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Department of Orthopedics, Northern Jiangsu People’s Hospital, Yangzhou, China
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The role of this study was to evaluate the impact of gut microbiota depletion on the progression of osteoarthritis (OA) and osteoporosis (OP). We conducted an experimental mouse model of OA and OP over an 8-week period. The model involved destabilization of the medial meniscus and bilateral ovariectomy (OVX). To deplete the gut microbiota, we administered a course of antibiotics for 8 weeks. The severity of OA was assessed through micro-CT scanning, X-rays, and immunohistochemical staining. Microbiome analysis was performed using PCR of 16S DNA on fecal samples, and the levels of serum lipopolysaccharide, interleukin 6, tumor necrosis factor-α (TNF-α), osteocalcin, and estrogen were measured using enzyme-linked immunosorbent assay. We found that in comparison to the OVX+OA group, the OVX+OA+ABT group exhibited increased bone mineral density (P < 0.0001), bone volume fraction (P = 0.0051), and trabecular number (P = 0.0023) in the metaphyseal bone. Additionally, cartilage injury and levels of matrix metalloproteinase 13 were reduced in the OVX+OA+ABT group compared to the OVX+OA group. Moreover, the OVX+OA+ABT group demonstrated decreased relative abundance of Bacteroidetes, serum lipopolysaccharide (P = 0.0005), TNF-α (P < 0.0001), CTX-1 (P = 0.0002), and increased expression of bone formation markers. These findings were further supported by correlation network analyses. Depletion of gut microbiota was shown to protect against bone loss and cartilage degradation by modulating the composition of the gut microbiota in osteoporosis and osteoarthritis.
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During pregnancy, all major physiological systems undergo remarkable changes, driven largely by alterations in the maternal hormonal milieu. In healthy pregnancies, maternal cardiovascular and metabolic adaptation to pregnancy occurs to support fetal growth and maternal well-being. Impaired maternal adaptation to pregnancy is associated with a range of pregnancy complications, including gestational diabetes and preeclampsia. There is growing recognition of the importance of different maternal microbiota, including in the gut, vagina and oral cavity, in supporting normal maternal adaptations to pregnancy as well as evidence for microbial disturbances associating with pregnancy pathologies. Here, we aim to summarise emerging evidence demonstrating that differences in maternal microbiota associate with pregnancy outcomes and discuss potential therapeutic approaches under development that might restore an ‘optimal’ microbiome. In particular, we highlight recent work by ourselves and others exploring the role of the oral microbiome in pregnancy, given established links between poor oral health (e.g. periodontitis) and adverse pregnancy outcomes. Our research has focussed on specific nitrate-reducing oral bacteria which play a role in the generation of nitric oxide (NO) and other bioactive nitrogen oxides associated with cardiovascular health and maternal cardiovascular adaption to pregnancy. Ongoing research aims to define whether altered microbial profiles have clinical utility in the prediction of pregnancy pathologies, and whether interventions designed to optimise specific maternal microbiota could help prevent future complications.
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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CONICET – Universidad de Buenos Aires, Instituto de Investigaciones Biomédicas (INBIOMED), Buenos Aires, Argentina
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For many years, research in the field of steroid synthesis has aimed to understand the regulation of the rate-limiting step of steroid synthesis, i.e. the transport of cholesterol from the outer to the inner mitochondrial membrane, and identify the protein involved in the conversion of cholesterol into pregnenolone. The extraordinary work by B Clark, J Wells, S R King, and D M Stocco eventually identified this protein and named it steroidogenic acute regulatory protein (StAR). The group’s finding was also one of the milestones in understanding the mechanism of nonvesicular lipid transport between organelles. A notable feature of StAR is its high degree of phosphorylation. In fact, StAR phosphorylation in the acute phase is required for full steroid biosynthesis. As a contribution to this subject, our work has led to the characterization of StAR as a substrate of kinases and phosphatases and as an integral part of a mitochondrion-associated multiprotein complex, essential for StAR function and cholesterol binding and mitochondrial transport to yield maximum steroid production. Results allow us to postulate the existence of a specific cellular microenvironment where StAR protein synthesis and activation, along with steroid synthesis and secretion, are performed in a compartmentalized manner, at the site of hormone receptor stimulation, and involving the compartmentalized formation of the steroid molecule-synthesizing complex.
