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Yuehui Zhang, Min Hu, Wenyan Jia, Guoqi Liu, Jiao Zhang, Bing Wang, Juan Li, Peng Cui, Xin Li, Susanne Lager, Amanda Nancy Sferruzzi-Perri, Yanhua Han, Songjiang Liu, Xiaoke Wu, Mats Brännström, Linus R Shao, and Håkan Billig

Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance and a high risk of miscarriage during pregnancy. Similarly, in rats, maternal exposure to 5α-dihydrotestosterone (DHT) and insulin from gestational day 7.5 to 13.5 leads to hyperandrogenism and insulin resistance and subsequently increased fetal loss. A variety of hormonal and metabolic stimuli are able to trigger different types of regulated cell death under physiological and pathological conditions. These include ferroptosis, apoptosis and necroptosis. We hypothesized that, in rats, maternal hyperandrogenism and insulin-resistance-induced fetal loss is mediated, at least in part, by changes in the ferroptosis, apoptosis and necroptosis pathways in the gravid uterus and placenta. Compared with controls, we found that co-exposure to DHT and insulin led to decreased levels of glutathione peroxidase 4 (GPX4) and glutathione, increased glutathione + glutathione disulfide and malondialdehyde, aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition and activated ERK/p38/JNK phosphorylation in the gravid uterus. In addition, we observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction in the uteri of rats co-exposed to DHT and insulin. However, in the placenta, DHT and insulin exposure only partially altered the expression of ferroptosis-related markers (e.g. region-dependent GPX4, glutathione + glutathione disulfide, malondialdehyde, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). Moreover, we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA in placentas of rats co-exposed to DHT and insulin. Further, DHT + insulin-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal hyperandrogenism and insulin resistance causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Our data also suggest that apoptosis and necroptosis may play a role in coordinating or compensating for hyperandrogenism and insulin-resistance-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

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Jia-Jiun Yan, Yi-Chun Lee, Yi-Ling Tsou, Yung-Che Tseng, and Pung-Pung Hwang

Timely adjustment of osmoregulation upon acute salinity stress is essential for the survival of euryhaline fish. This rapid response is thought to be tightly controlled by hormones; however, there are still questions unanswered. In this work, we tested the hypothesis that the endocrine hormone, insulin-like growth factor 1 (Igf1), a slow-acting hormone, is involved in the activation of salt secretion mechanisms in euryhaline medaka (Oryzias melastigma) during acclimation to acute salinity stress. In response to a 30-ppt seawater (SW) challenge, Na+/Cl secretion was enhanced within 0.5 h, with concomitant organization of ionocyte multicellular complexes and without changes in expression of major transporters. Igf1 receptor inhibitors significantly impair the Na+/Cl secretion and ionocyte multicellular complex responses without affecting transporter expression. Thus, Igf1 may activate salt secretion as part of the teleost response to acute salinity stress by exerting effects on transporter function and enhancing the formation of ionocyte multicellular complexes. These findings provide new insights into hormonal control of body fluid ionic/osmotic homeostasis during vertebrate evolution.

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Tatiana Ederich Lehnen, Rafael Marschner, Fernanda Dias, Ana Luiza Maia, and Simone Magagnin Wajner

Imbalances in redox status modulate type 3 deiodinase induction in nonthyroidal illness syndrome. However, the underlying mechanisms that lead to D3 dysfunction under redox imbalance are still poorly understood. Here we evaluated D3 induction, redox homeostasis, and their interrelationships in the liver, muscle, and brain in an animal model of NTIS. Male Wistar rats were subjected to left anterior coronary artery occlusion and randomly separated into two groups and treated or not (placebo) with the antioxidant N-acetylcysteine. Sham animals were used as controls. Animals were killed 10 or 28 days post-MI induction and tissues were immediately frozen for biochemical analysis. D3 activity, protein oxidation and antioxidant defenses were measured in liver, muscle, and brain. Compared to those of the sham group, the levels of D3 expression and activity were increased in the liver (P = 0.002), muscle (P = 0.03) and brain (P = 0.01) in the placebo group. All tissues from the placebo animals showed increased carbonyl groups (P < 0.001) and diminished sulfhydryl levels (P < 0.001). Glutathione levels were decreased and glutathione disulfide levels were augmented in all examined tissues. The liver and muscle showed augmented levels of glutathione peroxidase, glutathione reductase and thioredoxin reductase activity (P = 0.001). NAC prevented all the alterations described previously. D3 dysfunction in all tissues correlates with post-MI-induced protein oxidative damage and altered antioxidant defenses. NAC treatment prevents D3 dysfunction, indicating that reversible redox-related remote D3 activation explains, at least in part, the thyroid hormone derangements of NTIS.

