Mouse models of PPAR-γ deficiency: dissecting PPAR-γ's role in metabolic homoeostasis

2005 ◽  
Vol 33 (5) ◽  
pp. 1053-1058 ◽  
Author(s):  
S.L. Gray ◽  
E. Dalla Nora ◽  
A.J. Vidal-Puig
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Mouse Models ◽  
Murine Models ◽  
Metabolic Processes ◽  
Glucose Homoeostasis ◽  
Ppar Γ ◽  
The Metabolic Syndrome

The identification of humans with mutations in PPAR-γ (peroxisome-proliferator-activated receptor-γ) has underlined its importance in the pathogenesis of the metabolic syndrome. Genetically modified mice provide powerful tools to dissect the mechanisms by which PPAR-γ regulates metabolic processes. Ablation of PPAR-γ in vivo is lethal and thus dissection of PPAR-γ function using mouse models has relied on the development of tissue and isoform-specific ablation and mouse models of human mutations. These models exhibit phenotypes of partial PPAR-γ impairment and are useful to elucidate how PPAR-γ regulates specific metabolic processes. These murine models have confirmed the involvement of PPAR-γ in adipose tissue development, maintenance and distribution. The mechanism involved in PPAR-γ regulation of glucose homoeostasis is obscure as both agonism and partial impairment of PPAR-γ increase insulin sensitivity. While adipose tissue is likely to be the primary target for the insulin-sensitizing effects of PPAR-γ, some murine models suggest PPAR-γ expressed outside adipose tissue may also contribute actively to maintain glucose homoeostasis. Interestingly, mutations in PPAR-γ that cause severe insulin resistance in humans when expressed in mice do not result in insulin insensitivity. However, these murine models can recapitulate the effects in fuel partitioning, post-prandial lipid handling and vasculature dysfunction observed in humans. In summary, these murine models of PPAR-γ have provided useful in vivo systems to dissect the function of PPAR-γ, but additionally have revealed a picture of complexity. These models have confirmed a key role for PPAR-γ in the metabolic syndrome; however, they challenge the concept that insulin resistance is the main factor linking the clinical manifestations of the metabolic syndrome.

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

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
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.

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

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 97 ◽  
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.

scholarly journals Exercise Induced Adipokine Changes and the Metabolic Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
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.

scholarly journals Tissue factor pathways linking obesity and inflammation

2015 ◽  
Vol 35 (03) ◽  
pp. 279-283 ◽  
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.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
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.

scholarly journals Inflammation, obesity, and thrombosis

Blood ◽  
2013 ◽  
Vol 122 (20) ◽  
pp. 3415-3422 ◽  
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.

scholarly journals Visceral obesity, metabolic syndrome, insulin resistance and cancer

2011 ◽  
Vol 71 (1) ◽  
pp. 181-189 ◽  
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.

scholarly journals Mediterranean diet, endothelial function and vascular inflammatory markers

2006 ◽  
Vol 9 (8A) ◽  
pp. 1073-1076 ◽  
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.

scholarly journals A combination of polymorphisms in HSD11B1 associates with in vivo 11β-HSD1 activity and metabolic syndrome in women with and without polycystic ovary syndrome

2011 ◽  
Vol 165 (2) ◽  
pp. 283-292 ◽  
Author(s):  
Alessandra Gambineri ◽  
Federica Tomassoni ◽  
Alessandra Munarini ◽  
Roland H Stimson ◽  
Roberto Mioni ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Mrna Levels ◽  
Nucleotide Polymorphisms ◽  
Ovary Syndrome ◽  
The Metabolic Syndrome ◽  
Expression And Activity

ObjectiveRegeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11β-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11β-HSD1 expression and activity are unknown.MethodsWe explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11β-HSD1 expression and activity in a nested study of 40 women from this cohort.ResultsHSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort=2.77 (95% confidence interval (CI) 1.16–6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1±0.7 nmol/min versus 12.1±1.1, P=0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion.ConclusionsWe conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11β-HSD1 expression and activity, which associates with the metabolic syndrome.

Effect of voluntary exercise on peripheral tissue glucocorticoid receptor content and the expression and activity of 11β-HSD1 in the Syrian hamster

2006 ◽  
Vol 100 (5) ◽  
pp. 1483-1488 ◽  
Author(s):  
Agnes E. Coutinho ◽  
Jonathan E. Campbell ◽  
Sergiu Fediuc ◽  
Michael C. Riddell
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Enzyme Activity ◽  
Adipose Tissue ◽  
Protein Expression ◽  
Aerobic Exercise ◽  
Visceral Adipose Tissue ◽  
The Metabolic Syndrome ◽  
Visceral Adipose

Recent findings indicate that elevated levels of glucocorticoids (GC), governed by the expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and GC receptors (GR), in visceral adipose tissue and skeletal muscle lead to increased insulin resistance and the metabolic syndrome. Paradoxically, evidence indicates that aerobic exercise attenuates the development of the metabolic syndrome even though it stimulates acute increases in circulating GC levels. To investigate the hypothesis that training alters peripheral GC action to maintain insulin sensitivity, young male hamsters were randomly divided into sedentary (S) and trained (T) groups ( n = 8 in each). The T group had 24-h access to running wheels over 4 wk of study. In muscle, T hamsters had lower 11β-HSD1 protein expression (19.2 ± 1.40 vs. 22.2 ± 0.96 optical density, P < 0.05), similar 11β-HSD1 enzyme activity (0.9 ± 0.27% vs. 1.1 ± 0.26), and lower GR protein expression (9.7 ± 1.86 vs. 15.1 ± 1.78 optical density, P < 0.01) than S hamsters. In liver, 11β-HSD1 protein expression tended to be lower in T compared with S (19.2 ± 0.56 vs. 21.4 ± 1.05, P = 0.07), whereas both enzyme activity and GR protein expression were similar. In contrast, visceral adipose tissue contained ∼2.7-fold higher 11β-HSD1 enzyme activity in T compared with S (12.9 ± 3.3 vs. 4.8 ± 1.5% conversion, P < 0.05) but was considerably smaller in mass (0.24 ± 0.02 vs. 0.71 ± 0.06 g). Thus the intracellular adaptation of GC regulators to exercise is tissue specific, resulting in decreases in GC action in skeletal muscle and increases in GC action in visceral fat. These adaptations may have important implications in explaining the protective effects of aerobic exercise on insulin resistance and other symptoms of the metabolic syndrome.

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