in Lafora progressive myoclonus epilepsy, patients exhibit an accumulation of inclusion bodies in several tissues, containing glycogen with increased phosphorylation, longer chain lengths and irregular branch points. This abnormal structure is thought to make glycogen insoluble and resistant to degradation. Consequently, its accumulation becomes toxic to neurons, leading to cell death. Although the genes responsible have been identified, studies in the past two decades are only beginning to shed light into their molecular functions.

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Ghania Ramdani, Nadine Schall, Hema Kalyanaraman, Nisreen Wahwah, Sahar Moheize, Jenna J Lee, Robert L Sah, Alexander Pfeifer, Darren E Casteel and Renate B Pilz

NO/cGMP signaling is important for bone remodeling in response to mechanical and hormonal stimuli, but the downstream mediator(s) regulating skeletal homeostasis are incompletely defined. We generated transgenic mice expressing a partly-activated, mutant cGMP-dependent protein kinase type 2 (PKG2R242Q) under control of the osteoblast-specific Col1a1 promoter to characterize the role of PKG2 in post-natal bone formation. Primary osteoblasts from these mice showed a two- to three-fold increase in basal and total PKG2 activity; they proliferated faster and were resistant to apoptosis compared to cells from WT mice. Male Col1a1-Prkg2 R242Q transgenic mice had increased osteoblast numbers, bone formation rates and Wnt/β-catenin-related gene expression in bone and a higher trabecular bone mass compared to their WT littermates. Streptozotocin-induced type 1 diabetes suppressed bone formation and caused rapid bone loss in WT mice, but male transgenic mice were protected from these effects. Surprisingly, we found no significant difference in bone micro-architecture or Wnt/β-catenin-related gene expression between female WT and transgenic mice; female mice of both genotypes showed higher systemic and osteoblastic NO/cGMP generation compared to their male counterparts, and a higher level of endogenous PKG2 activity may be responsible for masking effects of the PKG2R242Q transgene in females. Our data support sexual dimorphism in Wnt/β-catenin signaling and PKG2 regulation of this crucial pathway in bone homeostasis. This work establishes PKG2 as a key regulator of osteoblast proliferation and post-natal bone formation.

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Marian Joëls

The brain is continuously exposed to varying levels of adrenal corticosteroid hormones such as corticosterone in rodents and cortisol in humans. Natural fluctuations occur due to ultradian and circadian variations or are caused by exposure to stressful situations. Brain cells express two types of corticosteroid receptors, i.e. mineralocorticoid and glucocorticoid receptors, which differ in distribution and affinity. These receptors can mediate both rapid non-genomic and slow gene-mediated neuronal actions. As a consequence of these factors, natural (e.g. stress-induced) shifts in corticosteroid level are associated with a complex mosaic of time- and region-dependent changes in neuronal activity. A series of experiments in humans and rodents have revealed that these time- and region-dependent cellular characteristics are also reflected in distinct cognitive patterns after stress. Thus, directly after a peak of corticosteroids, attention and vigilance are increased, and areas involved in emotional responses and simple behavioral strategies show enhanced activity. In the aftermath of stress, areas involved in higher cognitive functions become activated allowing individuals to link stressful events to the specific context and to store information for future use. Both phases of the brain’s response to stress are important to face a continuously changing environment, promoting adaptation at the short as well as long term. We argue that a balanced response during the two phases is essential for resilience. This balance may become compromised after repeated stress exposure, particularly in genetically vulnerable individuals and aggravate disease manifestation. This not only applies to psychiatric disorders but also to neurological diseases such as epilepsy.