Adipose tissue, skeletal muscle, and insulin resistance across ethnicities—systems biology in action

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

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Mitochondria-associated ER membranes in glucose homeostasis and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00271.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. E1053-E1060

Author(s):

Logan K. Townsend ◽

Henver S. Brunetta ◽

Marcelo A. S. Mori

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Endoplasmic Reticulum ◽

Adipose Tissue ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Glucose Homeostasis ◽

Calcium Homeostasis ◽

Adenine Nucleotides ◽

Current Controversy

Obesity and insulin resistance (IR) are associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction in several tissues. Although for many years mitochondrial and ER function were studied separately, these organelles also connect to produce interdependent functions. Communication occurs at mitochondria-associated ER membranes (MAMs) and regulates lipid and calcium homeostasis, apoptosis, and the exchange of adenine nucleotides, among other things. Recent evidence suggests that MAMs contribute to organelle, cellular, and systemic metabolism. In obesity and IR models, metabolic tissues such as the liver, skeletal muscle, pancreas, and adipose tissue present alterations in MAM structure or function. The purpose of this mini review is to highlight the MAM disruptions that occur in each tissue during obesity and IR and its relationship with glucose homeostasis and IR. We also discuss the current controversy that surrounds MAMs’ role in the development of IR.

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The Adipokines in Cancer Cachexia

International Journal of Molecular Sciences ◽

10.3390/ijms21144860 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4860 ◽

Cited By ~ 1

Author(s):

Michele Mannelli ◽

Tania Gamberi ◽

Francesca Magherini ◽

Tania Fiaschi

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Therapeutic Strategies ◽

Skeletal Muscle Wasting ◽

Circulating Levels

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

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MECHANISMS IN ENDOCRINOLOGY: Skeletal muscle lipotoxicity in insulin resistance and type 2 diabetes: a causal mechanism or an innocent bystander?

Acta Endocrinologica ◽

10.1530/eje-16-0488 ◽

2017 ◽

Vol 176 (2) ◽

pp. R67-R78 ◽

Cited By ~ 37

Author(s):

Charlotte Brøns ◽

Louise Groth Grunnet

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Cellular Localization ◽

Future Research ◽

Causal Mechanism ◽

Increased Risk ◽

Adipose Tissue Expandability

Dysfunctional adipose tissue is associated with an increased risk of developing type 2 diabetes (T2D). One characteristic of a dysfunctional adipose tissue is the reduced expandability of the subcutaneous adipose tissue leading to ectopic storage of fat in organs and/or tissues involved in the pathogenesis of T2D that can cause lipotoxicity. Accumulation of lipids in the skeletal muscle is associated with insulin resistance, but the majority of previous studies do not prove any causality. Most studies agree that it is not the intramuscular lipids per se that causes insulin resistance, but rather lipid intermediates such as diacylglycerols, fatty acyl-CoAs and ceramides and that it is the localization, composition and turnover of these intermediates that play an important role in the development of insulin resistance and T2D. Adipose tissue is a more active tissue than previously thought, and future research should thus aim at examining the exact role of lipid composition, cellular localization and the dynamics of lipid turnover on the development of insulin resistance. In addition, ectopic storage of fat has differential impact on various organs in different phenotypes at risk of developing T2D; thus, understanding how adipogenesis is regulated, the interference with metabolic outcomes and what determines the capacity of adipose tissue expandability in distinct population groups is necessary. This study is a review of the current literature on the adipose tissue expandability hypothesis and how the following ectopic lipid accumulation as a consequence of a limited adipose tissue expandability may be associated with insulin resistance in muscle and liver.

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4126 Intermuscular adipose tissue secretes pro-inflammatory, extracellular matrix, and lipid signals related to insulin resistance and type 2 diabetes

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.73 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 9-9

Author(s):

Darcy Kahn ◽

Simona Zarini ◽

Emily Macias ◽

Amanda Garfield ◽

Kathleen Harrison ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Extracellular Matrix ◽