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Edra London, Michelle Bloyd, and Constantine A Stratakis

Both direct and indirect evidence demonstrate a central role for the cAMP-dependent protein kinase (PKA) signaling pathway in the regulation of energy balance and metabolism across multiple systems. However, the ubiquitous pattern of PKA expression across cell types poses a challenge in pinpointing its tissue-specific regulatory functions and further characterizing its many downstream effects in certain organs or cells. Mouse models of PKA deficiency and over-expression and studies in living cells have helped clarify PKA function in adipose tissue (AT), liver, adrenal, pancreas, and specific brain nuclei, as they pertain to energy balance and metabolic dysregulation. Limited studies in humans suggest differential regulation of PKA in AT of obese compared to lean individuals and an overall dysregulation of PKA signaling in obesity. Despite its complexity, under normal physiologic conditions, the PKA system is tightly regulated by changes in cAMP concentrations upstream via adenylate cyclase and downstream by phosphodiesterase-mediated cAMP degradation to AMP and by changes in PKA holoenzyme stability. Adjustments in the PKA system appear to be important to the development and maintenance of the obese state and its associated metabolic perturbations. In this review we discuss the important role of PKA in obesity and its involvement in resistance to obesity, through studies in humans and in mouse models, with a focus on the regulation of PKA in energy expenditure, intake behavior, and lipid and glucose metabolism.

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Amanda J Genders, Timothy Connor, Shona Morrison, Simon T Bond, Brian G Drew, Peter J Meikle, Kirsten F Howlett, and Sean L McGee

Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.

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Yu Wang, Airong Wu, Liting Xi, Ji Yang, Wenjing Zhou, Yuming Wang, Shuang Liang, Weixin Yu, Yue Wang, and Jinzhou Zhu

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Patrycja Kurowska, Ewa Mlyczynska, Monika Dawid, Malgorzata Grzesiak, Joëlle Dupont, and Agnieszka Rak

Vaspin, visceral-adipose-tissue derived serine protease inhibitor, plays important roles in inflammation, obesity, and glucose metabolism. Our recent research has shown the expression and role of vaspin in the function of ovarian follicles. However, whether vaspin regulates steroidogenesis and luteolysis in the corpus luteum (CL) is still unknown. The aim of this study was first to determine the expression of vaspin and its receptor GRP78 in porcine CL at the early, middle, and late stages of the luteal phase. Next, we investigated the hormonal regulation of vaspin levels in luteal cells in response to luteinizing hormone (LH), progesterone (P4), and prostaglandin PGE2 and PGF2α. Finally, we determined vaspin’s direct impact on luteal cells steroidogenesis, luteolysis and kinases phosphorylation. Our results are the first to show higher vaspin/GRP78 expression in middle and late vs early stages; immunohistochemistry showed cytoplasmic vaspin/GRP78 localization in small and large luteal cells. In vitro, we found that LH, P4, PGE2, and PGF2α significantly decreased vaspin levels. Furthermore, vaspin stimulated steroidogenesis by the activation of the GRP78 receptor and protein kinase A (PKA). Also, vaspin increased the ratio of luteotropic PGE2 to luteolytic PGF2α secretion via GRP78 and mitogen-activated kinase (MAP3/1). Moreover, vaspin, in a dose-dependent manner, decreased GRP78 expression, while it, in a time-dependent manner, increased kinases PKA and MAPK3/1 phosphorylation. Taken together, we found that vaspin/GRP78 expression depends on the luteal phase stage and vaspin affects luteal cells endocrinology, indicating that vaspin is a new regulator of luteal cells steroidogenesis and CL formation.

