Depletion of CD40 on CD11c+ cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH

Abstract The co-stimulatory CD40-CD40L dyad plays a central role in fine-tuning immune reactions, including obesity-induced inflammation. Genetic ablation of CD40L reduced adipose tissue inflammation, while absence of CD40 resulted in aggravated metabolic dysfunction in mice. During obesity, CD40 expressing CD11c+ dendritic cells (DC) and macrophages accumulate in adipose tissue and liver. We investigated the role of CD40+CD11c+ cells in the metabolic syndrome and nonalcoholic steatohepatitis (NASH). DC-CD40-ko mice (CD40fl/flCD11ccre) mice were subjected to obesity or NASH. Obesity and insulin resistance were induced by feeding mice a 54% high fat diet (HFD). NASH was induced by feeding mice a diet containing 40% fat, 20% fructose and 2% cholesterol. CD40fl/flCD11ccre mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40fl/flCD11ccre mice had higher plasma and hepatic cholesterol levels and developed profound liver steatosis. Overall, regulatory T cell numbers were decreased in these mice. In NASH, absence of CD40 on CD11c+ cells slightly decreased liver inflammation but did not affect liver lipid accumulation. Our experiments suggest that CD40 expressing CD11c+ cells can act as a double-edged sword: CD40 expressing CD11c+ cells contribute to liver inflammation during NASH but are protective against the metabolic syndrome via induction of regulatory T cells.

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Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2017-0371 ◽

2018 ◽

Vol 96 (1) ◽

pp. 97-102 ◽

Cited By ~ 1

Author(s):

Hanin Aburasayn ◽

Rami Al Batran ◽

Keshav Gopal ◽

Malak Almutairi ◽

Amina Eshreif ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Female Offspring ◽

Metabolic Dysfunction ◽

Insulin Resistant ◽

The Metabolic Syndrome ◽

Rate Versus ◽

Increased Risk ◽

Study Completion ◽

Reduced Rate

The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers.

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The Relationship between Epicardial Adipose Tissue Thickness and Serum Interleukin-17a Level in Patients with Isolated Metabolic Syndrome

Biomolecules ◽

10.3390/biom9030097 ◽

2019 ◽

Vol 9 (3) ◽

pp. 97 ◽

Cited By ~ 4

Author(s):

Esra Demir ◽

Nazmiye Harmankaya ◽

İrem Kıraç Utku ◽

Gönül Açıksarı ◽

Turgut Uygun ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Epicardial Adipose Tissue ◽

Control Group ◽

Model Assessment ◽

Tissue Thickness ◽

The Metabolic Syndrome ◽

Epicardial Adipose Tissue Thickness ◽

The Relationship

In this study, it was aimed to investigate the relationship between the epicardial adipose tissue thickness (EATT) and serum IL-17A level insulin resistance in metabolic syndrome patients. This study enrolled a total of 160 subjects, of whom 80 were consecutive patients who applied to our outpatient clinic and were diagnosed with metabolic syndrome, and the other 80 were consecutive patients who were part of the control group with similar age and demographics in whom the metabolic syndrome was excluded. The metabolic syndrome diagnosis was made according to International Diabetes Federation (IDF)-2005 criteria. EATT was measured with transthoracic echocardiography (TTE) in the subjects. IL-17A serum levels were determined using the ELISA method. Fasting blood glucose, HDL, triglyceride, and fasting insulin levels were significantly higher in the metabolic syndrome group compared to the control group. In addition, the metabolic syndrome group had significantly higher high-sensitivity C-reactive protein (hs-CRP) and Homeostatic Model Assessment Insulin Resistance (HOMA-IR) levels than the control group. Similarly, serum IL-17A levels were significantly elevated in the metabolic syndrome group compared to the control group statistically (p < 0.001). As well, EATT was higher in the metabolic syndrome than the control group. Conclusion: By virtue of their proinflammatory properties, EATT and IL-17 may play an important role in the pathogenesis of the metabolic syndrome.

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Exercise Induced Adipokine Changes and the Metabolic Syndrome

Journal of Diabetes Research ◽

10.1155/2014/726861 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 71

Author(s):

Saeid Golbidi ◽

Ismail Laher

Keyword(s):

Physical Activity ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

The Body ◽

Beneficial Effects ◽

The Metabolic Syndrome ◽

Before And After ◽

Inflammatory State ◽

Exercise Induced

The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is characterized by the deposition of adipose tissue in various parts of the body; it is now evident that adipose tissue also acts as an endocrine organ capable of secreting many cytokines that are though to be involved in the pathophysiology of obesity, insulin resistance, and metabolic syndrome. Adipokines, or adipose tissue-derived proteins, play a pivotal role in this scenario. Increased secretion of proinflammatory adipokines leads to a chronic inflammatory state that is accompanied by insulin resistance and glucose intolerance. Lifestyle change in terms of increased physical activity and exercise is the best nonpharmacological treatment for obesity since these can reduce insulin resistance, counteract the inflammatory state, and improve the lipid profile. There is growing evidence that exercise exerts its beneficial effects partly through alterations in the adipokine profile; that is, exercise increases secretion of anti-inflammatory adipokines and reduces proinflammatory cytokines. In this paper we briefly describe the pathophysiologic role of four important adipokines (adiponectin, leptin, TNF-α, and IL-6) in the metabolic syndrome and review some of the clinical trials that monitored these adipokines as a clinical outcome before and after exercise.

