Etiology Of Insulin Resistance Research Articles

Insulin resistance in chronic kidney disease: a systematic review.

Insulin resistance (IR) is an early metabolic alteration in chronic kidney disease (CKD) patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the end stage of kidney failure. The skeletal muscle represents the primary site of IR in CKD, and alterations at sites beyond the insulin receptor are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier and faster but may not be adequate in patients with CKD because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity because this technique allows a direct measure of skeletal muscle sensitivity to insulin. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances that are prominent in renal diseases, including physical inactivity, chronic inflammation, oxidative stress, vitamin D deficiency, metabolic acidosis, anemia, adipokine derangement, and altered gut microbiome. IR contributes to the progression of renal disease by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention, and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction, and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.

Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance.

Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance.

Animal models of insulin resistance: A review.

Insulin resistance can be seen as a molecular and genetic mystery, with a role in the pathophysiology of type 2 diabetes mellitus. It is a basis for a number of chronic diseases like hypertension, dyslipidemia, glucose intolerance, coronary heart disease, cerebral vascular disease along with T2DM, thus the key is to cure and prevent insulin resistance. Critical perspicacity into the etiology of insulin resistance have been gained by the use of animal models where insulin action has been modulated by various transgenic and non-transgenic models which is not possible in human studies. The following review comprises the pathophysiology involved in insulin resistance, various factors causing insulin resistance, their screening and various genetic and non-genetic animal models highlighting the pathological and metabolic characteristics of each.

Metabolomic Response of Skeletal Muscle to Aerobic Exercise Training in Insulin Resistant Type 1 Diabetic Rats.

The etiology of insulin resistance in Type 1 Diabetes (T1D) is unknown, however it affects approximately 20% of T1D patients. Intramyocellular lipids (IMCL) have been identified as a mechanism of insulin resistance. We examined skeletal muscle of T1D rats to determine if alterations in lipid metabolism were evident and whether aerobic exercise training improves IMCL and insulin resistance. To do so, 48 male Sprague-Dawley rats were divided into control (C), sedentary diabetes (D) and diabetes exercise (DX) groups. Following multiple low-dose Streptozotocin (STZ) injections (20 mg/kg), glycemia (9–15 mM) was maintained using insulin treatment. DX were treadmill trained at high intensity (~75% V02max; 5days/week) for 10 weeks. The results demonstrate that D exhibited insulin resistance compared with C and DX, indicated by decreased glucose infusion rate during a hyperinsulinemic-euglycemic clamp (p < 0.05). There were no differences between C and DX, suggesting that exercise improved insulin resistance (p < 0.05). Metabolomics analysis revealed a significant shift in lipid metabolism whereby notable fatty acid metabolites (arachidonic acid, palmitic acid and several polyunsaturated fatty acids) were significantly elevated in D compared to C and DX. Based on the intermediates observed, insulin resistance in T1D is characterized by an insulin-desensitizing intramyocellular fatty acid metabolite profile that is ameliorated with exercise training.

Obesity-related insulin resistance: implications for the surgical patient.

In healthy surgical patients, preoperative fasting and major surgery induce development of insulin resistance (IR). IR can be present in up to 41% of obese patients without diabetes and this can rise in the postoperative period, leading to an increased risk of postoperative complications. Inflammation is implicated in the aetiology of IR. This review examines obesity-associated IR and its implications for the surgical patient. Searches of the Medline and Science Citation Index databases were performed using various key words in combinations with the Boolean operators AND, OR and NOT. Key journals, nutrition and metabolism textbooks and the reference lists of key articles were also hand searched. Adipose tissue has been identified as an active endocrine organ and the chemokines secreted as a result of macrophage infiltration have a role in the pathogenesis of IR. Visceral adipose tissue appears to be the most metabolically active, although results across studies are not consistent. Results from animal and human studies often provide conflicting results, which has rendered the pursuit of a common mechanistic pathway challenging. Obesity-associated IR appears, in part, to be related to inflammatory changes associated with increased adiposity. Postoperatively, the surgical patient is in a proinflammatory state, so this finding has important implications for the obese surgical patient.

Mitochondrial Function and Diabetes: Consequences for Skeletal and Cardiac Muscle Metabolism.

