The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing’s syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1−/−) following 4 months high-fat feeding. We found that high fat-fed 11β-HSD1−/− mice were protected from age-related glucose intolerance and hyperinsulinemia when compared to age/diet-matched WTs. By contrast, aged 11β-HSD1−/− mice were not protected from the onset of sarcopenia observed in the aged WTs. Young 11β-HSD1−/− mice were partially protected from diet-induced obesity; however, this partial protection was lost with age. Despite greater overall obesity, the aged 11β-HSD1−/− animals stored fat in more metabolically safer adipose depots as compared to the aged WTs. Serum analysis revealed both WT and 11β-HSD1−/− mice had an age-related increase in morning corticosterone. Surprisingly, 11β-HSD1 oxo-reductase activity in the liver and skeletal muscle was unchanged with age in WT mice and decreased in gonadal adipose tissue. These data suggest that deletion of 11β-HSD1 in high fat-fed, but not chow-fed, male mice protects from age-related insulin resistance and supports a metabolically favourable fat distribution.
Stuart A Morgan, Laura L Gathercole, Zaki K Hassan-Smith, Jeremy Tomlinson, Paul M Stewart, and Gareth G Lavery
Lara H Sattgast, Adam J Branscum, Natali Newman, Steven W Gonzales, Mary Lauren Benton, Erich J Baker, Kathleen A Grant, Russell T Turner, and Urszula T Iwaniec
Insulin-like growth factor 1 (IGF-1) influences bone turnover. Transient decreases in IGF-I levels and/or bioavailability may contribute to the detrimental effects of alcohol on bone. The goals of this non-human primate study were to i) evaluate the 20-h response of bone turnover markers to ethanol consumption and ii) assess how ethanol consumption influences the relationship between IGF-1 and these markers. Osteocalcin (bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, bone resorption), IGF-1, and IGF binding protein 1 (IGFBP-1) were measured in plasma from male rhesus macaques (N = 10, 8.4 ± 0.3 years) obtained at 12:00, 16:00, and 06:00 h during two phases: pre-ethanol (alcohol-naïve) and ethanol access. During the ethanol access phase, monkeys consumed 1.5 g/kg/day ethanol (4% w/v) beginning at 10:00 h. Osteocalcin and CTX were lower, and the ratio of osteocalcin to CTX was higher at each time point during ethanol access compared to the pre-ethanol phase. Pre-ethanol marker levels did not vary across time points, but markers varied during ethanol access. IGF-1 levels, but not IGFBP-1 levels, varied during the pre-ethanol phase. In contrast, IGF-1 levels were stable during ethanol access but IGFBP-1 levels varied. There were positive relationships between IGF-1 and turnover markers during the pre-ethanol phase, but not during ethanol access. In conclusion, chronic ethanol consumption reduces levels of bone turnover markers and blocks the normal positive relationship between IGF-1 and turnover markers and alters the normal relationship between IGF-1 and IGFBP-1. These findings support the hypothesis that chronic alcohol consumption leads to growth hormone/IGF-1 resistance.
Shiho Fujisaka, Yoshiyuki Watanabe, and Kazuyuki Tobe
The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains comprising more than 1,000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70–90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.
Adriana María Belén Abiuso, María Luisa Varela, Trinidad Raices, Griselda Irusta, Juan Manuel Lazzati, Marcos Besio Moreno, Alina Cavallotti, Alicia Belgorosky, Omar Pedro Pignataro, Esperanza Berensztein, and Carolina Mondillo
Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.
Brittany Duggan, Daniel M Marko, Raveen Muzaffar, Darryl Y. Chan, and Jonathan D Schertzer
Small molecule kinase inhibitors (SMKIs) are a class of therapeutic drugs that target protein kinases in diseases such as cancer. SMKIs are often designed to inhibit kinases involved in cell proliferation, but these drugs alter cell metabolism and endocrine control of organismal metabolism. SMKI treatment in diabetic cancer patients reveals that certain SMKIs improve blood glucose control and can mitigate insulin dependence or diabetic medication requirements in both Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). Certain SMKIs can preserve functional β-cell mass and increase insulin secretion or insulin sensitivity. It is not yet clear why different SMKIs can have opposing effects on insulin and blood glucose. Understanding the therapeutic effects of these drugs in T1D and T2D is complicated by overlapping off-target effects of SMKIs. The potency of inhibition of the intended protein kinase and inhibition of multiple off-target kinases may underpin conflicting reports of how certain SMKIs alter blood glucose and insulin. We summarize the effects of SMKIs on the intended and off-target kinases that can alter blood glucose and insulin, including c-Abl, c-Kit, EGFR, and VEGF. Inhibition of PDGFRβ consistently lowers blood glucose in T1D and T2D. The effects of SMKIs on the kinases that regulate immune pathways, such as BTK and RIPKs mediate many of the diverse effects of these drugs on metabolism. We highlight that inhibition of RIPK2 by SMKIs is a central node in metabolism that influences key metabolic pathways including lipolysis, blood glucose control, insulin secretion, and insulin resistance.
