The delicate balance between fat and muscle: adipokines in metabolic disease and musculoskeletal inflammation
Introduction
Diabetes has reached epidemic proportions in industrialized societies and is expected to become a major problem in public health, with an estimated 220 million people affected by the year 2010 [1]. Rising rates in the occurrence of type 2 diabetes are directly related to lifestyle changes in the past few decades, and an increase in the prevalence of obesity worldwide. Diabetes, defined as a state of improper regulation of glucose and lipid metabolism by insulin, leads to uncontrolled hepatic glucose production and inadequate uptake of glucose into muscles and fat [2]. Compensatory insulin secretion progressively leads to hyperplasia and eventual failure of pancreatic islet β-cells, resulting in chronic hyperglycemia. Resistance to insulin action is the initial defect in the development of diabetes, and obesity is a potent and well-established risk factor for the development of this resistance. In particular, the ‘male pattern obesity’, with an excess of visceral fat, is significantly associated with perturbed lipid metabolism, chronic subclinical inflammation and oxidative stress, commonly known as the metabolic syndrome [3••].
The molecular pathways that link increased adipose mass to peripheral insulin responsiveness remain the subject of intense research efforts. Adipose tissue serves not only as a repository for excess lipids but is also an endocrine organ, which responds to metabolic signals through the release of soluble proteins, termed adipokines. Abnormal adipocyte physiology leads to alterations in the secretory profile of these adipokines, with detrimental consequences on local and peripheral glucose and lipid metabolism (Figure 1). In the obese state, both the absolute number and the ratio of large, lipid-laden adipocytes increase relative to smaller-sized adipocytes, partly responsible for the changes in adipokine release [4]. By contrast, atrophic adipose tissue, observed after starvation, in cachexia or in lipodistrophy, contains small, poorly developed adipocytes that exhibit profound alterations in adipose gene expression and adipokine release into serum.
The metabolic disturbances that are associated with altered adipocyte size and anatomical distribution are not only due to alterations in the adipokine release, but they are also a reflection of chronically elevated lipid levels in the circulation. A chronic excess of systemic lipid availability leads to an accumulation of triglycerides in skeletal muscle and the liver, as well as increased intracellular concentrations of free fatty acids (FFAs) [5]. FFAs negatively impact insulin signaling. The phenomenon referred to as lipotoxicity is thought to be partially causative of accelerated progression of insulin resistance. Lipid accumulation in skeletal muscle is of particular importance because this tissue is the primary site of insulin-stimulated glucose disposal. Here, we discuss the role of adipokines and inflammatory cytokines in the development of the metabolic syndrome and analyze mechanisms by which pathological accumulation of fat in skeletal muscle influences energy metabolism.
Section snippets
Adipokines and metabolic diseases
During the past few years, many studies have demonstrated the role of adipokines as modulators of insulin action, adjusting metabolic parameters and maintaining overall energy balance. One of these factors, leptin, is a key regulator of central functions that are mediated by the arcuate nucleus, including food intake, energy expenditure and other neuroendocrine functions. Leptin also regulates a variety of peripheral metabolic mechanisms in skeletal muscle, liver, pancreas and other tissues [6]
Obesity-induced inflammation and diabetes
Many of the complications of obesity are due to a milieu of chronic subclinical inflammation. The origin of this inflammation resides, in part, in adipose tissue itself. Large-scale gene expression profiling of the obese phenotype revealed a differential regulation of many pro-inflammatory genes when compared with white adipose tissue of lean individuals 42., 43.. However, the molecular mechanisms by which an inflammatory response is initiated in obesity and how this results in metabolic
Common pathways for metabolic and inflammatory signals
Many genetic and biochemical studies have been undertaken to identify common molecular targets in insulin-signaling and inflammatory pathways in metabolic diseases. The key regulatory stages of insulin-dependent glucose metabolism are uptake, glucose phosphorylation and storage in the form of glycogen, most importantly in skeletal muscle and the liver. The most crucial step in insulin signal transduction is the phosphorylation of the insulin receptor upon insulin binding and subsequent tyrosine
Intramyocellular and extramyocellular fat
Abdominal fat is an important predictor of insulin resistance in humans with both normal and increased adiposity [73]. The current opinion implies that visceral adipocytes might be more resistant to the antilipolytic actions of insulin and thus preferentially release FFA into the circulation [74]. Impaired storage of FFA in adipocytes leads to a forced partitioning of these FFAs into muscle and liver. In support of this idea, transgenic mouse models of lipoatrophy with reduced or absent fat
Conclusions
Adipokines and FFAs are at the core of the development of muscular insulin resistance. Adipose depots within muscle tissue are not immune to expansion during weight gain and are likely to alter the local secretion profile. However, compared to the main adipose depots in the subcutaneous and central regions, adipocytes within skeletal muscle have not been characterized with respect to changes that are induced in the obese and/or insulin-resistant state. The availability of new technology, such
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
ARN was supported by a post-doctoral fellowship from the Swiss National Science Foundation. PES is supported by NIH grant R01-DK55758. We thank Dr. Dan Stein, Albert Einstein College of Medicine, for kindly providing the pictures of intra- and intermyocellular lipid accumulation that were used in the figures. Thanks to Maria Trujillo and Martin Fisher for critical reading of the manuscript.
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