The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance
Introduction
The prevalence of obesity has reached epidemic proportions globally, with more than 1 billion adults being overweight, of whom at least 300 million are obese [1]. This poses a major public health issue, since obesity is a major contributor to the global burden of chronic diseases. Abdominal obesity plays a central role in the metabolic syndrome and is a major risk factor for chronic diseases, such as type 2 diabetes mellitus and cardiovascular disease [2]. Not surprisingly, the prevalence of obesity-related disorders is also increasing at an alarming rate. In fact, obesity is the most important risk factor for the development of type 2 diabetes [3], which is further stressed by the fact that obesity, body fat distribution and weight gain throughout adulthood are important predictors of diabetes [3], [4]. Furthermore, adiposity is associated with insulin resistance even over relatively normal ranges of body fatness. Although the relationship between obesity, insulin resistance and cardiovascular disease is well-recognized [5], the mechanisms involved remain relatively poorly understood.
Adipose tissue dysfunction plays a crucial role in the pathogenesis of obesity-related insulin resistance and type 2 diabetes, as has recently been reviewed [6], [7], [8]. The aim of this review is to discuss the evidence that enlarged adipocytes, an impaired adipose tissue blood flow (ATBF), adipose tissue hypoxia, local inflammation in adipose tissue and adipose tissue macrophage infiltration seem to be interrelated and may lead to disturbances in adipokine secretion, lipid overflow, and excessive fat storage in non-adipose tissues, which together may result in the development and/or progression of insulin resistance.
Section snippets
Adipose tissue as lipid storage depot
Obesity is the result of an imbalance between energy intake and energy expenditure. When energy intake exceeds energy expenditure the energy surplus is stored in various organs. Adipose tissue is the main lipid storage depot in our body, and is of crucial importance in buffering the daily influx of dietary fat entering the circulation. Adipose tissue exerts its buffering action by suppressing the release of non-esterified fatty acids into the circulation and by increasing the clearance of
Importance of adipose tissue blood flow in lipid metabolism
Tissue-specific regulation of blood flow is required to meet local metabolic and physiological demands under varying conditions. Blood flow may be an important regulator of metabolism in both muscle [27] and adipose tissue [28], [29], [30]. There is evidence that disturbances in adipose tissue blood flow (ATBF) may affect adipose tissue lipid handling, thereby contributing to an increased lipid supply to non-adipose tissues, which in turn may lead to ectopic fat deposition as discussed above.
Link between adipocyte size and insulin resistance
Enlargement of adipocytes is frequently observed in obesity and has also been demonstrated in pre-diabetic individuals and in type 2 diabetics [48], [49], [50]. The increased adipocyte size may represent a failure in the recruitment of new adipocytes due to impaired differentiation, which may have a genetic origin [51]. An impaired adipocyte differentiation appears to be a precipitating factor in the development of type 2 diabetes [49], [50]. In accordance with this, it has recently been shown
Adipose tissue as an endocrine organ
Until recently, adipose tissue was seen as a passive organ for energy storage. Research of the past decade has shown the complex nature of adipose tissue and clearly demonstrated that the traditional view of adipose tissue is no longer valid. Adipocytes are now known to express and secrete a variety of adipokines, which may act at both the local (autocrine and/or paracrine) and systemic (endocrine) level. These factors among others include cytokines, growth factors, adiponectin, resistin,
Importance of inflammation in insulin resistance
Studies in the past decade left little doubt that inflammatory pathways are critical in the mechanisms underlying insulin resistance and type 2 diabetes, at least in cultured cells and animal models [112], [113], [114], [115], [116]. Accumulating evidence suggests that this may also be the case in humans. Much progress has been made in identifying mechanisms by which the inflammatory response may cause insulin resistance. Dysregulation of adipokine production and/or secretion may both have
Adipose tissue inflammation and macrophage infiltration
Adipose tissue is a heterogeneous tissue containing different cell types, including mature adipocytes, pre-adipocytes, endothelial cells, vascular smooth muscle cells, leukocytes, monocytes and macrophages. Due to this heterogeneity, several studies have been performed to establish the cellular origin of the adipokines that are expressed in adipose tissue. Macrophages are now recognized as important non-adipocyte cells that contribute to adipose tissue production of inflammatory factors. In
Role for adipose tissue hypoxia in insulin resistance?