Ying Sze, Joana Fernandes, Zofia M Kołodziejczyk, and Paula J Brunton
Stress during pregnancy negatively affects the fetus and increases the risk for affective disorders in adulthood. Excess maternal glucocorticoids are thought to mediate fetal programming; however, whether they exert their effects directly or indirectly remains unclear. During pregnancy, protective mechanisms including maternal hypothalamic–pituitary–adrenal (HPA) axis hyporesponsiveness and placental 11β-hydroxysteroid dehydrogenase (11βHSD) type 2, which inactivates glucocorticoids, limit mother-to-fetus glucocorticoid transfer. However, whether repeated stress negatively impacts these mechanisms is not known. Pregnant rats were exposed to repeated social stress on gestational days (GD) 16–20 and several aspects of HPA axis and glucocorticoid regulation, including concentrations of glucocorticoids, gene expression for their receptors (Nr3c1, Nr3c2), receptor chaperones (Fkbp51, Fkbp52) and enzymes that control local glucocorticoid availability (Hsd11b1, Hsd11b2), were investigated in the maternal, placental and fetal compartments on GD20. The maternal HPA axis was activated following stress, though the primary driver was vasopressin, rather than corticotropin-releasing hormone. Despite the stress-induced increase in circulating corticosterone in the dams, only a modest increase was detected in the circulation of female fetuses, with no change in the fetal brain of either sex. Moreover, there was no change in the expression of genes that mediate glucocorticoid actions or modulate local concentrations in the fetal brain. In the placenta labyrinth zone, stress increased Hsd11b2 expression only in males and Fkbp51 expression only in females. Our results indicate that any role glucocorticoids play in fetal programming is likely indirect, perhaps through sex-dependent alterations in placental gene expression, rather than exerting effects via direct crossover into the fetal brain.
Juan Bernal, Beatriz Morte, and Diego Diez
Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood–brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan–Herndon–Dudley syndrome, with altered thyroid hormone concentrations in the blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory, given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.
Elliott Neal, Vinod Kumar, Karin Borges, and James SM Cuffe
Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague-Dawley rats were assigned to a control or B12 deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited availability of the TCA cycle intermediates citrate and succinate. This was associated with increased Mut mRNA levels and citrate synthase activity and lower succinyl-CoA availability. One carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.
Sofie Dinesen, Alisar El-Faitarouni, and Louise T Dalgaard
Different types of small non-coding RNAs, especially microRNAs (miRNAs), may be found in the circulation, either protein bound or enclosed in extracellular vesicles. During gestation, and particular during gestational diabetes mellitus (GDM), the levels of several miRNAs are altered. Worldwide the incidence of GDM is increasing, in part driven by the current obesity epidemic. This is a point of public health concern, because offspring of women with GDM frequently suffer from short and long-term complications of maternal GDM. This has prompted the investigation of whether levels of specific miRNA species, detected early in gestation, may be used as diagnostic or prognostic markers for development of GDM. Here, we summarize mechanisms of RNA secretion, and review circulating miRNAs associated with GDM. Several miRNAs are associated with GDM: miR-29a-3p and miR-29b-3p are generally upregulated in GDM pregnancies, also when measured prior to the development of GDM, while miR-16-5p is consistently upregulated in GDM pregnancies, especially in late gestation. miR-330-3p in circulation is increased in late gestation GDM women, especially in those with poor insulin secretion. miR-17-5p, miR-19a/b-3p, miR-223-3p, miR-155-5p, miR-125-a/b-5p, miR-210-3p and miR-132 are also associated with GDM, but less so and with more contradictory results reported. There could be a publication bias as miRNAs identified early are investigated the most, suggesting that it is likely that additional, more recently detected miRNAs could also be associated with GDM. Thus, circulating miRNAs show potential as biomarkers of GDM diagnosis or prognosis, especially multiple miRNAs containing prediction algorithms show promise, but further studies are needed.
Gabriel O de Souza, Fernanda M Chaves, Josiane N Silva, João A B Pedroso, Martin Metzger, Renata Frazão, and Jose Donato
Recent studies indicated an important role of connexins, gap junction proteins, in the regulation of metabolism. However, most of these studies focused on the glial expression of connexins, whereas the actions of connexins in neurons are still poorly investigated. Thus, the present study had the objective to investigate the possible involvement of gap junctions, and in particular connexin 43 (CX43), for the central regulation of energy homeostasis. Initially, we demonstrated that hypothalamic CX43 expression was suppressed in fasted mice. Using whole-cell patch-clamp recordings, we showed that pharmacological blockade of gap junctions induced hyperpolarization and decreased the frequency of action potentials in 50–70% of agouti-related protein (AgRP)-expressing neurons, depending on the blocker used (carbenoxolone disodium, TAT-Gap19 or Gap 26). When recordings were performed with a biocytin-filled pipette, this intercellular tracer was detected in surrounding cells. Then, an AgRP-specific CX43 knockout (AgRPΔCX43) mouse was generated. AgRPΔCX43 mice exhibited no differences in body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Metabolic responses to 24 h fasting or during refeeding were also not altered in AgRPΔCX43 mice. However, AgRPΔCX43 male, but not female mice, exhibited a partial protection against high-fat diet-induced obesity, even though no significant changes in energy intake or expenditure were detected. In summary, our findings indicate that gap junctions regulate the activity of AgRP neurons, and AgRP-specific CX43 ablation is sufficient to mildly prevent diet-induced obesity specifically in males.