Short stature and osteoporosis are common in Duchenne muscular dystrophy (DMD) and its pathophysiology may include an abnormality of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which is further exacerbated by long-term glucocorticoid (GC) treatment. Hence, an agent that has anabolic properties and may improve linear growth would be beneficial in this setting and therefore requires further exploration. A 5-week-old x-linked muscular dystrophy (mdx) mice were used as a model of DMD. They were treated with prednisolone ± GH + IGF-1 for 4 weeks and then compared to control mdx mice to allow the study of both growth and skeletal structure. GC reduced cortical bone area, bone fraction, tissue area and volume and cortical bone volume, as assessed by micro computed tomography (CT) In addition, GC caused somatic and skeletal growth retardation but improved grip strength. The addition of GH + IGF-1 therapy rescued the somatic growth retardation and induced additional improvements in grip strength (16.9% increase, P  < 0.05 compared to control). There was no improvement in bone microarchitecture (assessed by micro-CT and static histomorphometry) or biomechanical properties (assessed by three-point bending). Serum bone turnover markers (Serum procollagen 1 intact N-terminal propeptide (P1NP), alpha C-terminal telopeptide (αCTX)) also remained unaffected. Further work is needed to maximise these gains before proceeding to clinical trials in boys with DMD.

Obesity and gestational diabetes during pregnancy have multiple short- and long-term consequences for both mother and child. One common feature of pregnancies complicated by maternal obesity and gestational diabetes is maternal hyperinsulinaemia, which has effects on the mother and her adaptation to pregnancy. Even though insulin does not cross the placenta insulin can act on the placenta as well affecting placental growth, angiogenesis and lipid metabolism. Obese and gestational diabetic pregnancies are often characterised by maternal hyperglycaemia resulting in exposure of the fetus to high levels of glucose, which freely crosses the placenta. This leads to stimulation of fetal ß-cells and insulin secretion in the fetus. Fetal hyperglycaemia/hyperinsulinaemia has been shown to cause multiple complications in fetal development, such as altered growth trajectories, impaired neuronal and cardiac development and early exhaustion of the pancreas. These changes could increase the susceptibility of the offspring to develop cardiometabolic diseases later in life. In this review, we aim to summarize and review the mechanisms by which maternal and fetal hyperinsulinaemia impact on (i) maternal health during pregnancy; (ii) placental and fetal development; (iii) offspring energy homeostasis and long-term cardiometabolic health; (iv) how interventions can alleviate these effects.

Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To determine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradiol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mERα-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were absent in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in the skeleton are mERα-dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrating mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mERα signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manner. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.

Kisspeptin neurons, i.e. KNDy neurons, in the arcuate nucleus (ARC) coexpress neurokinin B and dynorphin and regulate gonadotropin-releasing hormone/luteinizing hormone (LH) pulses. Because it remains unclear whether these neurons are associated with reproductive dysfunction in diabetic females, we examined the expression of KNDy neurons detected by histochemistry in streptozotocin (STZ)-induced diabetic female rats 8 weeks after STZ injection. We also evaluated relevant metabolic parameters – glucose, 3-hydroxybutyrate, and non-esterified fatty acids – as indicators of diabetes progression. Severe diabetes with hyperglycemia and severe ketosis suppressed the mRNA expression of KNDy neurons, resulting in low plasma LH levels and persistent diestrus. In moderate diabetes with hyperglycemia and moderate ketosis, kisspeptin-immunoreactive cells and plasma LH levels were decreased, while the mRNA expression of KNDy neurons remained unchanged. Mild diabetes with hyperglycemia and slight ketosis did not affect KNDy neurons and plasma LH levels. The number of KNDy cells was strongly and negatively correlated with plasma 3-hydroxybutyrate levels. The vaginal smear analysis showed unclear proestrus in diabetic rats 3–5 days after STZ injection, and the mRNA expression of kisspeptin in the ARC was decreased 2 weeks after STZ injection in severely diabetic rats. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV), which induce an LH surge, were unaffected at 2 and 8 weeks after STZ injection regardless of the diabetes severity. These results suggest that diabetes mellitus progression in females may negatively affect ARC kisspeptin neurons but not AVPV kisspeptin neurons, implicating a potential role of ARC kisspeptin neurons in menstrual disorder and infertility.

