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Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 23287

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Prof. Dr. Jean-François Tanti

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Guest Editor

Université Côte D'Azur, INSERM, C3M, Team “Cellular and Molecular Physiopathology of Obesity”, 06204 Nice, France
Interests: obesity, type 2 diabetes; metabolic syndrome; insulin resistance; adipose tissue; insulin signaling; adipose tissue inflammation
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Dear Colleagues,

International Journal of Molecular Sciences (ISSN 1422-0067, IF 4.556) is currently running a Special Issue focused on "Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction". Prof. Jean-François Tanti is serving as Guest Editor for this Issue. Based on your excellent expertise, we would be thrilled if you could submit a paper to this Issue.

Insulin resistance (IR) is defined as the impaired intracellular signaling of endogenous and exogenous insulin. IR is a major key player in those metabolic derangements that characterize pathological conditions (e.g., diabesity and metabolic syndrome). Adipocyte and adipose tissue dysfunction belong to the primary defects in obesity and may link obesity to several health problems, including increased risk of insulin resistance, type 2 diabetes, and fatty liver disease.

This Special Issue focuses on the study of the mechanisms of insulin resistance and adipose tissue dysfunction in obesity and type 2 diabetes. Potential topics include but are not limited to decipher the cellular and molecular mechanisms involved in insulin resistance, and the pathophysiological mechanisms connecting adipose tissue dysfunction to the development of insulin resistance, type 2 diabetes, or fatty liver. We warmly welcome original papers and reviews on this widely discussed topic.

Prof. Dr. Jean-François Tanti
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

insulin resistance
obesity
type 2 diabetes
adipose tissue dysfunction
white adipose tissue (WAT)

Related Special Issue

Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (9 papers)

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Research

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16 pages, 2295 KiB

Open AccessArticle

Improved Adipose Tissue Function after Single Anastomosis Duodeno-Ileal Bypass with Sleeve-Gastrectomy (SADI-S) in Diet-Induced Obesity

by Sara Becerril, Carlota Tuero, Javier A. Cienfuegos, Amaia Rodríguez, Victoria Catalán, Beatriz Ramírez, Víctor Valentí, Rafael Moncada, Xabier Unamuno, Javier Gómez-Ambrosi and Gema Frühbeck

Int. J. Mol. Sci. 2022, 23(19), 11641; https://doi.org/10.3390/ijms231911641 - 1 Oct 2022

Cited by 4 | Viewed by 1532

Abstract

Bariatric surgery has been recognized as the safest and most effective procedure for controlling type 2 diabetes (T2D) and obesity in carefully selected patients. The aim of the present study was to compare the effects of Sleeve Gastrectomy (SG) and Single Anastomosis Duodenoileal Bypass with SG (SADI-S) on the metabolic profile of diet-induced obese rats. A total of 35 four-week-old male Wistar rats were submitted to surgical interventions (sham operation, SG and SADI-S) after 4 months of being fed a high-fat diet. Body weight, metabolic profile and the expression of molecules involved in the control of subcutaneous white (SCWAT), brown (BAT) and beige (BeAT) adipose tissue function were analyzed. SADI-S surgery was associated with significantly decreased amounts of total fat pads (p < 0.001) as well as better control of lipid and glucose metabolism compared to the SG counterparts. An improved expression of molecules involved in fat browning in SCWAT and in the control of BAT and BeAT differentiation and function was observed following SADI-S. Together, our findings provide evidence that the enhanced metabolic improvement and their continued durability after SADI-S compared to SG rely, at least in part, on the improvement of the BeAT phenotype and function. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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12 pages, 1718 KiB

Open AccessArticle

In Vitro and In Vivo Validation of GATA-3 Suppression for Induction of Adipogenesis and Improving Insulin Sensitivity

by Hend Al-Jaber, Nura A. Mohamed, Vijay K. Govindharajan, Samir Taha, Jomon John, Sharique Halim, Maha Alser, Shamma Al-Muraikhy, Najeha Rizwana Anwardeen, Abdelali Agouni, Abdelbary Elhissi, Hamda A. Al-Naemi, Layla Al-Mansoori and Mohamed A. Elrayess

Int. J. Mol. Sci. 2022, 23(19), 11142; https://doi.org/10.3390/ijms231911142 - 22 Sep 2022

