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Hui-Fang Wang, Qing-Qing Yu, Rui-Fang Zheng, and Ming Xu

Cardiovascular complications of type 2 diabetes mellitus (T2DM) are associated with vascular remodeling in the arteries. Perivascular sympathetic neurons release an abundance of trophic factors to regulate vascular function via a paracrine signaling. Netrin-1, a diffusible protein that can be secreted outside the cell, is one of common signals of ‘conversation’ between nerve and vessel. The present study investigated whether netrin-1 is a novel modulator of sympathetic neurons paracrine signaling and played a critical role in vascular adventitial remodeling under T2DM. Vascular adventitial remodeling was observed in adventitial fibroblasts (AFs) responding to netrin-1 deficiency in the supernatant from primary rat superior cervical ganglia (SCG) neurons, shown as AFs proliferation, migration, and collagen deposition. Conditioned medium from the high glucose (HG)-treated SCG neurons contributed to AFs remodeling, which was effectively alleviated by exogenous netrin-1 supplementation. Further, it was found that uncoordinated-5-B (Unc5b) was mainly expressed in AFs among netrin-1 specific receptors. Treatment of netrin-1 inhibited H2O2 production derived from NADPH oxidase 4 (NOX4) through the UNC5b/CAMP/PKA signal pathway in AFs remodeling. In vivo, aorta adventitial remodeling was accompanied with the downregulation of netrin-1 in the perivascular sympathetic nerve in T2DM rats. Such abnormalities were restored by netrin-1 intervention, which was associated with the inhibition of NOX4 expression in the aorta adventitia. In conclusion, netrin-1 is a novel modulator of sympathetic neurons paracrine signaling to maintain AFs function. Vascular adventitial remodeling was aggravated by sympathetic neurons paracrine signaling under hyperglycemia, which was ameliorated by netrin-1 treatment through the UNC5b/CAMP/PKA/NOX4 pathway.

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Qiaoyuan Zheng, Hesheng Xiao, Hongjuan Shi, Tingru Wang, Lina Sun, Wenjing Tao, Thomas D Kocher, Minghui Li, and Deshou Wang

The impacts of androgens and glucocorticoids on spermatogenesis have intrigued scientists for decades. 11β-hydroxylase, encoded by cyp11c1, is the key enzyme involved in the synthesis of 11-ketotestosterone and cortisol, the major androgen and glucocorticoid in fish, respectively. In the present study, a Cyp11c1 antibody was produced. Western blot and immunohistochemistry showed that Cyp11c1 was predominantly expressed in the testicular Leydig cells and head kidney interrenal cells. A mutant line of cyp11c1 was established by CRISPR/Cas9. Homozygous mutation of cyp11c1 caused a sharp decrease of serum cortisol and 11-ketotestosterone, and a delay in spermatogenesis which could be rescued by exogenous 11-ketotestosterone or testosterone, but not cortisol treatment. Intriguingly, this spermatogenesis restored spontaneously, indicating compensatory effects of other androgenic steroids. In addition, loss of Cyp11c1 led to undersized testes with a smaller efferent duct and disordered spermatogenic cysts in adult males. However, a small amount of viable sperm was produced. Taken together, our results demonstrate that cyp11c1 is important for testicular development, especially for the initiation and proper progression of spermatogenesis. 11-ketotestosterone is the most efficient androgen in tilapia.

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Tristan S Allemann, Gursimran K Dhamrait, Naomi J Fleury, Tamara N Abel, Prue H Hart, Robyn M Lucas, Vance B Matthews, and Shelley Gorman

