Adiponectin is an abundant adipokine with pleiotropic protective effects against a cluster of obesity-related cardiometabolic disorders. However, its role in adaptive thermogenesis has scarcely been ...explored. Here we showed that chronic cold exposure led to a markedly elevated production of adiponectin in adipocytes of subcutaneous white adipose tissue (scWAT), which in turn bound to M2 macrophages in the stromal vascular fraction. Chronic cold exposure-induced accumulation of M2 macrophages, activation of beige cells, and thermogenic program were markedly impaired in scWAT of adiponectin knockout (ADN KO) mice, whereas these impairments were reversed by replenishment with adiponectin. Mechanistically, adiponectin was recruited to the cell surface of M2 macrophages via its binding partner T-cadherin and promoted the cell proliferation by activation of Akt, consequently leading to beige cell activation. These findings uncover adiponectin as a key efferent signal for cold-induced adaptive thermogenesis by mediating the crosstalk between adipocytes and M2 macrophages in scWAT.
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•Cold exposure selectively induces adiponectin accumulation in subcutaneous WAT•Adiponectin KO mice are resistant to subcutaneous adipose browning during cold adaptation•Cold-induced M2 macrophage proliferation requires adiponectin in subcutaneous WAT•T-cadherin serves as an anchor for tethering of adiponectin to M2 macrophages
Adiponectin protects against a cluster of obesity-related metabolic complications through multiple mechanisms. This study shows that chronic cold exposure induces adiponectin accumulation in subcutaneous fat, which is indispensable for subcutaneous adipose browning via promoting M2 macrophage proliferation. These findings suggest a key role of adiponectin in mediating crosstalk between innate immunity and adaptive thermogenesis.
Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective ...activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exerciseinduced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.
BACKGROUND—Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both ...peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive.
METHODS AND RESULTS—The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein Emice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.
CONCLUSIONS—FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
Earlier laboratory work by the authors indicated satisfactory performance of glass powder (GLP) in concrete as a pozzolanic material. The powder was manufactured from mixed colour waste packaging ...glass comprising soda-lime glass. In order to investigate the performance of GLP in concrete under field conditions, a field trial was conducted using a 40 MPa concrete mixture, incorporating various proportions of GLP (0%, 20%, and 30%) as cement replacement. Ten mixture formulations, some of which also included sand-size crushed glass aggregate particles, were used to cast ten concrete slabs (1.5
×
2.5
×
0.25 m). Cylinders and prisms were also manufactured from the same batches at the time of casting for the measurement of compressive and splitting tensile strength, flexural strength, shrinkage, expansion, ultrasonic pulse velocity, volume of permeable voids, and chloride permeability. Core samples were drilled from the slabs at various ages for the same tests (except tensile and flexural), as well as for microstructural examination. Results showed that strength gain was slower in GLP-bearing concrete up to 28 days, but at the age of 404 days all the mixtures exceeded the 40 MPa target and achieved about 55 MPa strength.
Mixtures containing GLP also performed satisfactorily with respect to drying shrinkage and alkali reactivity, and there were indications that GLP reduces the chloride ion penetrability of the concrete, thereby reducing the risk of chloride induced corrosion of the steel reinforcement in concrete. The results demonstrated that GLP can be incorporated into 40 MPa concrete at dosage rates of 20–30% to replace cement without harmful effects. The use of GLP provides for considerable value-added utilisation of waste glass in concrete and significant reductions in the production of green house gases by the cement industry.
Neutrophils in type 1 diabetes Huang, Juan; Xiao, Yang; Xu, Aimin ...
Journal of diabetes investigation,
September 2016, Letnik:
7, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin‐producing pancreatic β‐cells triggered by genetic and ...environmental factors. The initiation and progression of the disease involves a complicated interaction between β‐cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil‐derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell–cell interactions with other immune and non‐immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes.
Type 1 diabetes (T1D) is an autoimmune disease involved in complex interactions between β cells and cells of both the innate and adaptive immune systems. Increasing studies in recent years indicated that neutrophils play an important part in the initiation and pathogenesis of autoimmune T1D. Our manuscript will discuss the relationship between neutrophils and autoimmune T1D to better understand the roles of these cells in the initiation and development of T1D.
