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"Xu, Aimin"
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Adipose Extracellular Vesicles in Intercellular and Inter-Organ Crosstalk in Metabolic Health and Diseases
Adipose tissue (AT) is a highly heterogeneous and dynamic organ that plays important roles in regulating energy metabolism and insulin sensitivity. In addition to its classical roles in nutrient sensing and energy storage/dissipation, AT secretes a large number of bioactive molecules (termed adipokines) participating in immune responses and metabolic regulation through their paracrine and/or endocrine actions. Adipose-derived extracellular vesicles (ADEVs), including exosomes, microvesicles (MVs), and apoptotic bodies, have recently emerged as a novel class of signal messengers, mediating intercellular communications and inter-organ crosstalk. In AT, ADEVs derived from adipocytes, immune cells, mesenchymal stem cells, endothelial cells are actively involved in modulation of immune microenvironment, adipogenesis, browing of white adipose tissue, adipokine release and tissue remodeling. Furthermore, ADEVs exert their metabolic actions in distal organs (such as liver, skeletal muscle, pancreas and brain) by sending genetic information (mainly in the form of microRNAs) to their target cells for regulation of gene expression. Here, we provide an updated summary on the nature and composition of ADEVs, and their pathophysiological functions in regulating immune responses, whole-body insulin sensitivity and metabolism. Furthermore, we highlight the latest clinical evidence supporting aberrant production and/or function of ADEVs as a contributor to obesity-related chronic inflammation and metabolic complications and discuss the opportunities and challenges in developing novel therapies by targeting ADEVs.
Journal Article
The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic
Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis through a heterodimeric receptor complex comprising FGF receptor 1 (FGFR1) and β-klotho. Administration of FGF21 to rodents or non-human primates causes considerable pharmacological benefits on a cluster of obesity-related metabolic complications, including a reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, cardiovascular disorders and non-alcoholic steatohepatitis (NASH). However, native FGF21 is unsuitable for clinical use owing to poor pharmacokinetic and biophysical properties. A large number of long-acting FGF21 analogues and agonistic monoclonal antibodies for the FGFR1–β-klotho receptor complexes have been developed. Several FGF21 analogues and mimetics have progressed to early phases of clinical trials in patients with obesity, type 2 diabetes mellitus and NASH. In these trials, the primary end points of glycaemic control have not been met, whereas substantial improvements were observed in dyslipidaemia, hepatic fat fractions and serum markers of liver fibrosis in patients with NASH. The complexity and divergence in pharmacology and pathophysiology of FGF21, interspecies variations in FGF21 biology, the possible existence of obesity-related FGF21 resistance and endogenous FGF21 inactivation enzymes represent major obstacles to clinical implementation of FGF21-based pharmacotherapies for metabolic diseases.Fibroblast growth factor 21 (FGF21) confers considerable pharmacological benefits on a cluster of obesity-related metabolic complications when administered to preclinical models. This Review discusses FGF21 analogues and mimetics and highlights their efficacy in preclinical models and clinical trials. The challenges in developing FGF21-based therapeutics are also considered.
Journal Article
Mesenchymal stem cell-derived extracellular vesicles for immunomodulation and regeneration: a next generation therapeutic tool?
Mesenchymal stem cells (MSCs) can be widely isolated from various tissues including bone marrow, umbilical cord, and adipose tissue, with the potential for self-renewal and multipotent differentiation. There is compelling evidence that the therapeutic effect of MSCs mainly depends on their paracrine action. Extracellular vesicles (EVs) are fundamental paracrine effectors of MSCs and play a crucial role in intercellular communication, existing in various body fluids and cell supernatants. Since MSC-derived EVs retain the function of protocells and have lower immunogenicity, they have a wide range of prospective therapeutic applications with advantages over cell therapy. We describe some characteristics of MSC-EVs, and discuss their role in immune regulation and regeneration, with emphasis on the molecular mechanism and application of MSC-EVs in the treatment of fibrosis and support tissue repair. We also highlight current challenges in the clinical application of MSC-EVs and potential ways to overcome the problem of quality heterogeneity.
Journal Article
Obesity, Bone Loss, and Periodontitis: The Interlink
Obesity and periodontitis are both common health concerns that have given rise to considerable economic and societal burden worldwide. There are established negative relationships between bone metabolism and obesity, obesity and diabetes mellitus (DM), and DM and periodontitis, to name a few, with osteoporosis being considered a long-term complication of obesity. In the oral cavity, bone metabolic disorders primarily display as increased risks for periodontitis and alveolar bone loss. Obesity-driven alveolar bone loss and mandibular osteoporosis have been observed in animal models without inoculation of periodontopathogens. Clinical reports have also indicated a possible association between obesity and periodontitis. This review systematically summarizes the clinical periodontium changes, including alveolar bone loss in obese individuals. Relevant laboratory-based reports focusing on biological interlinks in obesity-associated bone remodeling via processes like hyperinflammation, immune dysregulation, and microbial dysbiosis, were reviewed. We also discuss the potential mechanism underlying obesity-enhanced alveolar bone loss from both the systemic and periodontal perspectives, focusing on delineating the practical considerations for managing periodontal disease in obese patients.
Journal Article
Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation
Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.