An early hallmark in the development of type 2 diabetes is the resistance to the effect of insulin in skeletal muscle and in the heart. Since mitochondrial function was found to be diminished in patients with type 2 diabetes, it was suggested that this defect might be involved in the etiology of insulin resistance. Although several hypotheses were suggested, yet unclear is the mechanistic link between these two phenomena. Herein, we review the evidence for disturbances in mitochondrial function in skeletal muscle and the heart in the diabetic state. Also the mechanisms involved in improving mitochondrial function are considered and, whenever possible, human data is cited. Reported evidence shows that interventions that improve skeletal muscle mitochondrial function also improve insulin sensitivity in humans. In the heart, available data from animal studies suggests that enhancement of mitochondrial function can reverse aging-induced changes in heart function, and can be protective against cardiomyopathy and heart failure. Mitochondria and their functions can be targeted with the aim of improving skeletal muscle insulin sensitivity and cardiac function. However, human clinical intervention studies are needed to fully substantiate the potential of mitochondria as a target to prevent cardiometabolic disease.

Targeting Mitochondrial Biogenesis to Treat Insulin Resistance

Over the last century, the prevalence of type 2 diabetes has dramatically increased, reaching the status of epidemic. Because insulin resistance is considered the primary cause of type 2 diabetes, the identification of the cellular processes and gene networks that lead to an impairment of insulin action in target tissues is of crucial importance for the development of new drugs and therapeutic strategies to treat or prevent the disease. Numerous studies in humans and animal models have shown that insulin resistance is frequently associated to reduced mitochondrial mass or oxidative function in insulin sensitive tissues, leading to the hypothesis that defective overall mitochondrial activity could play a relevant role in the etiology of insulin resistance and, therefore, in type 2 diabetes. Although the causal relationship between mitochondrial dysfunction and insulin resistance is still controversial, numerous studies show that lifestyle or pharmacological interventions that improve insulin sensitivity are frequently associated to an increase in mitochondrial function and whole body energy expenditure. Therefore, increasing mitochondrial mass and oxidative activity is viewed as a potential therapeutic approach for the treatment of insulin resistance. Here, we review the current knowledge on the role of mitochondria in the pathogenesis of insulin resistance and discuss some of the potential therapeutic strategies and pharmacological targets for the treatment of insulin resistance based on the activation of mitochondrial biogenesis and the increase of mitochondrial oxidative function.

Chemical-genetic induction of Malonyl-CoA decarboxylase in skeletal muscle.

BackgroundDefects in skeletal muscle fatty acid oxidation have been implicated in the etiology of insulin resistance. Malonyl-CoA decarboxylase (MCD) has been a target of investigation because it reduces the concentration of malonyl-CoA, a metabolite that inhibits fatty acid oxidation. The in vivo role of muscle MCD expression in the development of insulin resistance remains unclear.ResultsTo determine the role of MCD in skeletal muscle of diet induced obese and insulin resistant mouse models we generated mice expressing a muscle specific transgene for MCD (Tg-fMCDSkel) stabilized posttranslationally by the small molecule, Shield-1. Tg-fMCDSkel and control mice were placed on either a high fat or low fat diet for 3.5 months. Obese and glucose intolerant as well as lean control Tg-fMCDSkel and nontransgenic control mice were treated with Shield-1 and changes in their body weight and insulin sensitivity were determined upon induction of MCD. Inducing MCD activity >5-fold in skeletal muscle over two weeks did not alter body weight or glucose intolerance of obese mice. MCD induction further potentiated the defects in insulin signaling of obese mice. In addition, key enzymes in fatty acid oxidation were suppressed following MCD induction.ConclusionAcute induction of MCD in the skeletal muscle of obese and glucose intolerant mice did not improve body weight and decreased insulin sensitivity compared to obese nontransgenic controls. Induction of MCD in skeletal muscle resulted in a suppression of mitochondrial oxidative genes suggesting a redundant and metabolite driven regulation of gene expression.

The effects of thiamine treatment on pre-diabetic versus overt diabetic rat hearts: Role of non-oxidative glucose pathways

The etiology of insulin resistance is complex and multi-faceted. For example, metabolic perturbations associated with obesity and/or increased consumption of energy-dense foodstuffs, coupled with a sedentary lifestyle may fuel this process [1,2]. Nutrient excess, and more specifically excursions of acute hyperglycemia, can play a significant role in the development of insulin resistance and the associated onset of cardiovascular diseases [3,4].

UEG Week Vienna 2014 cutting edge symposium: Today's Science, Tomorrow's Medicine session features the immune system - a driving force in digestive health and disease.