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Tissue factor pathways linking obesity and inflammation

Hämostaseologie ◽

10.5482/hamo-14-11-0068 ◽

2015 ◽

Vol 35 (03) ◽

pp. 279-283 ◽

Cited By ~ 13

Author(s):

F. Samad ◽

W. Ruf

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Tissue Factor ◽

Clinical Markers ◽

Protease Activated Receptors ◽

Diet Induced Obesity ◽

The Metabolic Syndrome ◽

Amp Activated Protein Kinase ◽

G Protein Coupled

SummaryObesity is a major cause for a spectrum of metabolic syndrome-related diseases that include insulin resistance, type 2 diabetes, and steatosis of the liver. Inflammation elicited by macrophages and other immune cells contributes to the metabolic abnormalities in obesity. In addition, coagulation activation following tissue factor (TF) upregulation in adipose tissue is frequently found in obese patients and particularly associated with diabetic complications. Genetic and pharmacological evidence indicates that TF makes significant contributions to the development of the metabolic syndrome by signaling through G protein-coupled protease activated receptors (PARs). Adipocyte TF-PAR2 signaling contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas hematopoietic TF-PAR2 signaling is a major cause for adipose tissue inflammation, hepatic steatosis and inflammation, as well as insulin resistance. In the liver of mice on a high fat diet, PAR2 signaling increases transcripts of key regulators of gluconeogenesis, lipogenesis and inflammatory cytokines. Increased markers of hepatic gluconeogenesis correlate with decreased activation of AMP-activated protein kinase (AMPK), a known regulator of these pathways and a target for PAR2 signaling. Clinical markers of a TF-induced prothrombotic state may thus indicate a risk in obese patient for developing complications of the metabolic syndrome.

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The Polycystic Ovary Syndrome and the Metabolic Syndrome: A Possible Chronobiotic-Cytoprotective Adjuvant Therapy

International Journal of Endocrinology ◽

10.1155/2018/1349868 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 9

Author(s):

Eduardo Spinedi ◽

Daniel P. Cardinali

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Polycystic Ovary Syndrome ◽

White Adipose Tissue ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

The Metabolic Syndrome ◽

Obstructive Sleep ◽

The Impact

Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8–10% of women worldwide at reproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or without compensatory hyperinsulinemia, and hyperandrogenism are very common features of the polycystic ovary syndrome phenotype. Dysfunctional white adipose tissue has been identified as a major contributing factor for insulin resistance in polycystic ovary syndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndrome development. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting that some polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbances have been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovary syndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closely related to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. This review article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) the impact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy to improve the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatonin receptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and to increased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycystic ovary syndrome and could be applied from the initial phases of patients’ treatment.

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Inflammation, obesity, and thrombosis

Blood ◽

10.1182/blood-2013-05-427708 ◽

2013 ◽

Vol 122 (20) ◽

pp. 3415-3422 ◽

Cited By ~ 170

Author(s):

Fahumiya Samad ◽

Wolfram Ruf

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Plasminogen Activator Inhibitor ◽

Epidemiological Studies ◽

Clinical Markers ◽

Plasminogen Activator Inhibitor 1 ◽

Protease Activated Receptors ◽

The Metabolic Syndrome

Abstract Clinical and epidemiological studies support a connection between obesity and thrombosis, involving elevated expression of the prothrombotic molecules plasminogen activator inhibitor-1 and tissue factor (TF) and increased platelet activation. Cardiovascular diseases and metabolic syndrome–associated disorders, including obesity, insulin resistance, type 2 diabetes, and hepatic steatosis, involve inflammation elicited by infiltration and activation of immune cells, particularly macrophages, into adipose tissue. Although TF has been clearly linked to a procoagulant state in obesity, emerging genetic and pharmacologic evidence indicate that TF signaling via G protein-coupled protease-activated receptors (PAR2, PAR1) additionally drives multiple aspects of the metabolic syndrome. TF–PAR2 signaling in adipocytes contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas TF–PAR2 signaling in hematopoietic and myeloid cells drives adipose tissue inflammation, hepatic steatosis, and insulin resistance. TF-initiated coagulation leading to thrombin–PAR1 signaling also contributes to diet-induced hepatic steatosis and inflammation in certain models. Thus, in obese patients, clinical markers of a prothrombotic state may indicate a risk for the development of complications of the metabolic syndrome. Furthermore, TF-induced signaling could provide new therapeutic targets for drug development at the intersection between obesity, inflammation, and thrombosis.