Epidemiological and clinical studies have shown that obstructive sleep apnea (OSA) may contribute to the development of insulin resistance [164], [165], [166], possibly via cycles of intermittent hypoxia resulting from periodic collapse of the upper airway during sleep. Epidemiological studies have revealed an association between the degree of hypoxia and insulin resistance [164], [165], [166]. Interestingly, intermittent hypoxia causes acute insulin resistance in mice due to decreased skeletal
Summary and perspectives
Abdominal obesity is strongly associated with insulin resistance and the development of type 2 diabetes and cardiovascular disease. Enormous progress has been made over the past few years in the attempt to understand the mechanisms underlying obesity-related insulin resistance. It is now well-recognized that adipose tissue is a highly active metabolic and endocrine organ. Adipocytes are of crucial importance in buffering the daily influx of dietary fat and exert autocrine, paracrine and/or
References (203)
- et al.
Mechanism of insulin resistance in A-ZIP/F-1 fatless mice
J Biol Chem
(2000) - et al.
Adipose tissue metabolism in obesity: lipase action in vivo before and after a mixed meal
Metabolism
(1992) - et al.
Beta-adrenergic stimulation and abdominal subcutaneous fat blood flow in lean, obese, and reduced-obese subjects
Metabolism
(1995) Insulin resistance and vascular function
J Diabetes Complications
(2002)- et al.
“Vasocrine” signalling from perivascular fat: a mechanism linking insulin resistance to vascular disease
Lancet
(2005) - et al.
Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21–q23 and is associated with a common polymorphism in LMNA in Pima Indians
Mol Genet Metab
(2001) - et al.
In vitro reversal of hyperglycemia normalizes insulin action in fat cells from type 2 diabetes patients: is cellular insulin resistance caused by glucotoxicity in vivo?
Metabolism
(2003) Insensitivity of large rat adipocytes to the antilipolytic effects of insulin
J Lipid Res
(1977)- et al.
Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue
J Biol Chem
(1993) - et al.
Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects
J Biol Chem
(2003)
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem Biophys Res Commun
Banting lecture 1988. Role of insulin resistance in human disease
Diabetes
Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men
Diabetes Care
Associations of body composition with type 2 diabetes mellitus
Diabet Med
Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition
Circulation
Mechanisms of obesity-associated insulin resistance: many choices on the menu
Genes Dev
Disordered lipid metabolism and the pathogenesis of insulin resistance
Physiol Rev
Inflammation and insulin resistance
J Clin Invest
Adipose tissue and the insulin resistance syndrome
Proc Nutr Soc
Relation of triglyceride stores in skeletal muscle cells to central obesity and insulin sensitivity in European and South Asian men
Diabetologia
Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects
Diabetes
Skeletal muscle triglyceride levels are inversely related to insulin action
Diabetes
Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity
Am J Physiol
Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM
Int J Obes Relat Metab Disord
Liver triglycerides and metabolism
Int J Obes Relat Metab Disord
Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans
J Clin Invest
Effect of fatty acids on glucose production and utilization in man
J Clin Invest
Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans
Diabetes
Interaction of non-esterified fatty acid and insulin in control of triacylglycerol secretion by Hep G2 cells
Biochem J
Effects of free fatty acids and glucose on splanchnic insulin dynamics
Diabetes
Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes
Diabetes
Free fatty acids impair hepatic insulin extraction in vivo
Diabetes
Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases?
Clin Sci (Lond)
Lipoatrophy, lipodystrophy, and insulin resistance
Ann Intern Med
Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice
J Clin Invest
Role of blood flow in the regulation of muscle glucose uptake
Annu Rev Nutr
Influence of blood flow on fatty acid mobilization form lipolytically active adipose tissue
Pflugers Arch
Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue
J Clin Invest
Effects of epinephrine infusion on adipose tissue: interactions between blood flow and lipid metabolism
Am J Physiol
Nitric oxide and beta-adrenergic stimulation are major regulators of preprandial and postprandial subcutaneous adipose tissue blood flow in humans
Circulation
Subcutaneous adipose tissue blood flow varies between superior and inferior levels of the anterior abdominal wall
Int J Obes Relat Metab Disord
Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load
Acta Physiol Scand
Effects of an oral and intravenous fat load on adipose tissue and forearm lipid metabolism
Am J Physiol
Angiotensin II: a major regulator of subcutaneous adipose tissue blood flow in humans
J Physiol
Integrative physiology of human adipose tissue
Int J Obes Relat Metab Disord
Endocrine role of the renin–angiotensin system in human adipose tissue and muscle: effect of beta-adrenergic stimulation
Hypertension
Relationship between blood pressure, metabolic variables and blood flow in obese subjects with or without non-insulin-dependent diabetes mellitus
Eur J Clin Invest
Subcutaneous abdominal adipose tissue blood flow: variation within and between subjects and relationship to obesity
Clin Sci (Lond)
Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans
J Clin Endocrinol Metab
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