Adipose Tissue ◽

Functional Role ◽

Vastus Lateralis ◽

Laparoscopic Bariatric Surgery ◽

Intermuscular Adipose Tissue

OBJECTIVES/GOALS: Intermuscular adipose tissue (IMAT) has been associated with insulin resistance and type 2 diabetes, yet mechanistic studies addressing the functional role of IMAT are lacking. The aim of this work was to identify novel mechanisms by which IMAT may directly impact skeletal muscle metabolism. METHODS/STUDY POPULATION: We quantified the secretome of IMAT, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) to determine if there are differences between depots in the secretion of cytokines, eicosanoids, FFAs and proteins that influence metabolic function. SAT and VAT biopsies from patients undergoing laparoscopic bariatric surgery and IMAT extracted from vastus lateralis biopsies of individuals with Obesity were cultured for 48 hours in DMEM, and the conditioned media was analyzed using nanoflow HPLC-MS, multiplex ELISAs and LC/MS/MS for proteins, cytokines and eicosanoids/FFA, respectively. RESULTS/ANTICIPATED RESULTS: IMAT secretion of various extracellular matrix proteins (fibrinogen-β, collagenV1a3, fibronectin) was significantly different than VAT and SAT. Pro-inflammatory cytokine secretion of IFNg, TNFa, IL-8 and IL-13 from IMAT was higher than VAT and significantly higher than SAT (p < 0.05). IMAT secretes significantly more pro-inflammatory eicosanoids TXB2 and PGE2 than VAT (p = 0.02, 0.05) and SAT (p = 0.01, 0.04). IMAT and VAT have significantly greater basal lipolysis assessed by FFA release rates compared to SAT (p = 0.01, 0.04). DISCUSSION/SIGNIFICANCE OF IMPACT: These data begin to characterize the disparate secretory properties of SAT, VAT and IMAT and suggest a metabolically adverse secretome of IMAT, that due to its proximity to skeletal muscle may play an important functional role in the pathogenesis of insulin resistance and type 2 diabetes.

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Collagen 24 α1 Is Increased in Insulin-Resistant Skeletal Muscle and Adipose Tissue

International Journal of Molecular Sciences ◽

10.3390/ijms21165738 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5738

Author(s):

Xiong Weng ◽

De Lin ◽

Jeffrey T. J. Huang ◽

Roland H. Stimson ◽

David H. Wasserman ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Insulin Resistant ◽

Global View ◽

Novel Association ◽

Visceral Adipose ◽

Subcutaneous Adipose

Aberrant extracellular matrix (ECM) remodelling in muscle, liver and adipose tissue is a key characteristic of obesity and insulin resistance. Despite its emerging importance, the effective ECM targets remain largely undefined due to limitations of current approaches. Here, we developed a novel ECM-specific mass spectrometry-based proteomics technique to characterise the global view of the ECM changes in the skeletal muscle and liver of mice after high fat (HF) diet feeding. We identified distinct signatures of HF-induced protein changes between skeletal muscle and liver where the ECM remodelling was more prominent in the muscle than liver. In particular, most muscle collagen isoforms were increased by HF diet feeding whereas the liver collagens were differentially but moderately affected highlighting a different role of the ECM remodelling in different tissues of obesity. Moreover, we identified a novel association between collagen 24α1 and insulin resistance in the skeletal muscle. Using quantitative gene expression analysis, we extended this association to the white adipose tissue. Importantly, collagen 24α1 mRNA was increased in the visceral adipose tissue, but not the subcutaneous adipose tissue of obese diabetic subjects compared to lean controls, implying a potential pathogenic role of collagen 24α1 in obesity and type 2 diabetes.

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Reversion of insulin resistance in the rat during late pregnancy by 72-h glucose infusion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1995.269.5.e858 ◽

1995 ◽

Vol 269 (5) ◽

pp. E858-E863 ◽

Cited By ~ 15

Author(s):

P. Ramos ◽

E. Herrera

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Glucose Utilization ◽

Late Pregnancy ◽

Glucose Infusion ◽

Continuous Intravenous Infusion ◽

Pregnant Rats ◽

Bidistilled Water ◽

Insulin Responsiveness

To determine whether sustained exaggerated hyperinsulinemia in normoglycemic rats modifies insulin responsiveness during pregnancy, 17-day-pregnant and virgin rats were studied after receiving a continuous intravenous infusion (35 ml/day) of either 50% glucose or bidistilled water (controls) for 72 h. Plasma glucose was unchanged, whereas insulin was highly increased, and the effect was more marked in pregnant than in virgin rats. Insulin responsiveness, estimated under the hyperinsulinemic euglycemic clamp with 0.8 IU insulin.h-1.kg-1, was lower in control pregnant than in virgin rats but higher in pregnant than in virgin rats in those that had received the glucose infusion. The tissue glucose utilization metabolic index (GUI) was estimated with 2-deoxy-D-[1-3H]glucose in the clamped rats. The GUI was lower in heart, white- and red-fiber skeletal muscle, and adipose tissue in control pregnant rats than in control virgin rats, and, although the glucose infusion decreased that index in both red-fiber muscle and adipose tissue in virgin rats, glucose increased the index in red-fiber muscle in pregnant rats to the level found in virgin controls. Results therefore show that, when unaccompanied by hypoglycemia, sustained exaggerated hyperinsulinemia decreases insulin responsiveness in virgin rats but reverts insulin resistance in late-pregnant rats.

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