UEG Week Vienna 2014 cutting edge symposium: Today's Science, Tomorrow's Medicine session features the immune system - a driving force in digestive health and disease.

Downregulation of IRS-1 in adipose tissue of offspring of obese mice is programmed cell-autonomously through post-transcriptional mechanisms.

We determined the effects of maternal diet-induced obesity on offspring adipose tissue insulin signalling and miRNA expression in the aetiology of insulin resistance in later life. Although body composition and glucose tolerance of 8-week-old male offspring of obese dams were not dysregulated, serum insulin was significantly (p<0.05) elevated. Key insulin signalling proteins in adipose tissue were down-regulated, including the insulin receptor, catalytic (p110β) and regulatory (p85α) subunits of PI3K as well as AKT1 and 2 (all p<0.05). The largest reduction observed was in IRS-1 protein (p<0.001), which was regulated post-transcriptionally. Concurrently, miR-126, which targets IRS-1, was up-regulated (p<0.05). These two features were maintained in isolated primary pre-adipocytes and differentiated adipocytes in-vitro. We have therefore established that maternal diet-induced obesity programs adipose tissue insulin resistance. We hypothesise that maintenance of the phenotype in-vitro strongly suggests that this mechanism is cell autonomous and may drive insulin resistance in later life.

Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only (P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity (P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

Carotid Body Denervation Prevents the Development of Insulin Resistance and Hypertension Induced by Hypercaloric Diets

Increased sympathetic activity is a well-known pathophysiological mechanism in insulin resistance (IR) and hypertension (HT). The carotid bodies (CB) are peripheral chemoreceptors that classically respond to hypoxia by increasing chemosensory activity in the carotid sinus nerve (CSN), causing hyperventilation and activation of the sympathoadrenal system. Besides its role in the control of ventilation, the CB has been proposed as a glucose sensor implicated in the control of energy homeostasis. However, to date no studies have anticipated its role in the development of IR. Herein, we propose that CB overstimulation is involved in the etiology of IR and HT, core metabolic and hemodynamic disturbances of highly prevalent diseases like the metabolic syndrome, type 2 diabetes, and obstructive sleep apnoea. We demonstrate that CB activity is increased in IR animal models and that CSN resection prevents CB overactivation and diet-induced IR and HT. Moreover, we show that insulin triggers CB, highlighting a new role for hyperinsulinemia as a stimulus for CB overactivation. We propose that CB is implicated in the pathogenesis of metabolic and hemodynamic disturbances through sympathoadrenal overactivation and may represent a novel therapeutic target in these diseases.

Plasma Branch Chain and Aromatic Amino Acid Levels are Associated with Insulin Resistance in Nonalcoholic Fatty Liver Disease (NAFLD)

Elevated plasma branch chain (BCAA) and aromatic (AAA) amino acids have been implicated in the etiology of insulin resistance (IR) and also in future diabetes. We tested the relationship of BCAA/AAA with metabolic parameters of insulin sensitivity and liver fat (LFAT), in patients with NAFLD. Fifty patients, 7 without NAFLD and 43 with NAFLD as determined by MRS (LFAT ≥5.5%) were studied. We measured: 1) Total body fat by DXA; 2) Hepatic IR index [HIRi] and muscle (Rd) insulin sensitivity; 3) Plasma BCAA/AAA by mass spectrometry. Patients with NAFLD had severe hepatic and muscle IR (by the euglycemic insulin clamp). Plasma BCAA/AAA were already ~20% higher (p&lt;0.05) with an increase in LFAT from 5.5 to 10%, compared to patients without NAFLD. A further increase in LFAT (from 11% to &gt;;50%) only resulted in a modest additional elevation in plasma BCAA/AAA. Despite this, LFAT showed correlations with leucine (r=0.39), isoleucine (r=0.44), valine (r=0.42), and tyrosine (r=0.50, all p&lt;0.01). Increased plasma BCAA/AAA correlated strongly with liver (HIRi) and muscle IR, especially under insulin‐stimulation: leucine (r=0.69/−0.58), isoleucine (r=0.65/−0.55), valine (r=0.57/−0.52) and tyrosine (r=0.68/−0.46), respectively (all p&lt;0.001). In conclusion, plasma BCAA/AAA are elevated in patients with NAFLD and are closely associated with hepatic and muscle IR. Tissue specific alterations in BCAA/AAA metabolism may contribute to the severity of IR in NAFLD. Support: Burroughs Wellcome Fund and the American Diabetes Association (K.C.)