Cited by 1 | Viewed by 1605

Abstract

Impaired adipogenesis is associated with the development of insulin resistance and an increased risk of type 2 diabetes (T2D). GATA Binding Protein 3 (GATA3) is implicated in impaired adipogenesis and the onset of insulin resistance. Therefore, we hypothesize that inhibition of GATA3 could promote adipogenesis, restore healthy fat distribution, and enhance insulin signaling. Primary human preadipocytes were treated with GATA3 inhibitor (DNAzyme hgd40). Cell proliferation, adipogenic capacity, gene expression, and insulin signaling were measured following well-established protocols. BALB/c mice were treated with DNAzyme hgd40 over a period of 2 weeks. Liposomes loaded with DNAzyme hgd40, pioglitazone (positive), or vehicle (negative) controls were administered subcutaneously every 2 days at the right thigh. At the end of the study, adipose tissues were collected and weighed from the site of injection, the opposite side, and the omental depot. Antioxidant enzyme (superoxide dismutase and catalase) activities were assessed in animals’ sera, and gene expression was measured using well-established protocols. In vitro GATA3 inhibition induced the adipogenesis of primary human preadipocytes and enhanced insulin signaling through the reduced expression of p70S6K. In vivo GATA3 inhibition promoted adipogenesis at the site of injection and reduced MCP-1 expression. GATA3 inhibition also reduced omental tissue size and PPARγ expression. These findings suggest that modulating GATA3 expression offers a potential therapeutic benefit by correcting impaired adipogenesis, promoting healthy fat distribution, improving insulin sensitivity, and potentially lowering the risk of T2D. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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15 pages, 12670 KiB

Open AccessArticle

Transcriptome Analyses of Adipose Tissue Samples Identify EGFL6 as a Candidate Gene Involved in Obesity-Related Adipose Tissue Dysfunction in Children

by Kathrin Landgraf, Andreas Kühnapfel, Maria Schlanstein, Ronald Biemann, Berend Isermann, Elena Kempf, Holger Kirsten, Markus Scholz and Antje Körner

Int. J. Mol. Sci. 2022, 23(8), 4349; https://doi.org/10.3390/ijms23084349 - 14 Apr 2022

Cited by 4 | Viewed by 1899

Abstract

Obesity develops early in childhood and is accompanied by early signs of adipose tissue (AT) dysfunction and metabolic disease in children. In order to analyse the molecular processes during obesity-related AT accumulation in children, we investigated genome-wide expression profiles in AT samples, isolated adipocytes, and stromal vascular fraction (SVF) cells and assessed their relation to obesity as well as biological and functional AT parameters. We detected alterations in gene expression associated with obesity and related parameters, i.e., BMI SDS, adipocyte size, macrophage infiltration, adiponectin, and/or leptin. While differential gene expression in AT and adipocytes shared an enrichment in metabolic pathways and pathways related to extracellular structural organisation, SVF cells showed an overrepresentation in inflammatory pathways. In adipocytes, we found the strongest positive association for epidermal growth factor-like protein 6 (EGFL6) with adipocyte hypertrophy. EGFL6 was also upregulated during in vitro adipocyte differentiation. In children, EGFL6 expression was positively correlated to parameters of AT dysfunction and metabolic disease such as macrophage infiltration into AT, hs-CRP, leptin levels, and HOMA-IR. In conclusion, we provide evidence for early alterations in AT gene expression related to AT dysfunction in children and identified EGFL6 as potentially being involved in processes underlying the pathogenesis of metabolic disease. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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12 pages, 1656 KiB

Open AccessArticle

Adipsin Serum Concentrations and Adipose Tissue Expression in People with Obesity and Type 2 Diabetes

by Margarete Milek, Yusef Moulla, Matthias Kern, Christine Stroh, Arne Dietrich, Michael R Schön, Daniel Gärtner, Tobias Lohmann, Miriam Dressler, Peter Kovacs, Michael Stumvoll, Matthias Blüher and Esther Guiu-Jurado

Int. J. Mol. Sci. 2022, 23(4), 2222; https://doi.org/10.3390/ijms23042222 - 17 Feb 2022

Cited by 16 | Viewed by 2935

Abstract

(1) Adipsin is an adipokine that may link increased fat mass and adipose tissue dysfunction to obesity-related cardiometabolic diseases. Here, we investigated whether adipsin serum concentrations and adipose tissue (AT) adipsin mRNA expression are related to parameters of AT function, obesity and type 2 diabetes (T2D). (2) Methods: A cohort of 637 individuals with a wide range of age and body weight (Age: 18–85 years; BMI: 19–70 kg/m²) with (n = 237) or without (n = 400) T2D was analyzed for serum adipsin concentrations by ELISA and visceral (VAT) and subcutaneous (SAT) adipsin mRNA expression by RT-PCR. (3) Results: Adipsin serum concentrations were significantly higher in patients with T2D compared to normoglycemic individuals. We found significant positive univariate relationships of adipsin serum concentrations with age (r = 0.282, p < 0.001), body weight (r = 0.264, p < 0.001), fasting plasma glucose (r = 0.136, p = 0.006) and leptin serum concentrations (r = 0.362, p < 0.001). Neither VAT nor SAT adipsin mRNA expression correlated with adipsin serum concentrations after adjusting for age, sex and BMI. Independent of T2D status, we found significantly higher adipsin expression in SAT compared to VAT (4) Conclusions: Our data suggest that adipsin serum concentrations are strongly related to obesity and age. However, neither circulating adipsin nor adipsin AT expression reflects parameters of impaired glucose or lipid metabolism in patients with obesity with or without T2D. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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16 pages, 1865 KiB

