1222-P: Adipose Tissue Antilipolytic Insulin Sensitivity Protects against Whole-Body Insulin Resistance and Lowers Acylcarnitine Accumulation in Adults with Obesity

<a>Objective</a>: The rs738409(G) single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene associates with increased risk and progression of nonalcoholic fatty liver disease (NAFLD). As the recently-described severe insulin-resistant diabetes (SIRD) cluster specifically relates to NAFLD, this study examined whether this SNP differently associates with hepatic lipid content (HCL) and insulin sensitivity in recent-onset diabetes mellitus. Research Design and Methods: A total of 917 participants of the German Diabetes Study underwent genotyping, hyperinsulinemic-euglycemic clamps with stable isotopic tracer dilution and magnetic resonance spectroscopy. Results: The G allele associated positively with HCL (β=0.36, p<0.01), independent of age, sex and BMI across the whole cohort, but not in the individual clusters. SIRD exhibited lowest whole-body insulin sensitivity compared to severe insulin-deficient (SIDD), moderate obesity-related (MOD), moderate age-related (MARD) and severe autoimmune diabetes clusters (SAID; all p<0.001). Interestingly, SIRD presented with higher prevalence of the rs738409(G) SNP compared to other clusters and the glucose-tolerant control group (p<0.05). HCL was higher in SIRD [13.6 (5.8;19.1)%] compared to MOD [6.4 (2.1;12.4)%, p<0.05], MARD [3.0 (1.0;7.9)%, p<0.001], SAID [0.4 (0.0;1.5)%, p<0.001] and the glucose tolerant group [0.9 (0.4;4.9)%, p<0.001]. Although the PNPLA3 polymorphism did not directly associate with whole-body insulin sensitivity in SIRD, the G allele carriers had higher circulating free fatty acid concentrations and greater adipose-tissue insulin resistance compared to non-carriers (both p<0.001). Conclusions: Members of the severe insulin resistant diabetes cluster are more frequently carriers of the rs738409(G) variant. The SNP-associated adipose-tissue insulin resistance and excessive lipolysis may contribute to their NAFLD.

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Early postnatal oestradiol exposure causes insulin resistance and signs of inflammation in circulation and skeletal muscle

Journal of Endocrinology ◽

10.1677/joe-08-0534 ◽

2009 ◽

Vol 201 (1) ◽

pp. 49-58 ◽

Cited By ~ 11

Author(s):

Camilla Alexanderson ◽

Elias Eriksson ◽

Elisabet Stener-Victorin ◽

Malin Lönn ◽

Agneta Holmäng

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Uncoupling Protein ◽

Female Rats ◽

Whole Body ◽

Low Grade ◽

Expression Of Genes ◽

Genes Encoding

Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.

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Dynamic Strength Training Improves Insulin Sensitivity without Altering Plasma Levels and Gene Expression of Adipokines in Subcutaneous Adipose Tissue in Obese Men

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-0382 ◽

2006 ◽

Vol 91 (12) ◽

pp. 5107-5112 ◽

Cited By ~ 94

Author(s):

E. Klimcakova ◽

J. Polak ◽

C. Moro ◽

J. Hejnova ◽

M. Majercik ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Strength Training ◽

Plasma Levels ◽

Dynamic Strength ◽

Whole Body ◽

Obese Subjects ◽

Dynamic Strength Training

Abstract Context: Obesity is characterized by a low-grade inflammatory state, which could play a role in insulin resistance. Dynamic strength training improves insulin sensitivity. Objective: The objective of this study was to investigate, in obese subjects, whether the insulin sensitizing effect of dynamic strength training is associated with changes in plasma levels and gene expression of adipokines potentially involved in the development of insulin resistance. Design: Twelve obese male subjects were investigated before and at the end of 3 months of dynamic strength training. Insulin sensitivity was evaluated using euglycemic-hyperinsulinemic clamp. Blood samples and needle biopsy samples of sc abdominal adipose tissue were obtained. The plasma levels and adipose tissue mRNA levels of adiponectin, leptin, IL-1β, IL-6, and TNF-α were determined. Results: The training induced an increase in the whole-body glucose disposal rate by 24% (P = 0.04). The body weight was not altered during the training. Plasma levels of leptin decreased during the training (16.6 ± 6.3 vs. 13.1 ± 5.7 ng/ml) by 21% (P < 0.02), whereas no change in plasma levels of other adipokines and C-reactive protein was observed. Gene expression of the investigated adipokines was not changed in sc adipose tissue during the training. Conclusions: In obese subjects, the dynamic strength training resulted in an improvement of whole-body insulin sensitivity. The increase in insulin sensitivity was not associated with training-induced modifications of plasma levels or adipose tissue gene expression of adipokines supposedly involved in the development of insulin resistance.