In previous preclinical studies, low (non-burning) doses of UV radiation (UVR) limited weight gain and metabolic dysfunction in mice fed with a high-fat diet. Here, we explored the effects of low-dose UVR on physical activity and food intake and mechanistic pathways in interscapular brown adipose tissue (iBAT). Young adult C57Bl/6J male mice, housed as individuals, were fed a high-fat diet and exposed to low-dose UVR (sub-oedemal, 1 kJ/m2 UVB, twice-a-week) or ‘mock’ treatment, with or without running wheel access (2 h, for ‘moderate’ physical activity) immediately after phototherapy. There was no difference in distance run in mice exposed to UVR or mock-treated over 12 weeks of exposure to running wheels (P = 0.14). UVR (alone) did not significantly affect food intake, adiposity, or signs of glucose dysfunction. Access to running wheels increased food intake (after 10 weeks, P ≤ 0.02) and reduced gonadal white adipose tissue and iBAT mass (P ≤ 0.03). Body weight and hepatic steatosis were lowest in mice exposed to UVR with running wheel access. In the iBAT of mice exposed to UVR and running wheels, elevated Atgl, Cd36, Fasn, Igf1, Pparγ, and Ucp1 mRNAs and reduced CD11c on F4-80 + MHC class II+ macrophages were observed, while renal Sglt2 mRNA levels were increased, compared to high-fat diet alone (P ≤ 0.03). Blood levels of 25-hydroxyvitamin D were not increased by exposure to UVR and/or access to running wheels. In conclusion, when combined with physical activity, low-dose UVR may more effectively limit adiposity (specifically, body weight and hepatic steatosis) and modulate metabolic and immune pathways in iBAT.

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Takuro Okamura, Yoshitaka Hashimoto, Takafumi Osaka, Takafumi Senmaru, Takuya Fukuda, Masahide Hamaguchi, and Michiaki Fukui

To investigate the role of microRNA (miRNA) in muscle atrophy, we performed microarray analysis of miRNA expression in skeletal muscles of Sham, orchiectomized (ORX) mice, and ORX mice treated with androgen and identified that the expression of miR-23b-3p in ORX mice was significantly higher than that in Sham mice (P = 0.007); however, miR-23b-3p expression in ORX mice treated with androgen was lower (P = 0.001). We also investigated the mechanism by which overexpression or knockdown of miR-23b-3p influences the expression of myosin heavy chain, muscle protein synthesis, ATP activity, and glucose uptake in C2C12 myotube cells. Moreover, we examined the serum miR-23b-3p levels among male subjects with type 2 diabetes and whether the serum miR-23b-3p levels could be a biomarker for muscle atrophy. The overexpression of miR-23b-3p in C2C12 myotube cells significantly upregulated the expression of myosin heavy chain, protein synthesis, ATP activity, and glucose uptake. Reporter assays raised a possible direct post-transcriptional regulation involving miR-23b-3p and the 3′-UTR of PTEN mRNA. Among subjects with type 2 diabetes, serum miR-23b-3p levels in the subjects with decreased muscle mass were significantly higher compared to the levels in the subjects without. Our results indicate that miR-23b-3p downregulates the expression of PTEN in myotube cells and induces the growth of myosin heavy chain. In addition, the serum level of miR-23b-3p can be used as a diagnostic marker for muscle atrophy.

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Xin Li, Hongjiao Li, Di Zhang, Guojin Xu, Jinglin Zhang, and Sheng Cui

MicroRNA-7 (miR-7) is an important modulator of a plenty of gene expressions and the interrelated biological processes, highly expressed in porcine pituitary. Norepinephrine (NE), acting as an important neurotransmitter or/and a hormone secreted excessively under stress, affects the synthesis and secretion of various hormones, including pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are the key hormones which regulate sexual maturation and reproductive functions. However, the relationship among NE, miR-7 and gonadotropin needs to be elucidated. The aim of this study was to identify whether miR-7 involved in the NE-adrenoceptor signaling pathway affects the synthesis and secretion of FSH and LH in porcine pituitary. Our results showed that the NE intracerebroventricular injection increased pituitary miR-7 level and the synthesis and secretion of FSH and LH in porcine, whereas the inhibition of either endogenous miR-7 or β-adrenergic receptors hindered the rise of FSH and LH synthesis induced by NE in cultured primary porcine anterior pituitary cells. Further, we identified the molecular type of β-adrenergic receptors and the signaling pathway in porcine pituitary, and we found that NE played its roles relying on adrenoceptor beta 2 (β2AR) and the RAF/MEK/ERK1/2 signaling pathway. The phosphorylation of ERK1/2 upregulated miR-7 level which subsequently enhanced FSH and LH synthesis by targeting to Golgi glycoprotein 1 (GLG1). These suggest that miR-7 mediates NE’s effect on promoting FSH and LH synthesis in porcine pituitary.