Endocrinology, SBMS, Faculty of Medicine, The University of Queensland, St Lucia, Qld, Australia
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Polycystic ovary syndrome (PCOS) is a common endocrinopathy occurring in reproductive-age women. Hyperandrogenism, polycystic ovaries, chronic anovulation, and metabolic aberrations are the common features in PCOS. Hormonal changes are causing pathological symptoms in women with PCOS. The various hormone alterations in PCOS have been demonstrated. Hormones, such as insulin, growth hormones (GH), ghrelin, LEAP-2, gonadotropin-releasing hormone (GnRH), insulin, the luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio, androgens, and estrogens, are all abnormal in PCOS women. These hormones are related to metabolic disorders, such as diabetes and insulin resistance, overweight and obesity, infertility, and disturbed menstrual cycle in PCOS patients. The pathological changes of these hormones, such as increased insulin, reduced GH, increased ghrelin, and leptin resistance, result in an increased prevalence of diabetes and obesity in PCOS women. A reduced GH, increased LEAP-2 levels, high LH basal, increased LH/FSH ratio, high androgens, and low estrogen are demonstrated in PCOS and linked to infertility. This narrative review aims to clarify the changes of hormone profiles, such as insulin, GH, LH, FSH, androgens, estrogen, progesterone, ghrelin, LEAP-2, asprosin, and subfatin, in PCOS, which may reveal novel targets for better diagnosis and treatment of PCOS.
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Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, Houston, Texas, USA
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Department of Cell and Microbiology, Weill Cornell Medical College, New York, New York, USA
Department of Genetics, The University of Texas Anderson Cancer Center, Houston, Texas, USA
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Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, Texas, USA
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Department of Cell and Microbiology, Weill Cornell Medical College, New York, New York, USA
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Metabolic syndrome (MetS) is an increasing global health threat and strong risk factor for type 2 diabetes (T2D). MetS causes both hyperinsulinemia and islet size overexpansion, and pancreatic β-cell failure impacts insulin and proinsulin secretion, mitochondrial density, and cellular identity loss. The low-density lipoprotein receptor knockout (LDLr −/−) model combined with high-fat diet (HFD) has been used to study alterations in multiple organs, but little is known about the changes to β-cell identity resulting from MetS. Osteocalcin (OC), an insulin-sensitizing protein secreted by bone, shows promising impact on β-cell identity and function. LDLr −/− mice at 12 months were fed chow or HFD for 3 months ± 4.5 ng/h OC. Islets were examined by immunofluorescence for alterations in nuclear Nkx6.1 and PDX1 presence, insulin–glucagon colocalization, islet size and %β-cell and islet area by insulin and synaptophysin, and mitochondria fluorescence intensity by Tomm20. Bone mineral density (BMD) and %fat changes were examined by Piximus Dexa scanning. HFD-fed mice showed fasting hyperglycemia by 15 months, increased weight gain, %fat, and fasting serum insulin and proinsulin; concurrent OC treatment mitigated weight increase and showed lower proinsulin-to-insulin ratio, and higher BMD. HFD increased %β and %islet area, while simultaneous OC-treatment with HFD was comparable to chow-fed mice. Significant reductions in nuclear PDX1 and Nkx6.1 expression, increased insulin–glucagon colocalization, and reduction in β-cell mitochondria fluorescence intensity were noted with HFD, but largely prevented with OC administration. OC supplementation here suggests a benefit to β-cell identity in LDLr −/− mice and offers intriguing clinical implications for countering metabolic syndrome.
Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
Diabetes and Nutritional Sciences, King's College London, London, UK
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Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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Sexual dimorphism in energy metabolism is now established and suggested to affect many aspects of metabolic diseases and in particular diabetes and obesity. This is strongly related to sex-based differences in whole-body insulin resistance. Women are more insulin sensitive compared to men, but this metabolic advantage gradually disappears after menopause or when insulin resistance progresses to hyperglycemia and diabetes. In this narrative review, first, we describe the pathophysiology related to insulin resistance and then we present the epidemiological evidence as well as the important biological factors that play a crucial role in sexual dimorphism in insulin sensitivity. We focus particularly on the differences in body fat and muscle mass distribution and function, in inflammation and in sex hormones between males and females. Most importantly, we describe the significant mechanistic differences in insulin sensitivity as well as glucose and lipid metabolism in key metabolic organs: liver, white adipose tissue, and skeletal muscle. Finally, we present the sex-based differences in response to different interventions and discuss important open research questions.
