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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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Wenjing Wu, Jiayao Fu, Yijing Gu, Yu Wei, Pengfei Ma and Junhua Wu

Emerging evidence has indicated that estrogen deficiency contributes to osteoporosis by affecting the level of inflammation. The inflammation microenvironment affects many cellular physiological processes, one of which may be cellular senescence according to previous studies. Senescent cells cannot function normally and secrete inflammatory cytokines and degradative proteins, which are referred to as senescence-associated secretory phenotype (SASP) factors, inducing further senescence and inflammation. Thus, stopping this vicious cycle may be helpful for postmenopausal osteoporosis treatment. Here, we used ovariectomized (OVX) mice as an estrogen-deficient model and confirmed that OVX bone marrow mesenchymal stem cells (BMSCs) displayed a senescent phenotype and upregulated SASP factor secretion both in vitro and in vivo. Furthermore, JAK2/STAT3, an important cytokine secretion-related signaling pathway that is associated with SASP secretion, was activated. Estrogen addition and estrogen receptor blockade confirmed that the JAK2/STAT3 axis participated in OVX BMSC senescence by mediating SASP factors. And JAK inhibition reduced SASP factor expression, alleviated senescence and enhanced osteogenic differentiation. Intraperitoneal injection of a JAK inhibitor, ruxolitinib, prevented bone loss in OVX mice. Collectively, our results revealed that JAK2/STAT3 plays an important role in the inflammation-senescence-SASP feedback loop in OVX BMSCs and that JAK inhibition could be a new method for treating postmenopausal osteoporosis.

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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.

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Ziping Jiang, Junduo Wu, Fuzhe Ma, Jun Jiang, Linlin Xu, Lei Du, Wenlin Huang, Zhaohui Wang, Ye Jia, Laijin Lu and Hao Wu

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a level and increased the expression of kelch-like ECH-associated protein 1 (Keap1) – a target of miR-200a and a negative regulator of NRF2. This led to inactivation of NRF2 signaling and exacerbation of OS and inflammation. MiR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG condition. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a’s actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered a miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity that protects against diabetic ED.

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Anneleen Segers, Louis Desmet, Shu Sun, Kristin Verbeke, Jan Tack and Inge Depoortere

The known crosstalk between short-chain fatty acids (SCFAs) and the circadian clock is tightly intertwined with feeding time. We aimed to investigate the role of the core clock gene Bmal1 and feeding time in the diurnal rhythms in plasma and caecal SCFAs levels and in their effect on the release of the hunger hormone ghrelin in the stomach and colon. WT, Bmal1-/- (ad libitum fed) and night-time-restricted-fed (RF)-Bmal1-/-- littermates were sacrificed at Zeitgeber time (ZT) 4 and 16. SCFA concentrations were measured by gas chromatography. To investigate the effect of SCFAs on ghrelin release, stomach and colonic full-thickness strips were incubated with Krebs or a SCFA mix mimicking plasma or caecal concentrations, after which octanoyl ghrelin release was measured by radioimmunoassay. Diurnal rhythms in caecal and plasma SCFAs oscillated in phase but rhythmic changes were abolished in Bmal1-/- mice. RF of Bmal1-/- mice restored fluctuations in caecal SCFAs. Plasma SCFA concentrations failed to affect gastric ghrelin release. The effect of caecal SCFA concentrations on colonic ghrelin release was rhythmic (inhibition at ZT 4, no effect at ZT 16). In Bmal1-/- mice, the inhibitory effect of SCFAs at ZT 4 was abolished. RF Bmal1-/- mice restored the inhibitory effect and increased colonic Clock expression. To conclude, diurnal fluctuations in caecal SCFAs and the effect of SCFAs on colonic ghrelin release are regulated by feeding time, independent of the core clock gene BMAL1. However, local entrainment of other clock genes might contribute to the observed effects.

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Nan Li, James A Oakes, Karl-Heinz Storbeck, Vincent T Cunliffe and Nils P Krone

Cytochrome P450 side-chain cleavage enzyme, encoded by the CYP11A1 gene, catalyzes the first and rate-limiting step of steroid hormone biosynthesis. Previous morpholino-knockdown studies in zebrafish suggested cyp11a2 is a functional equivalent of human CYP11A1 and is essential for interrenal steroidogenesis in zebrafish larvae. The role of Cyp11a2 in adult zebrafish, particularly in gonadal steroidogenesis, remains elusive. To explore the role of Cyp11a2 in adults, we developed zebrafish mutant lines by creating deletions in cyp11a2 using the CRISPR/Cas9 genomic engineering approach. Homozygous cyp11a2 mutant zebrafish larvae showed an upregulation of the hypothalamic–pituitary–interrenal axis. Furthermore, these Cyp11a2-deficient zebrafish demonstrated profound glucocorticoid and androgen deficiencies. Cyp11a2 homozygotes only developed into males with feminized secondary sex characteristics. Adult cyp11a2 −/− mutant fish showed a lack of natural breeding behaviors. Histological characterization revealed disorganized testicular structure and significantly decreased numbers of mature spermatozoa. These findings are further supported by the downregulation of the expression of several pro-male genes in the testes of cyp11a2 homozygous zebrafish, including sox9a, dmrt1 and amh. Moreover, the spermatogonia markers nanos2 and piwil1 were upregulated, while the spermatocytes marker sycp3 and spermatids marker odf3b were downregulated in the testes of cyp11a2 homozygous mutants. Our expression analysis is consistent with our histological studies, suggesting that spermatogonia are the predominant cell types in the testes of cyp11a2 homozygous mutants. Our work thus demonstrates the crucial role of Cyp11a2 in interrenal and gonadal steroidogenesis in zebrafish larvae and adults.

