Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance

ObjectiveHuman white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.DesignMesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR.ResultsWhile mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels.ConclusionMulti-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.

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Adipose-Derived Exosomes as Possible Players in the Development of Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms22147427 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7427

Author(s):

Arkadiusz Żbikowski ◽

Agnieszka Błachnio-Zabielska ◽

Mauro Galli ◽

Piotr Zabielski

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Biologically Active ◽

Whole Body ◽

Secretory Function ◽

Endocrine Organ ◽

Actual Knowledge ◽

Whole Body Metabolism

Adipose tissue (AT) is an endocrine organ involved in the management of energy metabolism via secretion of adipokines, hormones, and recently described secretory microvesicles, i.e., exosomes. Exosomes are rich in possible biologically active factors such as proteins, lipids, and RNA. The secretory function of adipose tissue is affected by pathological processes. One of the most important of these is obesity, which triggers adipose tissue inflammation and adversely affects the release of beneficial adipokines. Both processes may lead to further AT dysfunction, contributing to changes in whole-body metabolism and, subsequently, to insulin resistance. According to recent data, changes within the production, release, and content of exosomes produced by AT may be essential to understand the role of adipose tissue in the development of metabolic disorders. In this review, we summarize actual knowledge about the possible role of AT-derived exosomes in the development of insulin resistance, highlighting methodological challenges and potential gains resulting from exosome studies.

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Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue

GeroScience ◽

10.1007/s11357-021-00387-1 ◽

2021 ◽

Author(s):

Haihui Zhuang ◽

Sira Karvinen ◽

Timo Törmäkangas ◽

Xiaobo Zhang ◽

Xiaowei Ojanen ◽

...

Keyword(s):

Adipose Tissue ◽

Amino Acid ◽

White Adipose Tissue ◽

Aerobic Capacity ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Disease Risk ◽

Whole Body ◽

Whole Body Metabolism

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

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The pathological role of adipose tissue aging in the progression of systemic insulin resistance

Inflammation and Regeneration ◽

10.2492/inflammregen.35.178 ◽

2015 ◽

Vol 35 (4) ◽

pp. 178-184 ◽

Cited By ~ 1

Author(s):

Yohko Yoshida ◽

Ippei Shimizu ◽

Tohru Minamino

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Systemic Insulin Resistance ◽

Tissue Aging

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Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

10.1101/2020.01.13.904953 ◽

2020 ◽

Author(s):

Jessica A. Hall ◽

Deepti Ramachandran ◽

Hyun C. Roh ◽

Joanna R. DiSpirito ◽

Thiago Belchior ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Side Effects ◽

Ectopic Expression ◽

Bmp Signaling ◽

Whole Body ◽

Improve Insulin Sensitivity ◽

Induce Insulin Resistance ◽

Systemic Insulin Resistance

AbstractOvernutrition and obesity promote adipose tissue dysfunction, often leading to systemic insulin resistance. The thiazolidinediones (TZDs) are a potent class of insulin-sensitizing drugs and ligands of PPARγ that improve insulin sensitivity, but their use is limited due to significant side effects. Recently, we demonstrated a mechanism by which TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at Serine 273. However, the role of this modification has not been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ which cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm improved insulin sensitivity, as evidenced by increased whole-body glucose uptake. RNA-seq experiments reveal PPARγ S273 phosphorylation specifically enhances transcription of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find that Gdf3 can impact metabolism by inhibition of BMP signaling. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focuses attention on a putative target, Gdf3.

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An Increase in the Circulating Concentration of Monocyte Chemoattractant Protein-1 Elicits Systemic Insulin Resistance Irrespective of Adipose Tissue Inflammation in Mice

Endocrinology ◽

10.1210/en.2009-0926 ◽

2010 ◽

Vol 151 (3) ◽

pp. 971-979 ◽

Cited By ~ 64

Author(s):

Sanshiro Tateya ◽

Yoshikazu Tamori ◽

Takayuki Kawaguchi ◽

Hajime Kanda ◽

Masato Kasuga

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Macrophage Infiltration ◽

Whole Body ◽

Adipose Tissue Inflammation ◽

Monocyte Chemoattractant Protein 1 ◽

Tissue Inflammation ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Systemic Insulin Resistance

Chronic inflammation in adipose tissue is thought to be important for the development of insulin resistance in obesity. Furthermore, the level of monocyte chemoattractant protein-1 (MCP-1) is increased not only in adipose tissue but also in the circulation in association with obesity. However, it has remained unclear to what extent the increased circulating level of MCP-1 contributes to insulin resistance. We have now examined the relevance of circulating MCP-1 to the development of insulin resistance in mice. The plasma concentration of MCP-1 was increased chronically or acutely in mice to the level observed in obese animals by chronic subcutaneous infusion of recombinant MCP-1 with an osmotic pump or by acute intravenous infusion of MCP-1 with an infusion pump, respectively. Whole-body metabolic parameters as well as inflammatory changes in adipose tissue were examined. A chronic increase in the circulating level of MCP-1 induced insulin resistance, macrophage infiltration into adipose tissue, and an increase in hepatic triacylglycerol content. An acute increase in the circulating MCP-1 concentration also induced insulin resistance but not macrophage infiltration into adipose tissue. In addition, inhibition of signaling by MCP-1 and its receptor CCR2 by administration of a novel CCR2 antagonist ameliorated insulin resistance in mice fed a high-fat diet without affecting macrophage infiltration into adipose tissue. These data indicate that an increase in the concentration of MCP-1 in the circulation is sufficient to induce systemic insulin resistance irrespective of adipose tissue inflammation.