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H Y Li, Y X Liu, L Harvey, S Shafaeizadeh, E M van der Beek, and W Han

The prevalence of gestational diabetes mellitus (GDM) is estimated at 14% globally, and in some countries, such as Singapore, exceeds 20%. Both women and children exposed to GDM have an increased risk of later metabolic diseases, cardiovascular disease and other health issues. Beyond lifestyle changes and pharmaceutical intervention using existing type 2 diabetes medications for expecting women, there are limited treatment options for women with GDM; targeting better outcomes of potentially affected infants is unexplored. Numerous animal models have been generated for understanding of pathological processes of GDM development and for development of treatment strategies. These models, however, suffer from limited windows of opportunity to examine risk factors and potential intervention options. By combining short-term high-fat diet (HFD) feeding and low-dose streptozotocin (STZ) treatments before pregnancy, we have established a mouse model with marked transient gestation-specific hyperglycemia, which allows testing of nutritional and pharmacological interventions before, during and beyond pregnancy.

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Lili Men, Junjie Yao, Shanshan Yu, Yu Li, Siyuan Cui, Shi Jin, Guixin Zhang, Decheng Ren, and Jianling Du

The induction of endoplasmic reticulum (ER) stress is associated with adipogenesis, during which the inositol-requiring enzyme 1 alpha (IRE1α)-X-box-binding protein 1 (XBP1) pathway is involved. Selenoprotein S (SelS), which is an ER resident selenoprotein, is involved in ER homeostasis regulation; however, little is known about the role of SelS in regulating adipogenesis. In vivo studies showed that SelS protein levels in white adipose tissue were increased in obese subjects and high-fat diet (HFD)-fed mice. Moreover, we identified that SelS protein levels increased in the early phase of adipogenesis and then decreased in the late phase during adipogenesis. Overexpression of SelS promoted adipogenesis. Conversely, knockdown (KD) of SelS resulted in the inhibition of adipogenesis, which was related to increasing cell death, decreased mitotic clonal expansion, and cell cycle G1 arrest. In vivo studies also showed that ER stress markers (p-IRE1α/IRE1α, XBP1s, and Grp78) were significantly increased with upregulating of SelS expression in subcutaneous and visceral adipose tissues in the obese subjects and HFD-fed mice. Furthermore, in SelS KD cells, the levels of Grp78 were increased and the levels of p-IRE1α/IRE1α were unchanged , but mRNA levels of spliced XBP1 (XBP1s) produced by IRE1α-mediated splicing were decreased, suggesting a role of SelS in the modulation of IRE1α-XBP1 pathway. Moreover, inhibition of adipogenesis by SelS suppression can be rescued by overexpression of XBP1s. Thus, SelS appears to function as a novel regulator of adipogenesis through the IRE1α-XBP1 signaling pathway.

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Arturo Hernandez and M Elena Martinez

Male fertility involves the successful transmission of the genetic code to the next generation. It requires appropriately timed cellular processes during testis development, adequate support of spermatogenesis by hormonal cues from the reproductive axis and cellular cross-talk between germ and somatic cells. In addition to being the vessel of the father’s genome, increasing evidence shows that the mature sperm carries valuable epigenetic information – the epigenome – that, after fecundation, influences the development of the next generation, affecting biological traits and disease susceptibility. The epigenome of the germ line is susceptible to environmental factors, including exogenous chemicals and diet, but it is also affected by endogenous molecules and pathophysiological conditions. Factors affecting testis development and the epigenetic information of the germ line are critical for fertility and of relevance to the non-genetic but heritable component in the etiology of complex conditions. Thyroid hormones are one of those factors and their action, when untimely, produces profound effects on the developing testis, affecting spermatogenesis, steroidogenesis, testis size, reproductive hormones and fertility. Altered thyroid hormone states can also change the epigenetic information of the male germ line, with phenotypic consequences for future generations. In the context of past literature concerning the consequences of altered thyroid hormone action for testis development, here we review recent findings about the pathophysiological roles of the principal determinants of testicular thyroid hormone action. We also discuss limited work on the effects of thyroid hormone on the male germ line epigenome and the implications for the intergenerational transmission of phenotypes via epigenetic mechanisms.

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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.