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Tiffany K. Miles, Ana Rita Silva Moreira, Melody Allensworth-James, Angela Odle, Anessa Haney, Angus MacNicol, Melanie MacNicol, and Gwen V Childs

Anterior pituitary somatotropes are important metabolic sensors responding to leptin by secreting growth hormone (GH). However, reduced leptin signals caused by fasting have not always correlated with reduced serum GH. Reports show that fasting may stimulate or reduce GH secretion, depending on the species. Mechanisms underlying these distinct somatotrope responses to fasting remain unknown. To define the somatotrope response to decreased leptin signaling we examined markers of somatotrope function over different time periods of fasting. Male and mice were fasted for 24 and 48 h, with female mice fasted for 24 h compared to fed ad libitum controls. Body weight and serum glucose were reduced in both males and females, but, unexpectedly, serum leptin was reduced only in males. Furthermore, in males serum GH levels showed a biphasic response with significant reductions at 24 h followed by a significant rise at 48 h, which coincided with the rise in serum ghrelin levels. In contrast, females showed an increase in serum GH at 24. We then explored mechanisms underlying the differential somatotrope responses seen in males and observed that pituitary levels of Gh mRNA increased, with no distinction between acute and prolonged fasting. By contrast, the Ghrhr mRNA (encoding GH releasing hormone receptor) and the Ghsr mRNA (encoding the ghrelin receptor) were both greatly increased at prolonged fasting times coincident with increased serum GH. These findings show sex differences in the somatotrope and adipocyte responses to fasting and support an adaptive role for somatotropes in males in response to multiple metabolic signals.

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Weihua Liu, Yuqiang Ji, Haiping Chu, Mo Wang, Bin Yang, and Chunyan Yin

This study investigated the effects of Wnt5a/caveolin/JNK signaling pathway and SFRP5 protein on ox-LDL-induced apoptosis of HUVEC cells. The difference of serological indexes between healthy average weight and obese children and the expression of Wnt 5a and SFRP5 was detected by clinical examination, and the correlation between serum SFRP5, Wnt 5a and the vascular endothelial injury was detected. HUVEC cells were induced by ox-LDL to construct an endothelial injury model, siRNA-transfected cells were used to construct down-regulated SFRP5 and Wnt 5A expression groups, and recombination methods were used to construct up-regulated Wnt5a and SFRP5 expression groups. The expression of Wnt 5a, caveolin-1, JNK and apoptosis-related proteins under different treatments were detected by the Western blot method, and apoptosis was detected by flow cytometry. Serological results showed that the level of Sfrp5 in obese children was significantly lower than that in healthy children, and the level of Wnt5a was significantly higher than that in healthy children. Moreover, Ln Sfrp5 was significantly negatively correlated with Ang-2 in blood circulation, ICAM-1 and E-selectin selectin, but not with VCAM-1. When Wnt5a was up-regulated, the expression of caveolin-1 and JNK increased significantly, Bcl-2 decreased significantly, and the apoptotic rate increased significantly. Nevertheless, when Sfrp5 expression was up-regulated, the result was the opposite. SFRP5 and Wnt5a are involved in the vascular endothelial injury. Wnt5a can promote apoptosis of HUVEC cells through Wnt5a/JNK/Caveolin-1 pathway, while SFRP5 can inhibit apoptosis by interfering with this pathway.

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Russell T Turner, Adam J Branscum, Carmen P Wong, Urszula T Iwaniec, and Emily Morey-Holton

The gravitostat is purported to function as a leptin-independent, osteocyte-dependent mechanism for regulation of energy balance. If correct, reduced activation of gravitostat signaling caused by prolonged sitting may contribute to obesity. The gravitostat concept is supported by reduced body mass in rodents following surgical implantation of weighted capsules. However, the procedure induces a confounding injury response. We therefore sought to confirm a gravitostat by decreasing (microgravity and simulated microgravity) or increasing (simulated gravity) weight using less invasive models (spaceflight, hindlimb unloading and centrifugation). We also evaluated changes in weight following non-surgical injury (radiation). Male rats (Wistar, Sprague-Dawley and Fischer-344) ranging in age from 5-12 weeks at launch and flown for 4-19 days in low Earth orbit exhibited slightly lower (4-day flight) or no difference (all other studies) in weight compared to ground controls. Rats subjected to inflight (1.0 G) or ground (1.05 G and 1.56 G) centrifugation during a 19-day mission did not differ in weight. In female rats (Fischer-344), spaceflight (14 days) did not alter ovariectomy-induced weight gain. Finally, hindlimb unloading resulted in weight loss in lean and obese mice. The aforementioned findings are inconsistent with outcomes predicted by a gravitostat; namely, increased mass during weightlessness and decreased mass when subjected to <1 G simulated gravity. Injury (dose-associated graded increases in radiation) mimicked the leptin-independent weight changes attributed to a gravitostat. Taken together, these findings do not support gravitostat regulation of energy balance and suggest injury/stress as an alternative mechanism for weight loss induced by weighted capsules.