Summary
Fibroblast growth factor 21 (FGF21), a metabolic hormone predominantly produced by the liver, is also expressed in adipocytes and the pancreas. It regulates glucose and lipid metabolism ...through pleiotropic actions in these tissues and the brain. In mice, fasting leads to increased PPAR‐α mediated expression of FGF21 in the liver where it stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis, as an adaptive response to fasting and starvation. In the fed state, FGF21 acts as an autocrine factor in adipocytes, regulating the activity of PPAR‐γ through a feed‐forward loop mechanism. Administration of recombinant FGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects. Such findings highlight the potential role of FGF21 as a therapeutic agent for obesity‐related medical conditions. However, in human studies, high circulating FGF21 levels are found in obesity and its related cardiometabolic disorders including the metabolic syndrome, type 2 diabetes, non‐alcoholic fatty liver disease and coronary artery disease. These findings may indicate the presence of FGF21 resistance or compensatory responses to the underlying metabolic stress, and imply the need for supraphysiological doses of FGF21 to achieve therapeutic efficacy. On the other hand, serum FGF21 has been implicated as a potential biomarker for the early detection of these cardiometabolic disorders. This review summarizes recent developments in the understanding of FGF21, from physiological and clinical perspectives.
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on regulating glucose and lipid homeostasis and insulin sensitivity. However, the mechanisms underlying the ...metabolic actions of FGF21 remain unknown. Here we show that the insulin-sensitizing adipokine adiponectin is a downstream effector of FGF21. Treatments with FGF21 enhanced both expression and secretion of adiponectin in adipocytes, thereby increasing serum levels of adiponectin in mice. Adiponectin knockout mice were refractory to several therapeutic benefits of FGF21, including alleviation of obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis. Furthermore, the effects of FGF21 on attenuation of obesity-induced impairment in insulin signaling in liver and skeletal muscle were abrogated in adiponectin knockout mice, whereas FGF21-mediated activation of ERK1/ERK2 in adipose tissues remained unaffected. Therefore, adiponectin couples FGF21 actions in local adipocytes to liver and skeletal muscle, thereby mediating the systemic effects of FGF21 on energy metabolism and insulin sensitivity.
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•FGF21 induces expression and secretion of adiponectin in adipocytes•Therapeutic administration of FGF21 raises circulating FGF21 in mice•Adiponectin is obligatory for the glucose-lowering and insulin-sensitizing effects of FGF21•Adiponectin couples FGF21 actions from adipocytes to liver and skeletal muscle
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.
Exercise promotes adipose remodeling and improves obesity-induced metabolic disorders through mechanisms that remain obscure. Here, we identify the FGF21 signaling in adipose tissues as an obligatory ...molecular transducer of exercise conferring its metabolic benefits in mice. Long-term high fat diet-fed obese mice exhibit compromised effects of exogenous FGF21 on alleviation of hyperglycemia, hyperinsulinemia, and hyperlipidemia, accompanied with markedly reduced expression of FGF receptor-1 (FGFR1) and β-Klotho (KLB) in adipose tissues. These impairments in obese mice are reversed by treadmill exercise. Mice lacking adipose KLB are refractory to exercise-induced alleviation of insulin resistance, glucose dysregulation, and ectopic lipid accumulation due to diminished adiponectin production, excessive fatty acid release, and enhanced adipose inflammation. Mechanistically, exercise induces the adipose expression of FGFR1 and KLB via peroxisome proliferator-activated receptor-gamma-mediated transcriptional activation. Thus, exercise sensitizes FGF21 actions in adipose tissues, which in turn sends humoral signals to coordinate multi-organ crosstalk for maintaining metabolic homeostasis.
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•Long-term high fat diet impairs FGF21 sensitivity in adipose tissues•Exercise reverses diet-induced adipose FGF21 resistance by inducing FGFR1 and KLB•Mice lacking adipose KLB are refractory to the metabolic benefits of exercise•Exercise-induced adipose FGFR1 and KLB depends on PPARγ
Geng et al. identify FGF21 signaling in adipose tissues as an obligatory molecular transducer of exercise, conferring its metabolic benefits on systemic glucose and lipid metabolism and insulin sensitivity. Exercise sensitizes FGF21 actions in adipose tissues, which in turns sends humoral signals to coordinate multi-organ crosstalk for maintaining metabolic homeostasis.
Hepatic gluconeogenesis is a main source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast ...growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.
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