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Trassanee Chatmethakul and Robert D. Roghair

Consistent with the paradigm shifting observations of David Barker and colleagues that revealed a powerful relationship between decreased weight through 2 years of age and adult disease, intrauterine growth restriction (IUGR) and preterm birth are independent risk factors for the development of subsequent hypertension. Animal models have been indispensable in defining the mechanisms responsible for these associations and the potential targets for therapeutic intervention. Among the modifiable risk factors, micronutrient deficiency, physical immobility, exaggerated stress hormone exposure and deficient trophic hormone production are leading candidates for targeted therapies. With the strong inverse relationship seen between gestational age at delivery and the risk of hypertension in adulthood trumping all other major cardiovascular risk factors, improvements in neonatal care are required. Unfortunately, therapeutic breakthroughs have not kept pace with rapidly improving perinatal survival, and groundbreaking bench-to-bedside studies are urgently needed to mitigate and ultimately prevent the tsunami of prematurity-related adult cardiovascular disease that may be on the horizon. This review highlights our current understanding of the developmental origins of hypertension and draws attention to the importance of increasing the availability of lactation consultants, nutritionists, pharmacists, and physical therapists as critical allies in the battle that IUGR or premature infants are waging not just for survival but also for their future cardiometabolic health.

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Sui-lin Sun and Liang-ming Liu

Urotensin II (UII) is a polypeptide molecule with neurohormone-like activity. It has been confirmed that UII is widely distributed in numerous organs of different animal species from fish to mammals, including humans. The UII receptor is orphan G-protein coupled receptor 14, also known as UT. The tissue distribution of UII and UT is highly consistent, and their expression may be regulated by autocrine and paracrine mechanisms. In the body, UII has many physiological and pathophysiological activities, such as vasoconstrictor and vasodilatory actions, cell proliferation, pro-fibrosis, neuroendocrine activity, insulin resistance, and carcinogenic and inflammatory effects, which have been recognized only in recent years. In fact, UII is involved in the process of inflammatory injury and plays a key role in the onset and development of inflammatory diseases. In this paper, we will review the roles UII plays in inflammatory diseases.

Open access

Vikte Lionikaite, Karin L Gustafsson, Anna Westerlund, Sara H Windahl, Antti Koskela, Juha Tuukkanen, Helena Johansson, Claes Ohlsson, H Herschel Conaway, Petra Henning and Ulf H Lerner

Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5 µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20 µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60 µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone.

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Rumana Yasmeen, Qiwen Shen, Aejin Lee, Jacob H Leung, Devan Kowdley, David J DiSilvestro, Lu Xu, Kefeng Yang, Andrei Maiseyeu, Naresh C Bal, Muthu Periasamy, Paolo Fadda and Ouliana Ziouzenkova

Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

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Diego Safian, Najoua Ryane, Jan Bogerd and Rüdiger W Schulz

Follicle-stimulating hormone (Fsh) modulates vertebrate spermatogenesis by regulating somatic cell functions in the testis. We have found previously that zebrafish Fsh stimulated the differentiating proliferation of type A undifferentiated spermatogonia (Aund) in an androgen-independent manner by regulating the production of growth factors and other signaling molecules in both Sertoli (SCs) and Leydig cells (LCs). For example, Fsh triggered the release of Igf3 that subsequently activated β-catenin signaling to promote the differentiating proliferation of Aund. In the present study, we report that Fsh moreover uses the non-canonical Wnt pathway to promote the proliferation and accumulation of Aund. Initially, we found that the stimulatory effect of Fsh on the proliferation activity of Aund was further strengthened when β-catenin signaling was inhibited, resulting in an accumulation of Aund. We then showed that this Fsh-induced accumulation of Aund was associated with increased transcript levels of the non-canonical Wnt ligand, wnt5a. In situ hybridization of insl3 mRNA, a gene expressed in LCs, combined with Wnt5a immunocytochemistry identified LCs as the cellular source of Wnt5a in the adult zebrafish testis. Addition of an antagonist of Wnt5a to incubations with Fsh decreased both the proliferation activity and the relative section area occupied by Aund, while an agonist of Wnt5a increased these same parameters for Aund. Taken together, our data suggest that Fsh triggered LCs to release Wnt5a, which then promoted the proliferation and accumulation of Aund. Hence, Fsh uses non-canonical Wnt signaling to ensure the production of Aund, while also triggering β-catenin signaling via Igf3 to ensure spermatogonial differentiation.

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Rita Sharma, Quyen Luong, Vishva M Sharma, Mitchell Harberson, Brian Harper, Andrew Colborn, Darlene E Berryman, Niels Jessen, Jens Otto Lunde Jørgensen, John J Kopchick, Vishwajeet Puri and Kevin Y Lee

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

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Eun-Young Lee, Xilin Zhang, Junki Miyamoto, Ikuo Kimura, Tomoaki Taknaka, Kenichi Furusawa, Takahito Jomori, Kosuke Fujimoto, Satoshi Uematsu and Takashi Miki

Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.

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H H Farman, K L Gustafsson, P Henning, L Grahnemo, V Lionikaite, S Movérare-Skrtic, J Wu, H Ryberg, A Koskela, J Tuukkanen, E R Levin, C Ohlsson and M K Lagerquist

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

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Rebecca M Reynolds and Adrienne Gordon

Rates of obesity among women of reproductive age have risen dramatically in recent decades. Obesity impacts on health of women across their reproductive lifespan with adverse effects on not only fertility and short-term complications of pregnancy, but also on longer term health outcomes for both women and their children. This places considerable burden and cost on health services. Here, we review the evidence linking maternal obesity to adverse fertility, pregnancy and longer term health outcomes for women and their children. We discuss the outcomes of recent lifestyle, pharmacological and surgical intervention studies. As many of these studies have not shown a significant improvement in clinical outcomes, we discuss the need for better study design in future trials.

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Daniela Álvarez, Karina Ceballo, Sofía Olguín, Jonathan Martinez-Pinto, Manuel Maliqueo, Daniela Fernandois, Ramón Sotomayor-Zárate and Gonzalo Cruz

Maternal obesity causes a wide range of impairment in offspring, such as metabolic and reproductive dysfunctions. We previously demonstrated that female offspring of obese rats have increased serum estradiol levels during early postnatal life, probably because of decreased hepatic cytochrome P450 3A2 levels, which could lead to early onset of puberty and polycystic ovary condition in adulthood. Using metformin during pregnancy and nursing to improve the metabolic status of obese mothers could prevent the sequence of events that lead to an increase in postnatal serum estradiol levels in female offspring and, hence, reproductive dysfunction. We found that metformin prevented an increase in serum estradiol levels at postnatal day 14 in female offspring of obese mothers, which was associated with a restoration of hepatic cytochrome P450 3A2 levels to control values. Treatment using metformin could not prevent advanced puberty, but we observed that the number of antral follicles, follicular cysts and multi-oocyte follicles returned to control values in the female offspring of obese mothers treated with metformin. We also observed an increase in the levels of norepinephrine and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol in the ovaries, indicating increased sympathetic activity in female offspring induced by an obesogenic uterine environment. We found that this effect was prevented by metformin administration. From the results of this study, we concluded that metformin administration to obese mothers during pregnancy and nursing partially prevents ovarian dysfunction in female offspring during adulthood.