Open AccessArticle

Cold Exposure Drives Weight Gain and Adiposity following Chronic Suppression of Brown Adipose Tissue

by Peter Aldiss, Jo E. Lewis, Irene Lupini, Ian Bloor, Ramyar Chavoshinejad, David J. Boocock, Amanda K. Miles, Francis J. P. Ebling, Helen Budge and Michael E. Symonds

Int. J. Mol. Sci. 2022, 23(3), 1869; https://doi.org/10.3390/ijms23031869 - 7 Feb 2022

Cited by 3 | Viewed by 2756

Abstract

Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and β3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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20 pages, 6610 KiB

Open AccessArticle

TNFSF14-Derived Molecules as a Novel Treatment for Obesity and Type 2 Diabetes

by Mark Agostino, Jennifer Rooney, Lakshini Herat, Jennifer Matthews, Allyson Simonds, Susan E. Northfield, Denham Hopper, Markus P. Schlaich and Vance B. Matthews

Int. J. Mol. Sci. 2021, 22(19), 10647; https://doi.org/10.3390/ijms221910647 - 30 Sep 2021

Cited by 1 | Viewed by 2838

Abstract

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with glucose intolerance and insulin resistance, often culminating in Type 2 Diabetes (T2D). Importantly, our team has recently shown that the TNF superfamily (TNFSF) member protein, TNFSF14, has been reported to protect against high fat diet induced obesity and pre-diabetes. We hypothesized that mimics of TNFSF14 may therefore be valuable as anti-diabetic agents. In this study, we use in silico approaches to identify key regions of TNFSF14 responsible for binding to the Herpes virus entry mediator and Lymphotoxin β receptor. In vitro evaluation of a selection of optimised peptides identified six potentially therapeutic TNFSF14 peptides. We report that these peptides increased insulin and fatty acid oxidation signalling in skeletal muscle cells. We then selected one of these promising peptides to determine the efficacy to promote metabolic benefits in vivo. Importantly, the TNFSF14 peptide 7 reduced high fat diet-induced glucose intolerance, insulin resistance and hyperinsulinemia in a mouse model of obesity. In addition, we highlight that the TNFSF14 peptide 7 resulted in a marked reduction in liver steatosis and a concomitant increase in phospho-AMPK signalling. We conclude that TNFSF14-derived molecules positively regulate glucose homeostasis and lipid metabolism and may therefore open a completely novel therapeutic pathway for treating obesity and T2D. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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Review

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13 pages, 1146 KiB

Open AccessReview

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

by Jocelyne Magré and Xavier Prieur

Int. J. Mol. Sci. 2022, 23(2), 740; https://doi.org/10.3390/ijms23020740 - 11 Jan 2022

Cited by 8 | Viewed by 2796

Abstract

Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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12 pages, 692 KiB

Open AccessReview

by Simon Lecoutre, Karine Clément and Isabelle Dugail

Int. J. Mol. Sci. 2022, 23(2), 632; https://doi.org/10.3390/ijms23020632 - 6 Jan 2022

Cited by 4 | Viewed by 2774

Abstract

Adipose tissue dysfunction is strongly associated with obesity and its metabolic complications such as type 2 diabetes and cardiovascular diseases. It is well established that lipid-overloaded adipose tissue produces a large range of secreted molecules that contribute a pro-inflammatory microenvironment which subsequently disseminates towards multi-organ metabolic homeostasis disruption. Besides physiopathological contribution of adipose-derived molecules, a new paradigm is emerging following the discovery that adipocytes have a propensity to extrude damaged mitochondria in the extracellular space, to be conveyed through the blood and taken up by cell acceptors, in a process called intercellular mitochondria transfer. This review summarizes the discovery of mitochondria transfer, its relation to cell quality control systems and recent data that demonstrate its relevant implication in the context of obesity-related adipose tissue dysfunction. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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18 pages, 3898 KiB

Open AccessReview

Adipocyte Biology from the Perspective of In Vivo Research: Review of Key Transcription Factors

by Maria N. Evseeva, Maria S. Balashova, Konstantin Y. Kulebyakin and Yury P. Rubtsov

Int. J. Mol. Sci. 2022, 23(1), 322; https://doi.org/10.3390/ijms23010322 - 28 Dec 2021

Cited by 8 | Viewed by 2979

Abstract

Obesity and type 2 diabetes are both significant contributors to the contemporary pandemic of non-communicable diseases. Both disorders are interconnected and associated with the disruption of normal homeostasis in adipose tissue. Consequently, exploring adipose tissue differentiation and homeostasis is important for the treatment and prevention of metabolic disorders. The aim of this work is to review the consecutive steps in the postnatal development of adipocytes, with a special emphasis on in vivo studies. We gave particular attention to well-known transcription factors that had been thoroughly described in vitro, and showed that the in vivo research of adipogenic differentiation can lead to surprising findings. Full article

(This article belongs to the Special Issue Mechanisms of Insulin Resistance and Adipose Tissue Dysfunction)

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