Journal Article
Approximations of the generalized-Euler-constant function and the generalized Somos’ quadratic recurrence constant
In this paper, we provide an estimate for approximating the generalized-Euler-constant function γ(z)=∑k=1∞zk−1(1k−lnk+1k)\\(\\gamma (z)=\\sum_{k=1}^{\\infty }z ^{k-1} (\\frac{1}{k}-\\ln \\frac{k+1}{k} )\\) by its partial sum γN−1(z)\\(\\gamma _{N-1}(z)\\) when 0
Journal Article
Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2
Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (
Ldha
), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.
Adipocyte tissue macrophages (ATM) are recruited and activated in obesity. The authors show that adipocytes release lactate as a signal of inflammation and that this metabolite can enhance obesity associated inflammation through stimulation of ATM by direct binding with PHD2.
Journal Article
Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction
There is a close anatomical and functional relationship between adipose tissue and blood vessels. The crosstalk between these two organs is vital to both metabolic and vascular homeostasis. On the one hand, adipose tissue is highly vascularized, and maintenance of ample supply of blood flow is essential for both expansion and metabolic functions of adipose tissue. Vascular endothelium also secretes many factors to regulate adipogenesis and adipose tissue remodeling. On the other hand, almost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which regulates vascular function by producing a large number of “vasocrine” molecules. Under the normal conditions, PVAT exerts its anti-contractile effects by release of vasorelaxants (such as adipocyte-derived relaxation factors and adiponectin) that promote both endothelium-dependent and –independent relaxations of blood vessels. However, PVAT in obesity becomes highly inflamed and induces vascular dysfunction by augmented secretion of vasoconstriction factors (such as the major components of renin-angiotensinogen-aldosterone system and superoxide) and pro-inflammatory adipokines (such as TNF-α and adipocyte fatty acid binding protein), the latter of which are important contributors to endothelial activation, vascular inflammation and neointimal formation. Furthermore, several adipocyte-derived adipokines impair vascular function indirectly, by acting in the brain to activate sympathetic nerve system (such as leptin) or by exerting their actions in major metabolic organs to induce vascular insulin resistance, which in turn aggravates endothelial dysfunction. Aberrant secretion of adipokines and other vasoactive factors in adipose tissue is a major contributor to the onset and progression of obesity-related metabolic and vascular complications.
Journal Article
MDM2 induces pro-inflammatory and glycolytic responses in M1 macrophages by integrating iNOS-nitric oxide and HIF-1α pathways in mice
M1 macrophages induce protective immunity against infection, but also contribute to metabolic and inflammatory diseases. Here we show that the E3 ubiquitin ligase, MDM2, promotes the glycolytic and inflammatory activities of M1 macrophage by increasing the production of IL-1β, MCP-1 and nitric oxide (NO). Mechanistically, MDM2 triggers the ubiquitination and degradation of E3 ligase, SPSB2, to stabilize iNOS and increases production of NO, which s-nitrosylates and activates HIF-1α for triggering the glycolytic and pro-inflammatory programs in M1 macrophages. Myeloid-specific haplodeletion of MDM2 in mice not only blunts LPS-induced endotoxemia and NO production, but also alleviates obesity-induced adipose tissue-resident macrophage inflammation. By contrast, MDM2 haplodeletion induces higher mortality, tissue damage and bacterial burden, and also suppresses M1 macrophage response, in the cecal ligation and puncture-induced sepsis mouse model. Our findings thus identify MDM2 as an activator of glycolytic and inflammatory responses in M1 macrophages by connecting the iNOS-NO and HIF-1α pathways.
Proinflammatory macrophages mediate protective immunity but also contribute to inflammatory diseases. Here the authors show that the E3 ligase, MDM2, induces nitric oxide from macrophage, potentially triggering the s-nitrosylation and activation of HIF-1α for the production of inflammatory cytokines, to protect mice from sepsis but aggravate obesity-induced inflammation.
Journal Article
Exerkines and cardiometabolic benefits of exercise: from bench to clinic
Regular exercise has both immediate and long-lasting benefits on cardiometabolic health, and has been recommended as a cornerstone of treatment in the management of diabetes and cardiovascular conditions. Exerkines, which are defined as humoral factors responsive to acute or chronic exercise, have emerged as important players conferring some of the multiple cardiometabolic benefits of exercise. Over the past decades, hundreds of exerkines released from skeletal muscle, heart, liver, adipose tissue, brain, and gut have been identified, and several exerkines (such as FGF21, IL-6, and adiponectin) have been exploited therapeutically as exercise mimetics for the treatment of various metabolic and cardiovascular diseases. Recent advances in metagenomics have led to the identification of gut microbiota, a so-called “hidden” metabolic organ, as an additional class of exerkines determining the efficacy of exercise in diabetes prevention, cardiac protection, and exercise performance. Furthermore, multiomics-based studies have shown the feasibility of using baseline exerkine signatures to predict individual responses to exercise with respect to metabolic and cardiorespiratory health. This review aims to explore the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise by fine-tuning inter-organ crosstalk, and discuss the roadmaps for translating exerkine-based discovery into the therapeutic application and personalized medicine in the management of the cardiometabolic disease.
In this review, A. Xu & colleagues describe the molecular pathways whereby exerkine networks mediate the cardiometabolic adaptations to exercise and discuss the potential translation of exerkine-based discovery into therapeutic application and personalized medicine.
Journal Article