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ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Mediators of Inflammation ◽

10.1155/2017/7281986 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Lakshini Weerasekera ◽

Caroline Rudnicka ◽

Qing-Xiang Sang ◽

Joanne E. Curran ◽

Matthew P. Johnson ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Mouse Model ◽

White Adipose Tissue ◽

Mononuclear Cells ◽

Western World ◽

Diet Induced Obesity ◽

The Metabolic Syndrome

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

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Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

10.21203/rs.3.rs-57182/v1 ◽

2020 ◽

Author(s):

Vanessa Pellegrinelli ◽

Segio Rodriguez-Cuenca ◽

Christine Rouault ◽

Hanna Schilbert ◽

Sam Virtue ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Inflammatory Responses ◽

Vital Role ◽

Metabolic Dysfunction ◽

Collagen Turnover ◽

Metabolic Complications ◽

Genetic Ablation ◽

Metabolic Dysfunctions ◽

Inflammatory Macrophages

Abstract Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

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Visceral obesity, metabolic syndrome, insulin resistance and cancer

Proceedings of The Nutrition Society ◽

10.1017/s002966511100320x ◽

2011 ◽

Vol 71 (1) ◽

pp. 181-189 ◽

Cited By ~ 116

Author(s):

Suzanne L. Doyle ◽

Claire L. Donohoe ◽

Joanne Lysaght ◽

John V. Reynolds

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Systemic Inflammation ◽

Visceral Adipose Tissue ◽

Tumour Progression ◽

Visceral Adiposity ◽

Oesophageal Adenocarcinoma ◽

The Metabolic Syndrome ◽

Visceral Adipose

This paper presents emerging evidence linking visceral adiposity and the metabolic syndrome (MetSyn) with carcinogenesis. The link between obesity and cancer has been clearly identified in a multitude of robust epidemiological studies. Research is now focusing on the role of visceral adipose tissue in carcinogenesis; as it is recognised as an important metabolic tissue that secretes factors that systemically alter the immunological, metabolic and endocrine milieu. Excess visceral adipose tissue gives rise to a state of chronic systemic inflammation with associated insulin resistance and dysmetabolism, collectively known as the MetSyn. Prospective cohort studies have shown associations between visceral adiposity, the MetSyn and increased risk of breast cancer, colorectal cancer and oesophageal adenocarcinoma. Furthermore, visceral adiposity and the MetSyn have been associated with increased tumour progression and reduced survival. The mechanisms by which visceral adiposity and the MetSyn are thought to promote tumorigenesis are manifold. These include alterations in adipokine secretion and cell signalling pathways. In addition, hyperinsulinaemia, subsequent insulin resistance and stimulation of the insulin-like growth factor-1 axis have all been linked with visceral adiposity and promote tumour progression. Furthermore, the abundance of inflammatory cells in visceral adipose tissue, including macrophages and T-cells, create systemic inflammation and a pro-tumorigenic environment. It is clear from current research that excess visceral adiposity and associated dysmetabolism play a central role in the pathogenesis of certain cancer types. Further research is required to elucidate the exact mechanisms at play and identify potential targets for intervention.

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Mediterranean diet, endothelial function and vascular inflammatory markers

Public Health Nutrition ◽

10.1017/s1368980007668529 ◽

2006 ◽

Vol 9 (8A) ◽

pp. 1073-1076 ◽

Cited By ~ 58

Author(s):

Katherine Esposito ◽

Miryam Ciotola ◽

Dario Giugliano

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Endothelial Dysfunction ◽

Low Grade ◽

The Metabolic Syndrome ◽

Inflammatory State ◽

Triggering Factor ◽

Inflammatory Milieu ◽

Visceral Adipose

AbstractObjectivesTo discuss present knowledge about the relation between adipose tissue, inflammation and the Mediterranean-style diet.DesignReview of the literature and personal perspectives.Setting and resultsRecent studies indicate that adipose tissue is an endocrine organ producing numerous proteins, collectively referred to as adipokines, with broad biological activity, which play an important autocrine role in obesity-associated complications. Adipose tissue in general and visceral fat in particular are thought to be key regulators of inflammation which is heavily involved in the onset and development of atherothrombotic disease. Moreover, chronic inflammation may also represent a triggering factor in the origin of the metabolic syndrome and type 2 diabetes mellitus. An increased release of proinflammatory adipokines from the visceral adipose tissue, associated with a reduced secretion of anti-inflammatory adipokines and cytokines, could determine a low-grade chronic inflammatory state which might play a role in the future development of the metabolic syndrome, diabetes and atherosclerosis through both insulin resistance and endothelial dysfunction. Interventions aimed at decreasing weight loss and improving adherence to a Mediterranean-style diet in people with obesity or metabolic syndrome decrease the inflammatory milieu and ameliorate both insulin resistance and endothelial dysfunction.ConclusionsAppropriate dietary patterns, as those associated with the eating model of Mediterranean-type diets, represent therapeutic strategies to reduce inflammation and the associated metabolic and cardiovascular risk.

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