A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice

The aetiology of insulin resistance is still an enigma. Mouse models are frequently employed to study the underlying pathology. The most commonly used methods to monitor insulin resistance are the HOMA-IR, glucose or insulin tolerance tests and the hyperinsulinemic euglycaemic clamp (HIEC). Unfortunately, these tests disturb steady state glucose metabolism. Here we describe a method in which blood glucose kinetics can be determined in fasted mice without noticeably perturbing glucose homeostasis. The method involves an intraperitoneal injection of a trace amount of [6,6-(2)H2]glucose and can be performed repeatedly in individual mice. The validity and performance of this novel method was tested in mice fed on chow or high-fat diet for a period of five weeks. After administering the mice with [6,6-(2)H2]glucose, decay of the glucose label was followed in small volumes of blood collected by tail tip bleeding during a 90-minute period. The total amount of blood collected was less than 120 μL. This novel approach confirmed in detail the well-known increase in insulin resistance induced by a high-fat diet. The mice showed reduced glucose clearance rate, and reduced hepatic and peripheral insulin sensitivity. To compensate for this insulin resistance, β-cell function was slightly increased. We conclude that this refinement of existing methods enables detailed information of glucose homeostasis in mice. Insulin resistance can be accurately determined while mechanistic insight is obtained in underlying pathology. In addition, this novel approach reduces the number of mice needed for longitudinal studies of insulin sensitivity and glucose metabolism.

The effects of TNF‐alpha and Ceramide on Insulin Receptor signaling and its localization to Caveolae in C2C12 Myocytes

TNF‐α and ceramide are associated with the etiology of insulin resistance. There is evidence for the involvement of caveolae membrane rafts in the modulation of insulin signaling and glucose uptake. Thus, we propose to elucidate the signaling mechanisms by which TNF‐α and ceramide induce insulin resistance in C2C12 myocytes and the role of caveolins in the organization of this pathway within the membrane. We hypothesized that exposure of C2C12 myocytes to TNF‐α and ceramide will result in altered insulin signaling, decreased glucose uptake, and translocation of the insulin signaling cascade away from caveolae. C2C12 myocytes were treated with TNF‐α, ceramide, and insulin, individually and in combination. The treated cells were subjected to Western blot analysis for insulin receptor‐β (IR‐β), phosphorylated IR (p‐IR), Protein Kinase B (PKB or Akt), phosphorylated Akt (p‐Akt), Cav‐3, Glut‐4, and actin (as loading control). The total protein expression of IR, Cav‐3, and Glut‐4 was unaltered with treatment. However, there was a significant increase in the total expression of Akt in cells treated with TNF‐α. In addition, there was a significantly higher activation of Akt and IR in cells treated with TNF‐α after 48 hours exposure. This data suggests that the effect of TNF‐α on insulin signaling in a result of a cross‐talk mechanism. This data will further the identification of novel signaling mechanisms leading to insulin resistance as a prerequisite to improved diagnosis and therapeutic treatments for diabetes.

Abstract P433: Associations of CD4+ T Lymphocyte Subpopulations with Insulin Levels and Type 2 Diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA)

Background: Chronic inflammation is a characteristic feature of insulin resistance (IR) and type 2 diabetes (T2D). Elevated circulating levels of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), are predictive of disease onset suggesting contributions of adaptive immune responses in the etiology of T2D. Therefore, we hypothesized that increased populations of CD4 + effector/memory (EM) and T helper 1 (Th1) cells, and decreased populations of CD4 + naive cells, would be associated with high insulin levels and an increased risk of T2D. Methods: T cell subpopulations were measured in peripheral blood by flow cytometry, using CD4 + CD45RO + , CD4 + CD45RA + , CD4 + IFN-γ + , and CD4 + IL4 + as markers for EM, naive, Th1, and Th2 cells, respectively. Data for each subpopulation were reported as a percent of total CD4 + cells. Associations were explored with components of the metabolic syndrome, insulin measures, and type 2 diabetes in a random subset ( n =917) of the Multi-Ethnic Study of Atherosclerosis (MESA). T2D was defined by fasting glucose ≥126 mg/dL or use of glucose-lowering medications ( n =151). All variables were measured at Exam 4 (2005-2007), except for insulin which was measured at Exam 5 (2010-2012), and inflammatory biomarkers measured at Exam 1 (2000-2002). Results: Naive cells were inversely, and EM, and Th1 cells positively associated with insulin levels in minimally adjusted (age, gender, race/ethnicity) linear regression analyses that modeled insulin as the dependent variable. No significant associations were observed with Th2 cells. After further adjustment for the metabolic- and cardiovascular disease (CVD)-related variables, waist circumference, systolic blood pressure (BP), use of anti-hypertensive medication, smoking status, total- and HDL-cholesterol, use of lipid lowering medication, and IL-6, the association of insulin with Th1 cells, but not naive or EM cells, remained significant [β= 6.4 mU/L (± 1.69 mU/L) per standard deviation (SD) increase in Th1 cells (8.3%); p=0.0002]. Adjusting for body mass index (BMI) in place of waist circumference did not alter interpretation of the results. In standardized logistic regression models including cell subpopulations and metabolic- and CVD-related variables (as above) as the independent variables, naive cells were inversely associated with prevalent T2D [odds ratio (95% confidence interval)=0.78 (0.61-0.99)]. Conclusion: Increased populations of Th1 cells and decreased populations of CD4 + naive cells are associated with insulin levels and T2D, respectively, independent of measures of adiposity. These cross-sectional findings suggest that excess immune activation and Th1 bias, as reflected by these differences, may contribute to the etiology of IR and T2D.

