Angiopoietin-like Protein 4—A Novel Communicator Between Muscle and Fat

INTRODUCTION

Insulin, in concert with its physiological antagonists (ie, glucagon and catecholamines) is a central regulator of glucose, lipid, and amino acid metabolism. Moreover, overall fuel availability as well as tissue-specific energy states, energy storage capacities, and acute energy demand are actively communicated between the insulin-sensitive organs skeletal muscle, liver, adipose tissue, and brain. This interorgan communication is achieved by a complex network of tissue-derived hormones and by neuronal and metabolic signals, as well as by regulation of blood supply, and it allows well-coordinated and fine-tuned metabolic responses to avoid local energy imbalances []. Chronic disturbances of this network of communication, due to genetic, epigenetic, or environmental factors, are thought to contribute to common metabolic disorders, such as obesity, insulin resistance, hyperinsulinaemia, dyslipidemia, and subclinical inflammation, which may ultimately result in type 2 diabetes, cardiovascular disease, and certain malignancies [].

During the past 15 years, adipose tissue was recognized as an endocrine organ secreting a plethora of metabolically active factors encompassing peptides, proteins, enzymes, and metabolites, and adipose tissue hypertrophy was shown to lead to an imbalance in these secreted factors []. Among the aforementioned tissue-specific cross-talk mediators, adipocyte-derived long-chain nonesterified fatty acids (NEFA) and adipokines, such as leptin and adiponectin, were shown to be involved in the regulation of food intake, energy expenditure, insulin sensitivity, insulin secretion, inflammation, and atherogenesis [–].

More recently, liver-derived and muscle-derived factors of metabolic relevance were reported and named hepatokines and myokines, respectively. Elevated plasma concentrations of the hepatokine fetuin-A/

-Heremans-Schmid glycoprotein are determined by hepatic lipid deposition and provoke hypoadiponectinaemia, insulin resistance, and inflammatory responses [, ]. Moreover, fetuin-A was identified as an important risk factor for type 2 diabetes, myocardial infarction, and stroke [, ].

Interleukin (IL) 6 is up to now the best described myokine. This proinflammatory cytokine is released upon muscle work and was reported to induce insulin resistance in liver and adipose tissue []. In this way, hepatic glucose production and adipose tissue lipolysis are increased in order to supply the muscle with fuel. To allow the working muscle to meet its energy demand, IL-6 increases muscular fatty acid oxidation and stimulates muscular insulin sensitivity and glucose utilization [, ]. By contrast, chronically elevated plasma IL-6 concentrations predict type 2 diabetes [, ] and coronary heart disease [, ]. Recently, the list of myokines markedly expanded and currently comprises 18 cytokines, chemokines, growth, survival, and differentiation factors, and other hormonelike polypeptides all exerting auto-, para-, and/or endocrine functions. presents the currently known human myokines, their year of discovery, and their metabolic and vascular effects. The most recently identified myokine is angiopoietin-like protein (ANGPTL) 4, a hormonelike protein that was first cloned in 2000 by three groups in parallel and initially designated peroxisome proliferator-activated receptor angiopoietin-related protein [], hepatic fibrinogen/angiopoietin-related protein [], and fasting-induced adipose factor [].

Insulin-sensitive tissues, such as muscle, liver, fat, and brain, fine-tune their energy metabolism via a complex network of circulating metabolites and hormones. Chronic disturbances of this network are thought to contribute to metabolic disorders like obesity and insulin resistance. During the last few years, several metabolically relevant hormones produced by skeletal muscle, nowadays collectively termed myokines, were identified. The recently recognized myokine angiopoietin-like protein 4 (ANGPTL4) is produced and secreted upon peroxisome proliferator-activated receptor (PPAR) activation by long-chain nonesterified fatty acids and stimulates adipose tissue lipolysis. In this way, ANGPTL4 supplies the fasting as well as the exercised muscle—both characterized by increased PPAR activity—with fatty acids and supports PPAR-triggered fatty acid oxidation. Thus, elevation of muscle-derived ANGPTL4 may be a promising approach to reduce fat mass and to deplete intramyocellular lipids. However, ANGPTL4 is a two-edged sword: it also potently inhibits lipoprotein lipase; this function on the one hand may further contribute to fat loss, but on the other hand results in hypertriglyceridemia and hepatic steatosis, well-known risk factors for coronary heart disease and type 2 diabetes. Since ANGPTL4 may indeed represent an interesting novel target for the therapy of obesity and obesity-associated insulin resistance, much more has to be learned about this protein's biology to find ways to bypass its undesirable effects. The present review summarizes the current knowledge about ANGPTL4's structural features and its regulated expression/secretion, as well as its biological functions, and describes its novel role as a myokine.

Keywords

ANGPTL4, PPARδ, fatty acids, lipolysis, LPL,