It is now well established that, beyond its role in nutrient processing and absorption, the intestine and its accompanying gut microbiome constitute a major site of immunological and endocrine regulation that mediates whole-body metabolism. Despite the growing field of host-microbe research, few studies explore what mechanisms govern this relationship in the context of pregnancy. During pregnancy, significant maternal metabolic adaptations are made to accommodate the additional energy demands of the developing fetus and to prevent adverse pregnancy outcomes. Recent data suggest that the maternal gut microbiota may play a role in these adaptations, but changes to maternal gut physiology and the underlying intestinal mechanisms remain unclear. In this review, we discuss selective aspects of intestinal physiology including the role of the incretin hormone, glucagon-like peptide 1 (GLP-1), and the role of the maternal gut microbiome in the maternal metabolic adaptations to pregnancy. Specifically, we discuss how bacterial components and metabolites could mediate the effects of the microbiota on host physiology, including nutrient absorption and GLP-1 secretion and action, and whether these mechanisms may change maternal insulin sensitivity and secretion during pregnancy. Finally, we discuss how these pathways could be altered in disease states during pregnancy including maternal obesity and diabetes.

Pancreatic β-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8^−/− mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn²⁺ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N′,N′-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-β) treatment induced islet cell death, but to a lesser extent in islets from ZnT8^−/− mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8^−/− mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8^−/− mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, β-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

Global rates of obesity and type 2 diabetes mellitus (T2DM) are increasing globally concomitant with a rising prevalence of sleep deprivation and sleep disorders. Understanding the links between sleep, obesity and T2DM might offer an opportunity to develop better prevention and treatment strategies for these epidemics. Experimental studies have shown that sleep restriction is associated with changes in energy homeostasis, insulin resistance and β-cell function. Epidemiological cohort studies established short sleep duration as a risk factor for developing obesity and T2DM. In addition, small studies suggested that short sleep duration was associated with less weight loss following lifestyle interventions or bariatric surgery. In this article, we review the epidemiological evidence linking sleep duration to obesity and T2DM and plausible mechanisms. In addition, we review the impact of changes in sleep duration on obesity and T2DM.

Ghrelin is a peptide hormone secreted primarily by the stomach that acts upon the growth hormone secretagogue receptor (GHSR1), a G protein-coupled receptor whose functions include growth hormone secretion, appetite regulation, energy expenditure, regulation of adiposity, and insulin release. Following the discovery that GHSR1a stimulates food intake, receptor antagonists were developed as potential therapies to regulate appetite. However, despite reductions in signalling, the desired effects on appetite were absent. Studies in the past 15 years have demonstrated GHSR1a can interact with other transmembrane proteins, either by direct binding (i.e. heteromerisation) or via signalling cross-talk. These interactions have various effects on GHSR1a signalling including preferential coupling to one pathway (i.e. biased signalling), coupling to a unique G protein (G protein switching), suppression of GHSR1a signalling, and enhancement of signalling by both receptors. While many of these interactions have been shown in cells overexpressing the proteins of interest and remain to be verified in tissues, substantial evidence exists showing that GHSR1a and the dopamine receptor D1 (DRD1) form heteromers, which promote synaptic plasticity and formation of hippocampal memory. Additionally, a reduction in GHSR1a-DRD1 complexes in favour of establishment of GHSR1a-Aβ complexes correlates with Alzheimer’s disease, indicating that GHSR1a heteromers may have pathological functions. Herein, we summarise the evidence published to date describing interactions between GHSR1a and transmembrane proteins, discuss the experimental strengths and limitations of these studies, describe the physiological evidence for each interaction, and address their potential as novel drug targets for appetite regulation, Alzheimer’s disease, insulin secretion, and inflammation.

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.