Mice lacking NOX2 are hyperphagic and store fat preferentially in the liver

Chronic low-grade inflammation is an important contributor to the development of insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Obesity and high-fat feeding lead to infiltration of immune cells into metabolic tissues, promoting inflammation and insulin resistance. We hypothesized that macrophages from mice lacking NOX2 ( Cybb), an essential component of the NADPH oxidase complex highly expressed in immune cells and associated with their inflammatory response, would be less inflammatory and that these mice would be protected from the development of high-fat-induced insulin resistance. Bone marrow-derived macrophages from NOX2 knockout (NOX2-KO) mice expressed lower levels of inflammatory markers ( Nos2, Il6); however, NOX2-KO mice were hyperphagic and gained more weight than wild-type (WT) mice when fed either a chow or a high-fat (HF) diet. Surprisingly, NOX2-KO mice stored less lipid in epididymal white adipose tissue but more lipid in liver and had higher indexes of liver inflammation and macrophage infiltration than WT mice. Contrary to our hypothesis, HF-fed NOX2-KO mice were hyperinsulinemic and more insulin resistant than HF-fed WT mice, likely as a result of their higher hepatic steatosis and inflammation. In summary, NOX2 depletion promoted hyperphagia, hepatic steatosis, and inflammation with either normal or high-fat feeding, exacerbating insulin resistance. We propose that NOX2 participates in food intake control and lipid distribution in mice.

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IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes.

10.46940/semrj.02.1007 ◽

2021 ◽

pp. 1-13

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Diagnostic Value ◽

Low Grade ◽

Clinical Value ◽

Insulin Resistant ◽

Tnf Α ◽

Low Grade Inflammation

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

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Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011840 ◽

2020 ◽

Vol 295 (31) ◽

pp. 10842-10856 ◽

Cited By ~ 1

Author(s):

Wen Liu ◽

Ye Yin ◽

Meijing Wang ◽

Ting Fan ◽

Yuyu Zhu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Metabolic Disorders ◽

Metabolic Diseases ◽

Low Grade ◽

High Fat ◽

Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

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Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

Physiological Genomics ◽

10.1152/physiolgenomics.00179.2010 ◽

2011 ◽

Vol 43 (8) ◽

pp. 408-416 ◽

Cited By ~ 52

Author(s):

Isabel Rubio-Aliaga ◽

Baukje de Roos ◽

Manuela Sailer ◽

Gerard A. McLoughlin ◽

Mark V. Boekschoten ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Carbon Metabolism ◽

Dietary Intervention ◽

Liver Steatosis ◽

Oxidative Capacity ◽

Blood Cholesterol ◽

High Fat ◽

One Carbon Metabolism ◽

Fat Feeding

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. To characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from C57BL/6J mice obtained from two independent intervention trials. After 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and VLDL, and developed hepatic steatosis. Nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. The hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. Additionally, high choline levels were observed after the high-fat diet. Previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of one-carbon metabolism. The present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. In conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences.

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Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00669.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1590-E1598 ◽

Cited By ~ 62

Author(s):

Stella P. Kim ◽

Karyn J. Catalano ◽

Isabel R. Hsu ◽

Jenny D. Chiu ◽

Joyce M. Richey ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Free Fatty Acids ◽

Postprandial Glucose ◽

High Fat ◽

Glucose Levels ◽

Dog Model ◽

Fat Feeding ◽

Hypercaloric Diet

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.

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TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway

International Journal of Endocrinology ◽

10.1155/2020/6942307 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Junling Yang ◽

Ken-Ichiro Fukuchi

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epididymal Adipose Tissue ◽

Chow Diet ◽

Low Grade ◽

Interferon Β ◽

Tlr Signaling ◽

Normal Chow ◽

Low Grade Inflammation

Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

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Mechanisms Linking Inflammation to Insulin Resistance

International Journal of Endocrinology ◽

10.1155/2015/508409 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 159

Author(s):

Li Chen ◽

Rui Chen ◽

Hua Wang ◽

Fengxia Liang

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Insulin Signaling ◽

Experimental Studies ◽

Low Grade ◽

The World ◽

The Status ◽

Specific Factors ◽

Low Grade Inflammation

Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

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Luteolin Targets the Toll-Like Receptor Signaling Pathway in Prevention of Hepatic and Adipocyte Fibrosis and Insulin Resistance in Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu10101415 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1415 ◽

Cited By ~ 11

Author(s):

Eun-Young Kwon ◽

Myung-Sook Choi

Keyword(s):