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Department of Paediatric Endocrinology, Royal Hospital for Children, Glasgow, UK
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The integral role of the hypothalamic–pituitary–gonadal axis in reproductive processes makes it a prime therapeutic target. By inhibiting sex steroid synthesis, gonadotropin-releasing hormone (GnRH) analogues are used in the management of cancers, benign neoplasms, infertility and gender dysphoria. However, the wide application of these therapeutics raises concerns regarding the unintended effects upon the cardiovascular system. In males with prostate cancer, GnRH analogues when used as an androgen deprivation therapy appear to increase the risk of cardiovascular disease, which is the leading cause of death in this population. Therefore, due to the utilisation of GnRH analogues across the lifespan and gender spectrum, this relationship merits discussion. Existing data suggest an association between GnRH analogues and major adverse cardiovascular events in males. Conversely, females receiving GnRH analogues for breast cancer treatment appear to be at an increased risk of developing hypertension. In this narrative review, we describe the uses of GnRH analogues in adults, adolescents and children. We discuss whether sex plays a role in the cardiovascular effects of GnRH analogues and explore the significance of sex hormone receptors in the vasculature. We also consider confounding factors such as malignancy, advanced age and infertility.
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The solute carrier (SLC) family is a large group of membrane transport proteins. Their dysfunction plays an important role in the pathogenesis of thyroid cancer. The most well-known SLC is the sodium-iodide symporter (NIS), also known as sodium/iodide co-transporter or solute carrier family 5 member 5 (SLC5A5) in thyroid cancer. The dysregulation of NIS in thyroid cancer is well documented. The role of NIS in the uptake of iodide is critical in the treatment of thyroid cancer, radioactive iodide (RAI) therapy in particular. In addition to NIS, other SLC members may affect the autophagy, proliferation, and apoptosis of thyroid cancer cells, indicating that an alteration in SLC members may affect different cellular events in the evolution of thyroid cancer. The expression of the SLC members may impact the uptake of chemicals by the thyroid, suggesting that targeting SLC members may be a promising therapeutic strategy in thyroid cancer.
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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The Diabetes Institute, Ohio University, Athens, Ohio, USA
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Studies in humans and mice have determined that distinct subpopulations of adipocytes reside even within individual adipose tissue depots. Previously, our lab defined three white adipocyte subpopulations with stable and unique gene expression profiles, which were termed type 1, 2, and 3 adipocytes, respectively. Our previous studies demonstrated that type 2 adipocytes were highly responsive to the inflammatory cytokine, tumor necrosis factor alpha (TNFα). This study extends these findings to investigate the role of type 2 adipocytes in obesity. We found that treatment with TNFα increased lipolysis specifically in type 2 adipocytes, at least in part, through the reduction of fat-specific protein 27 (FSP27) expression. To assess the physiological role of lipolysis from this adipocyte subpopulation, a type2Ad-hFSP27tg mouse model was generated by overexpressing human FSP27 specifically in type 2 adipocytes. Glucose and insulin tolerance test analysis showed that male type2Ad-hFSP27tg mice on 60% high-fat diet exhibited improved glucose tolerance and insulin sensitivity, with no change in body weight compared to controls. These metabolic changes may, at least in part, be explained by the reduced lipolysis rate in the visceral fat of type2Ad-hFSP27tg mice. Although FSP27 overexpression in primary type 2 adipocytes was sufficient to acutely reduce TNFα-induced apoptosis in vitro, it failed to reduce macrophage infiltration in obesity in vivo. Taken together, these results strongly suggest that type 2 adipocytes contribute to the regulation of lipolysis and could serve as a potential therapeutic target for obesity-associated insulin resistance.
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Physiology and Pharmacology, Western University, London, Ontario, Canada
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Insulin resistance contributes to the development of various diseases, including type 2 diabetes and gestational diabetes. Even though gestational diabetes is specific to pregnancy, it can result in long-term glucose intolerance and type 2 diabetes after delivery. Given the substantial health and economic burdens associated with diabetes, it is imperative to better understand the mechanisms leading to insulin resistance and type 2 diabetes so that treatments targeted at reversing symptoms can be developed. Considering that the endocrine cells of the pancreas (islets of Langerhans) largely contribute to the pathogenesis of diabetes (beta-cell insufficiency and dysfunction), the elucidation of the various mechanisms of endocrine cell plasticity is important to understand. By better defining these mechanisms, targeted therapeutics can be developed to reverse symptoms of beta-cell deficiency and insulin resistance in diabetes. Animal models play an important role in better understanding these mechanisms, as techniques for in vivo imaging of endocrine cells in the pancreas are limited. Therefore, this review article will discuss the available rodent models of gestational and type 2 diabetes that are characterized by endocrine cell impairments in the pancreas, discuss the models with a comparison to human diabetes, and explore the potential mechanisms of endocrine cell plasticity that contribute to these phenotypes, as these mechanisms could ultimately be used to reverse blood glucose dysregulation in diabetes.