Of mice and men (and muscle mitochondria)

Of mice and men (and muscle mitochondria)

Metabolic Disturbance in PCOS: Clinical and Molecular Effects on Skeletal Muscle Tissue

Polycystic ovary syndrome is a complex hormonal disorder affecting the reproductive and metabolic systems with signs and symptoms related to anovulation, infertility, menstrual irregularity and hirsutism. Skeletal muscle plays a vital role in the peripheral glucose uptake. Since PCOS is associated with defects in the activation and pancreatic dysfunction of β-cell insulin, it is important to understand the molecular mechanisms of insulin resistance in PCOS. Studies of muscle tissue in patients with PCOS reveal defects in insulin signaling. Muscle biopsies performed during euglycemic hyperinsulinemic clamp showed a significant reduction in glucose uptake, and insulin-mediated IRS-2 increased significantly in skeletal muscle. It is recognized that the etiology of insulin resistance in PCOS is likely to be as complicated as in type 2 diabetes and it has an important role in metabolic and reproductive phenotypes of this syndrome. Thus, further evidence regarding the effect of nonpharmacological approaches (e.g., physical exercise) in skeletal muscle of women with PCOS is required for a better therapeutic approach in the management of various metabolic and reproductive problems caused by this syndrome.

IL-6 Is Not Necessary for the Regulation of Adipose Tissue Mitochondrial Content

BackgroundAdipose tissue mitochondria have been implicated as key mediators of systemic metabolism. We have shown that IL-6 activates AMPK, a mediator of mitochondrial biogenesis, in adipose tissue; however, IL-6−/− mice fed a high fat diet have been reported to develop insulin resistance. These findings suggest that IL-6 may control adipose tissue mitochondrial content in vivo, and that reductions in adipose tissue mitochondria may be causally linked to the development of insulin resistance in IL-6−/− mice fed a high fat diet. On the other hand, IL-6 has been implicated as a negative regulator of insulin action. Given these discrepancies the purpose of the present investigation was to further evaluate the relationship between IL-6, adipose tissue mitochondrial content and whole body insulin action.Methodology and Principal FindingsIn cultured epididymal mouse adipose tissue IL-6 (75 ng/ml) induced the expression of the transcriptional co-activators PGC-1α and PRC, reputed mediators of mitochondrial biogenesis. Similarly, IL-6 increased the expression of COXIV and CPT-1. These effects were absent in cultured subcutaneous adipose tissue and were associated with lower levels of GP130 and IL-6 receptor alpha protein content. Markers of mitochondrial content were intact in adipose tissue from chow fed IL-6−/− mice. When fed a high fat diet IL-6−/− mice were more glucose and insulin intolerant than controls fed the same diet; however this was not explained by decreases in adipose tissue mitochondrial content or respiration.Conclusions and SignificanceOur findings demonstrate depot-specific differences in the ability of IL-6 to induce PGC-1α and mitochondrial enzymes and demonstrate that IL-6 is not necessary for the maintenance of adipose tissue mitochondrial content in vivo. Moreover, reductions in adipose tissue mitochondria do not explain the greater insulin resistance in IL-6−/− mice fed a high fat diet. These results question the role of adipose tissue mitochondrial dysfunction in the etiology of insulin resistance.