Insulin Resistance ◽

Signaling Pathway ◽

Low Grade ◽

Toll Like Receptor ◽

High Fat ◽

Gene Expressions ◽

Tlr Signaling ◽

Low Grade Inflammation ◽

Tlr Signaling Pathway

This study was to investigate the protective role of luteolin on inflammation-mediated metabolic diseases, focusing on the role of luteolin in the modulation of the Toll-like receptor (TLR) signaling pathway. C57BL/6J mice were fed a normal, high-fat, or high-fat + 0.005% (w/w) luteolin diet for 16 weeks. Luteolin improved chronic low-grade inflammation by modulating the TLR signaling pathway, resulting in reduced pro-inflammatory cytokines and macrophage accumulation. A positive relationship was detected between gene expressions of Tlr5, Map2k7, Mapk12, Mapk13, and Mapk9 and lipogenesis in epididymal white adipose tissue (eWAT) of luteolin-treated mice, which was linked to attenuation of hepatic lipotoxicity by increasing free fatty acid (FFA) flux to the WAT. Luteolin prevented fibrosis by decreasing extracellular matrix accumulation and cathepsin gene expressions, while enhancing the hepatic antioxidant system. Emr1 and Ccl7, important markers inducing low-grade inflammation, were affected by advanced age and greater body weight, which were normalized by luteolin treatment. Luteolin improved insulin resistance by normalizing pancreatic islet dysfunction and differentially modulating the plasma glucagon-like peptide-1 and gastric inhibitory polypeptide levels. Our results suggest that luteolin ameliorates diet-induced obesity and its comorbidities. Overall, this study provides novel insights into the effect of luteolin on the links among adiposopathy, insulin resistance, hepatic steatosis, and fibrosis.

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The role of adipose tissue immune cells in obesity and low-grade inflammation

Journal of Endocrinology ◽

10.1530/joe-14-0283 ◽

2014 ◽

Vol 222 (3) ◽

pp. R113-R127 ◽

Cited By ~ 260

Author(s):

Milos Mraz ◽

Martin Haluzik

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Immune Cells ◽

Vascular Complications ◽

Cellular Component ◽

Low Grade ◽

Induced Changes ◽

Low Grade Inflammation

Adipose tissue (AT) lies at the crossroad of nutrition, metabolism, and immunity; AT inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest AT cellular component after adipocytes and as such play important roles in the maintenance of AT homeostasis. Obesity-induced changes in their number and activity result in the activation of local and later systemic inflammatory response, marking the transition from simple adiposity to diseases such as type 2 diabetes mellitus, arterial hypertension, and ischemic heart disease. This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.

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Pomegranate seed oil consumption during a period of high-fat feeding reduces weight gain and reduces type 2 diabetes risk in CD-1 mice

British Journal Of Nutrition ◽

10.1017/s0007114508159001 ◽

2008 ◽

Vol 102 (1) ◽

pp. 54-59 ◽

Cited By ~ 72

Author(s):

Brian K. McFarlin ◽

Kelley A. Strohacker ◽

Michael L. Kueht

Keyword(s):

Body Weight ◽

Weight Gain ◽

Seed Oil ◽

Low Grade ◽

High Fat ◽

Pomegranate Seed Oil ◽

Glucose Sensitivity ◽

Pomegranate Seed ◽

Low Grade Inflammation

The health benefits of pomegranate consumption have recently received considerable scientific focus, with most studies examining fruit and/or juice consumption. Pomegranate seed oil (POMo) is a rich source of 9-cis, 11-trans conjugate linolenic acid (CLA), which may offset the side-effects associated with weight gain. Male, wild-type CD-1 mice were divided into one of three groups (twenty per group): high-fat (HF), HF+seed oil (HF+POMo) or lean control (LN). In HF and HF+POMo, mice were provided access ad libitum to a high-fat chow (60 % of energy from fat). HF+POMo was supplemented with 61·79 mg POMo/d. LN consumed a restricted low-fat (10 % of energy from fat) chow to maintain body weight within 5 % of initial weight. Plasma was analysed for biomarkers associated with cholesterol profile (total cholesterol, HDL and TAG), glucose sensitivity (glucose and insulin), adipose tissue accumulation (leptin and adiponectin) and systemic low-grade inflammation (C-reactive protein and haptoglobin). The key findings of this study were that weight gain was associated with an increase in biomarkers of cholesterol profile, glucose sensitivity, adipose tissue accumulation and systemic low-grade inflammation (P < 0·05). POMo only altered body weight accumulation, final body weight, leptin, adiponectin and insulin (P < 0·05). We found that despite a similar level of energy intake, HF mice had a greater concentration of leptin and a lower concentration of adiponectin compared to HF+POMo mice. POMo intake was associated with an improvement in insulin sensitivity, suggesting that risk of developing type 2 diabetes may have been reduced; however, CVD risk did not change.

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