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Glycemic index differences of high-fat diets modulate primarily lipid metabolism in murine adipose tissue

Physiological Genomics ◽

10.1152/physiolgenomics.00042.2011 ◽

2011 ◽

Vol 43 (15) ◽

pp. 942-949 ◽

Cited By ~ 10

Author(s):

Evert M. van Schothorst ◽

Annelies Bunschoten ◽

Eline Verlinde ◽

Patrick Schrauwen ◽

Jaap Keijer

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glycemic Index ◽

Molecular Mechanisms ◽

Serum Levels ◽

Whole Body ◽

High Fat ◽

Beneficial Effects ◽

Ppar Γ

A low vs. high glycemic index of a high-fat (HF) diet (LGI and HGI, respectively) significantly retarded adverse health effects in adult male C57BL/6J mice, as shown recently (Van Schothorst EM, Bunschoten A, Schrauwen P, Mensink RP, Keijer J. FASEB J 23: 1092–1101, 2009). The LGI diet enhanced whole body insulin sensitivity and repressed HF diet-induced body and white adipose tissue (WAT) weight gain, resulting in significantly reduced serum leptin and resistin levels and increased adiponectin levels. We questioned how WAT is modulated and characterized the molecular mechanisms underlying the glycemic index-mediated effects using whole genome microarrays. This showed that the LGI diet mainly exerts its beneficial effects via substrate metabolism, especially fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression, in line with lower WAT mass. An important transcription factor showing enhanced expression is PPAR-γ. Furthermore, serum levels of triglycerides, total cholesterol, and HDL- and LDL-cholesterol were all significantly reduced by LGI diet, and simultaneously muscle insulin sensitivity was significantly increased as analyzed by protein kinase B/Akt phosphorylation. Cumulatively, even though these mice were fed an HF diet, the LGI diet induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones to treat insulin resistance and statins for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans.

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STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

10.2337/figshare.12985514 ◽

2020 ◽

Author(s):

Ada Admin ◽

Aaron R. Cox ◽

Natasha Chernis ◽

David A. Bader ◽

Pradip K Saha ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Tca Cycle ◽

Whole Body ◽

Low Grade ◽

Type I ◽

Obese Mice ◽

Fat Cell ◽

Relationship Of

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

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STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

10.1101/2020.04.10.036053 ◽

2020 ◽

Cited By ~ 1

Author(s):

Aaron R. Cox ◽

Natasha Chernis ◽

David A. Bader ◽

Pradip K Saha ◽

Peter M. Masschelin ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Tca Cycle ◽

Whole Body ◽

Low Grade ◽

Type I ◽

Obese Mice ◽

Diet Induced Obesity ◽

Relationship Of

AbstractObesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 fKO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with subcutaneous WAT hyperplasia. STAT1 fKO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNγ) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

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Influence of TNF-α and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00471.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. E108-E114 ◽

Cited By ~ 76

Author(s):

Rikke Krogh-Madsen ◽

Peter Plomgaard ◽

Kirsten Møller ◽

Bettina Mittendorfer ◽

Bente K. Pedersen

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Muscle Tissue ◽

Plasma Concentrations ◽

Whole Body ◽

Euglycemic Hyperinsulinemic Clamp ◽

Tnf Α

Inflammation is associated with insulin resistance, and both tumor necrosis factor (TNF)-α and interleukin (IL)-6 may affect glucose uptake. TNF induces insulin resistance, whereas the role of IL-6 is controversial. High plasma levels of IL-18 are associated with insulin resistance in epidemiological studies. We investigated the effects of TNF and IL-6 on IL-18 gene expression in skeletal muscle and adipose tissue. Nine human volunteers underwent three consecutive interventions, receiving an infusion of recombinant human (rh)IL-6, rhTNF, and saline. Insulin sensitivity was assessed by measurement of whole body glucose uptake with the stable isotope tracer method during a euglycemic hyperinsulinemic clamp (20 mU·min−1·kg−1), which was initiated 1 h after the IL-6-TNF-saline infusion. Cytokine responses were measured in plasma, muscle, and fat biopsies. Plasma concentrations of TNF and IL-6 increased 10- and 38-fold, respectively, during the cytokine infusions. Whole body insulin-mediated glucose uptake was significantly reduced during TNF infusion but remained unchanged during IL-6 infusion. TNF induced IL-18 gene expression in muscle tissue, but not in adipose tissue, whereas IL-6 infusion had no effect on IL-18 gene expression in either tissue. We conclude that TNF-induced insulin resistance of whole body glucose uptake is associated with increased IL-18 gene expression in muscle tissue, indicating that TNF and IL-18 interact, and both may have important regulatory roles in the pathogenesis of insulin resistance.

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Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass

Scientific Reports ◽

10.1038/s41598-021-94189-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Julie Abildgaard ◽

Thorkil Ploug ◽

Elaf Al-Saoudi ◽

Thomas Wagner ◽

Carsten Thomsen ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Visceral Fat ◽

Subcutaneous Adipose Tissue ◽

Immune Cell ◽

Whole Body ◽

Metabolic Dysfunction ◽

Adipocyte Hypertrophy ◽

Subcutaneous Adipose

AbstractMenopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

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Prevalence and features of impaired glucose tolerance in young underweight Japanese women

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab052 ◽

2021 ◽

Author(s):

Motonori Sato ◽

Yoshifumi Tamura ◽

Takashi Nakagata ◽

Yuki Someya ◽

Hideyoshi Kaga ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Japanese Women ◽

Normal Weight ◽

Whole Body ◽

Insulinogenic Index ◽

Matsuda Index ◽

Young Japanese Women

Abstract Objective In Japan, while it is known that underweight women over the age 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we aimed to investigate the prevalence and features of impaired glucose tolerance (IGT) in young Japanese underweight women. Designs and Methods In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. Results The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2 and Matsuda index, and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. Conclusions The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

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STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

10.2337/figshare.12985514.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Aaron R. Cox ◽

Natasha Chernis ◽

David A. Bader ◽

Pradip K Saha ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Tca Cycle ◽

Whole Body ◽

Low Grade ◽

Type I ◽

Obese Mice ◽

Fat Cell ◽

Relationship Of

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function and accelerated TCA cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.

Download Full-text