Glucocorticoids are essential in mammals to mature fetal organs and tissues in order to survive after birth. Hence, antenatal glucocorticoid treatment (termed antenatal corticosteroid therapy) can be life-saving in preterm babies and is commonly used in women at risk of preterm birth. While the effects of glucocorticoids on lung maturation have been well described, the effects on the fetal heart remain less clear. Experiments in mice have shown that endogenous glucocorticoid action is required to mature the fetal heart. However, whether the potent synthetic glucocorticoids used in antenatal corticosteroid therapy have similar maturational effects on the fetal heart is less clear. Moreover, antenatal corticosteroid therapy may increase the risk of cardiovascular disease in adulthood. Here, we present a narrative review of the evidence relating to the effects of antenatal glucocorticoid action on the fetal heart and discuss the implications for antenatal corticosteroid therapy.
Emma J Agnew, Jessica R Ivy, Sarah J Stock, and Karen E Chapman
Caroline M Gorvin
The calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CASR utilises multiple heterotrimeric G-proteins to mediate signalling effects including activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CASR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CASR signalling and trafficking mechanisms. The first, identified by studying a CASR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CASR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CASR internalisation and reduce multiple CASR-mediated signalling pathways. Furthermore, these studies showed that the CASR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11 pathway. Thus, studies of FHH- and ADH-associated mutations have revealed novel steps by which CASR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.
Tae Woo Jung, Yoon Hee Chung, Hyoung-Chun Kim, A M Abd El-Aty, and Ji Hoon Jeong
Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently identified novel hepatokine that causes insulin resistance in skeletal muscle by activating c-Jun N-terminal kinase (JNK), thereby driving atherosclerotic inflammation. However, the role of LECT2 in inflammation and insulin resistance in adipocytes has not been investigated. In this study, we report that LECT2 treatment of differentiated 3T3-L1 cells stimulates P38 phosphorylation in a dose-dependent manner. LECT2 also enhanced inflammation markers such as IκB phosphorylation, nuclear factor kappa beta (NF-κB) phosphorylation and IL-6 expression. Moreover, LECT2 treatment impaired insulin signaling in differentiated 3T3-L1 cells, as evidenced by the decreased levels of insulin receptor substrate (IRS-1) and Akt phosphorylation and reduced insulin-stimulated glucose uptake. Furthermore, LECT2 augmented lipid accumulation during 3T3-L1 cell differentiation by activating SREBP1c-mediated signaling. All these effects were significantly abrogated by siRNA-mediated silencing of P38, CD209 expression or a JNK inhibitor. Our findings suggest that LECT2 stimulates inflammation and insulin resistance in adipocytes via activation of a CD209/P38-dependent pathway. Thus, these results suggest effective therapeutic targets for treating inflammation-mediated insulin resistance.
Weijuan Shao, Vivian Szeto, Zhuolun Song, Lili Tian, Zhong-Ping Feng, M Cristina Nostro, and Tianru Jin
Pancreatic β-cell Tcf7l2 deletion or its functional knockdown suggested the essential role of this Wnt pathway effector in controlling insulin secretion, glucose homeostasis and β-cell gene expression. As the LIM homeodomain protein ISL1 is a suggested Wnt pathway downstream target, we hypothesize that it mediates metabolic functions of TCF7L2. We aimed to determine the role of ISL1 in mediating the function of TCF7L2 and the incretin hormone GLP-1 in pancreatic β-cells. The effect of dominant negative TCF7L2 (TCF7L2DN) mediated Wnt pathway functional knockdown on Isl1 expression was determined in βTCFDN mouse islets and in the rat insulinoma cell line INS-1 832/13. Luciferase reporter assay and chromatin immunoprecipitation were utilized to determine whether Isl1 is a direct downstream target of Tcf7l2. TCF7L2DN adenovirus infection and siRNA-mediated Isl1 knockdown on β-cell gene expression were compared. Furthermore, Isl1 knockdown on GLP-1 stimulated β-catenin S675 phosphorylation and insulin secretion was determined. We found that TCF7L2DN repressed ISL1 levels in βTCFDN islets and the INS-1 832/13 cell line. Wnt stimulators enhanced Isl1 promoter activity and binding of TCF7L2 on Isl1 promoter. TCF7L2DN adenovirus infection and Isl1 knockdown generated similar repression on expression of β-cell genes, including the ones that encode GLUT2 and GLP-1 receptor. Either TCF7L2DN adenovirus infection or Isl1 knockdown attenuated GLP-1-stimulated β-catenin S675 phosphorylation in INS-1 832/13 cells or mouse islets and GLP-1 stimulated insulin secretion in INS-1 832/13 or MIN6 cells. Our observations support the existence of TCF7L2–ISL1 transcriptional network, and we suggest that this network also mediates β-cell function of GLP-1.