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Eileen I Chang, Paul J Rozance, Stephanie R Wesolowski, Leanna M Nguyen, Steven C Shaw, Robert A Sclafani, Kristen K Bjorkman, Angela K Peter, William W Hay Jr and Laura D Brown

Intrauterine growth-restricted (IUGR) fetuses are born with reduced skeletal muscle mass. We hypothesized that reduced rates of myogenesis would contribute to fewer and smaller myofibers in IUGR fetal hindlimb muscle compared to the normally growing fetus. We tested this hypothesis in IUGR fetal sheep with progressive placental insufficiency produced by exposing pregnant ewes to elevated ambient temperatures from 38 to 116 days gestation (dGA; term = 147 dGA). Surgically catheterized control (CON, n = 8) and IUGR (n = 13) fetal sheep were injected with intravenous 5-bromo-2′-deoxyuridine (BrdU) prior to muscle collection (134 dGA). Rates of myogenesis, defined as the combined processes of myoblast proliferation, differentiation, and fusion into myofibers, were determined in biceps femoris (BF), tibialis anterior (TA), and flexor digitorum superficialis (FDS) muscles. Total myofiber number was determined for the entire cross-section of the FDS muscle. In IUGR fetuses, the number of BrdU+ myonuclei per myofiber cross-section was lower in BF, TA, and FDS (P < 0.05), total myonuclear number per myofiber cross-section was lower in BF and FDS (P < 0.05), and total myofiber number was lower in FDS (P < 0.005) compared to CON. mRNA expression levels of cyclins, cyclin-dependent protein kinases, and myogenic regulatory factors were lower (P < 0.05), and inhibitors of the cell cycle were higher (P < 0.05) in IUGR BF compared to CON. Markers of apoptosis were not different in IUGR BF muscle. These results show that in IUGR fetuses, reduced rates of myogenesis produce fewer numbers of myonuclei, which may limit hypertrophic myofiber growth. Fewer myofibers of smaller size contribute to smaller muscle mass in the IUGR fetus.

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Caroline Alfaia, Vincent Robert, Kevin Poissenot, Yves Levern, Daniel Guillaume, Shel-Hwa Yeo, William H Colledge and Isabelle Franceschini

Kiss1 neurons of the arcuate (ARC) nucleus form an interconnected network of cells that communicate via neurokinin B (encoded by Tac2) and its receptor (encoded by Tacr3) and play key roles in the control of the reproductive axis through sex hormone-regulated synthesis and release of kisspeptin peptides (Kp, encoded by Kiss1). The aim of this study was to determine whether the Kiss1 cell population of the ARC already displays sexually dimorphic features at embryonic age E16.5 in mice. At this time of development, Kiss1-GFP- and Kp-immunoreactive cell bodies were restricted to the ARC and not found in the pre-optic area (POA). The Kiss1-GFP cell population was identical in size between sexes but had significantly lower Kiss1, Tac2, and Tacr3 mRNA levels and lower Kp-ir fiber density in the POA in male compared to female fetuses. Receptors for androgen (Ar) and estrogen (Esr1, Esr2, Gpr30) and the Cyp19a1 gene (encoding the estradiol-producing enzyme aromatase) transcripts were also detected in fetal ARC Kiss1-GFP cells with significant sex differences for Ar (higher in males) and Esr1 (higher in females). Functional studies on primary cultures of sorted fetal Kiss1-GFP cells revealed a significant negative effect of estradiol treatment on neurite outgrowth on the fourth day of culture in the female group specifically. We conclude that the ARC Kiss1 cell population is already sexually differentiated at E16.5 and that its morphogenetic development may be particularly vulnerable to estradiol exposure at this early developmental time.

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Victoria Diedrich, Elena Haugg, Carola Dreier and Annika Herwig

Torpid states are used by many endotherms to save energy during winter. During torpor, metabolic rate is downregulated to fractions of resting metabolic rate and often associated with a severe drop in body temperature that challenges mammalian physiology. Understanding the mechanisms regulating this extreme depression of metabolism bears enormous potential for biomedical research. Torpor behavior has been extensively studied in the Djungarian hamster, also known as Siberian hamster. It is dependent on many preparatory adaptations of physiological and endocrine systems that are likely to be integrated by the hypothalamus eventually controlling metabolism. Although substantial knowledge exists about prerequisites and characteristics of torpor in this species, the cascade of events and their mechanisms of action are not well understood. This review summarizes the current state of knowledge about mechanisms of metabolic regulation in the Djungarian hamster focusing on the potential roles of thyroid hormone and glucose metabolism.