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Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation

Clinical Science ◽

10.1042/cs20120536 ◽

2013 ◽

Vol 124 (8) ◽

pp. 491-507 ◽

Cited By ~ 161

Author(s):

Silvia Bijland ◽

Sarah J. Mancini ◽

Ian P. Salt

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Protein Kinase ◽

Caloric Intake ◽

Whole Body ◽

Acid Oxidation ◽

Metabolic Dysfunction ◽

Nutrient Metabolism ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions.

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OR04-05 MYOD1 Is Associated with Eosinophil-Mediated Browning of Subcutaneous Adipose Tissue

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.918 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Ting Li ◽

Mia Y Masuda ◽

William E LeSuer ◽

Tianna M Stubblefield ◽

James D Hernandez ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Myogenic Differentiation ◽

Body Weight Gain ◽

Whole Body ◽

Interleukin 5 ◽

Subcutaneous White Adipose Tissue ◽

Fat Depots ◽

Whole Body Metabolism

Abstract A novel role for adipose tissue (AT)-resident eosinophils (EOS) in metabolism has been suggested. These data were obtained using genetic animal models with either whole-body overexpression of Interleukin-5 (IL-5Tg) leading to eosinophilia or gene ablation resulting in complete lack of EOS. These models limit the specificity of the findings. We hypothesized that AT-resident EOS play a specific role in whole-body metabolism. To this end, we generated a transgenic mouse model overexpressing human eotaxin-2 (hE2) under the control of a fat-specific aP2 promoter, which would exclusively recruit circulating EOS into AT (hEo2Tg), without any changes in the overall EOS numbers. Compared with wild type (WT) mice, AT-EOS numbers were markedly increased in multiple fat depots from hEo2Tg mice, including subcutaneous white adipose tissue (sWAT). After 12 weeks of high-fat diet (HFD), hEo2Tg mice showed significantly less body weight gain and fat mass compared with WT littermates. These changes were associated with an improvement in glucose tolerance. We also found increased oxygen consumption and heat production in hEo2Tg mice under room temperature conditions. The increased thermogenesis was accompanied with an increased expression of browning genes such as Ucp1, Prdm16, Dio2 in sWAT from hEo2Tg HFD mice. So far, our data suggest that AT-resident EOS promote browning of sWAT. This, in turn, protects our animals against development of HFD-induced obesity and insulin resistance. Next, whole transcriptome mRNA sequencing and bioinformatic analyses were performed and showed a significant increase of myogenic differentiation 1 (Myod1) gene expression in hEo2Tg sWAT mice. This was confirmed by qRT-PCR. Myod1 is a key regulator of skeletal muscle differentiation. Given the shared features between brown fat and skeletal muscle, we speculate that by increasing Myod1 gene expression, (AT)-resident EOS mediate sWAT browning. Additional studies are needed to determine the molecular mechanism(s) underling the regulation of Myod1 gene expression by AT-resident EOS and its effect on sWAT browning.

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ROCK1 isoform-specific deletion reveals a role for diet-induced insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00619.2013 ◽

2014 ◽

Vol 306 (3) ◽

pp. E332-E343 ◽

Cited By ~ 31

Author(s):

Seung-Hwan Lee ◽

Hu Huang ◽

Kangduk Choi ◽

Dae Ho Lee ◽

Jianjian Shi ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Tyrosine Phosphorylation ◽

Metabolic Regulation ◽

Rho Kinase ◽

Inhibitory Effect ◽

Whole Body ◽

Obese Mice ◽

Whole Body Metabolism

Rho kinase (ROCK) isoforms regulate insulin signaling and glucose metabolism negatively or positively in cultured cell lines and skeletal muscle. However, the in vivo function of the ROCK1 isoform in adipose tissue has not been addressed. To determine the specific role of the adipose ROCK1 isoform in the development of insulin resistance and obesity, mice lacking ROCK1 in adipose tissue globally or selectively were studied. Here, we show that insulin's ability to activate IRS-1/PI3K/Akt signaling was greatly enhanced in adipose tissue of ROCK1−/− mice compared with wild-type mice. These effects resulted from the inhibitory effect of ROCK1 on insulin receptor action, as evidenced by the fact that IR tyrosine phosphorylation was abolished in ROCK1−/− MEF cells when ROCK1 was reexpressed. Consistently, adipose-specific disruption of ROCK1 increased IR tyrosine phosphorylation in adipose tissue and modestly improved sensitivity to insulin in obese mice induced by high-fat feeding. This effect is independent of any changes in adiposity, number or size of adipocytes, and metabolic parameters, including glucose, insulin, leptin, and triglyceride levels, demonstrating a minimal effect of adipose ROCK1 on whole body metabolism. Enzymatic activity of ROCK1 in adipose tissue remained ∼50%, which likely originated from the fraction of stromal vascular cells, suggesting involvement of these cells for adipose metabolic regulation. Moreover, ROCK isoform activities were increased in adipose tissue of diet-induced or genetically obese mice. These data suggest that adipose ROCK1 isoform plays an inhibtory role for the regulation of insulin sensitivity in diet-induced obesity in vivo.

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