Associations between Fatty Acid-Binding Protein 4–A Proinflammatory Adipokine and Insulin Resistance, Gestational and Type 2 Diabetes Mellitus

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Abstract

There is ample scientific evidence to suggest a link between the fatty acid-binding protein 4 (FABP4) and insulin resistance, gestational (GDM), and type 2 (T2DM) diabetes mellitus. This novel proinflammatory adipokine is engaged in the regulation of lipid metabolism at the cellular level. The molecule takes part in lipid oxidation, the regulation of transcription as well as the synthesis of membranes. An involvement of FABP4 in the pathogenesis of obesity and insulin resistance seems to be mediated via FABP4-dependent peroxisome proliferator-activated receptor γ (PPARγ) inhibition. A considerable number of studies have shown that plasma concentrations of FABP4 is increased in obesity and T2DM, and that circulating FABP4 levels are correlated with certain clinical parameters, such as body mass index, insulin resistance, and dyslipidemia. Since plasma-circulating FABP4 has the potential to modulate the function of several types of cells, it appears to be of extreme interest to try to develop potential therapeutic strategies targeting the pathogenesis of metabolic diseases in this respect. In this manuscript, representing a detailed review of the literature on FABP4 and the abovementioned metabolic disorders, various mechanisms of the interaction of FABP4 with insulin signaling pathways are thoroughly discussed. Clinical aspects of insulin resistance in diabetic patients, including women diagnosed with GDM, are analyzed as well.

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Most cited references 83

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Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

Justin Odegaard, Roberto Ricardo-Gonzalez, Matthew H Goforth … (2007)

Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.

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A central role for inflammation in the pathogenesis of diabetic retinopathy.

Antonia Joussen, Vassiliki Poulaki, Minh Ly Le … (2004)

Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.

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An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).

J Lehmann, L B Moore, T A Smith-Oliver … (1995)

Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.

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Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 08 March 2019

Publication date Collection: March 2019

Volume: 8

Issue: 3

Electronic Location Identifier: 227

Affiliations

[1 ]Chair and Department of Internal Medicine, Medical University of Lublin, 20-081 Lublin, Poland; marcin.trojnar@ 123456umlub.pl (M.T.); jerzy.mosiewicz@ 123456umlub.pl (J.M.)

[2 ]Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-090 Lublin, Poland; jolapatro@ 123456wp.pl (J.P.-M.); b.leszczynska@ 123456umlub.pl (B.L.-G.)

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[* ]Correspondence: zkimber@ 123456poczta.onet.pl ; Tel.: +48-81-7244-769 (Ż.K.-T.)

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Jolanta Patro-Małysza https://orcid.org/0000-0002-4118-7698

Żaneta Kimber-Trojnar https://orcid.org/0000-0001-7295-0409

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Publisher ID: cells-08-00227

DOI: 10.3390/cells8030227

PMC ID: 6468522

PubMed ID: 30857223

SO-VID: 57f61e57-a1f1-4fd5-95ae-d601e484b28b

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Associations between Fatty Acid-Binding Protein 4–A Proinflammatory Adipokine and Insulin Resistance, Gestational and Type 2 Diabetes Mellitus

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Karger: Nutrition and Dietetics

Most cited references 83

Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

A central role for inflammation in the pathogenesis of diabetic retinopathy.

An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).

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