Nadia Bellofiore, Fiona Cousins, Peter Temple-Smith, Hayley Dickinson, and Jemma Evans
We recently discovered the first known menstruating rodent. With the exception of four bats and the elephant shrew, the common spiny mouse (Acomys cahirinus) is the only species outside the primate order to exhibit menses. There are few widely accepted theories on why menstruation developed as the preferred reproductive strategy of these select mammals, all of which reference the evolution of spontaneous decidualisation prior to menstrual shedding. Though menstruating species share several reproductive traits, there has been no identifiable feature unique to menstruating species. Such a feature might suggest why spontaneous decidualisation, and thus menstruation, evolved in these species. We propose that a ≥3-fold increase in progesterone during the luteal phase of the reproductive cycle is a unique characteristic linking menstruating species. We discuss spontaneous decidualisation as a consequence of high progesterone, and the potential role of prolactin in screening for defective embryos in these species to aid in minimising implantation of abnormal embryos. We further explore the possible impact of nutrition in selecting species to undergo spontaneous decidualisation and subsequent menstruation. We summarise the current knowledge of menstruation, discuss current pre-clinical models of menstruation and how the spiny mouse may benefit advancing our understanding of this rare biological phenomenon.
Yasmine Hachemi, Anna E Rapp, Ann-Kristin Picke, Gilbert Weidinger, Anita Ignatius, and Jan Tuckermann
Glucocorticoid hormones (GCs) have profound effects on bone metabolism. Via their nuclear hormone receptor – the GR – they act locally within bone cells and modulate their proliferation, differentiation, and cell death. Consequently, high glucocorticoid levels – as present during steroid therapy or stress – impair bone growth and integrity, leading to retarded growth and glucocorticoid-induced osteoporosis, respectively. Because of their profound impact on the immune system and bone cell differentiation, GCs also affect bone regeneration and fracture healing. The use of conditional-mutant mouse strains in recent research provided insights into the cell-type-specific actions of the GR. However, despite recent advances in system biology approaches addressing GR genomics in general, little is still known about the molecular mechanisms of GCs and GR in bone cells. Here, we review the most recent findings on the molecular mechanisms of the GR in general and the known cell-type-specific actions of the GR in mesenchymal cells and their derivatives as well as in osteoclasts during bone homeostasis, GC excess, bone regeneration and fracture healing.
Tarlliza R Nardelli, Emerielle C Vanzela, Keli C Benedicto, Flora Brozzi, André Fujita, Alessandra K Cardozo, Décio L Eizirik, Antonio C Boschero, and Fernanda Ortis
Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes IkBa, Fas, Mcp1, A20 and Cxcl10 and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.
Daniela Nasteska and David J Hodson
It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.
Emily Jane Gallagher and Derek LeRoith
José Luis Soengas, José Miguel Cerdá-Reverter, and María Jesús Delgado
Evidence indicates that central regulation of food intake is well conserved along the vertebrate lineage, at least between teleost fish and mammals. However, several differences arise in the comparison between both groups. In this review, we describe similarities and differences between teleost fish and mammals on an evolutionary perspective. We focussed on the existing knowledge of specific fish features conditioning food intake, anatomical homologies and analogies between both groups as well as the main signalling pathways of neuroendocrine and metabolic nature involved in the homeostatic and hedonic central regulation of food intake.