Adipokine FABP4 integrates energy stores and counterregulatory metabolic responses

Abstract

Although counterregulatory hormones and mediators of the fight-or-flight responses are well defined at many levels, how energy stores per se are integrated into this system remains an enigmatic question. Recent years have seen the adipose tissue become a central focus for mediating intracellular signaling and communication through the release of a variety of bioactive lipids and substrates, as well as various adipokines. A critical integration node among these mediators and responses is controlled by FA binding protein 4 (FABP4), also known as adipocyte protein 2 (aP2), which is highly expressed in adipose tissue and functions as a lipid chaperone protein. Recently, it was demonstrated that FABP4 is a secreted hormone that has roles in maintaining glucose homeostasis, representing a key juncture facilitating communication between energy-storage systems and distant organs to respond to life-threatening situations. However, chronic engagement of FABP4 under conditions of immunometabolic stress, such as obesity, exacerbates a number of immunometabolic diseases, including diabetes, asthma, cancer, and atherosclerosis. In both preclinical mouse models and humans, levels of circulating FABP4 have been correlated with metabolic disease incidence, and reducing FABP4 levels or activity is associated with improved metabolic health. In this review, we will discuss the intriguing emerging biology of this protein, including potential therapeutic options for targeting circulating FABP4.

Keywords: immunometabolism; metabolism; obesity.

Graphical abstract

Fig. 1.

Evidence for a key role of FABP4/aP2 in immunometabolic diseases. Genetic FABP4/aP2 deficiency, inhibition through small molecules, or Ab-mediated targeting efficiently attenuates the development of various immunometabolic phenotypes in mice. In humans, FABP4 has been identified as a common candidate gene for the development of both T2D and CHD. Conversely, evidence from low-expression variant carriers suggests that reduced FABP4 gene activity is associated with improved lipid parameters and reduction in cardiometabolic endpoints in man. In the setting of genetic deficiency or genetically reduced expression of FABP4/aP2, many of the improved metabolic phenotypes are enhanced or exclusively evident in the context of obesity, suggesting that the systemic effects of obesity on immunometabolic risk may be mediated through the adipokine FABP4/aP2. LAA, large artery atherosclerotic.

Fig. 2.

Regulation of FABP4/aP2 secretion from adipocytes. Circulating FABP4/aP2 levels are increased during obesity and regulated in response to feeding and fasting. In the fed state, insulin suppresses FABP4/aP2 secretion from adipocytes, whereas fasting and signals downstream of lipolytic stimuli induce secretion. Activation of the β-adrenergic receptor (β-AR) raises intracellular cAMP levels, which act to initiate lipolysis. Induction of FABP4/aP2 secretion requires the actions of lipolytic enzymes ATGL and HSL, and to a lesser extent MGL, and the liberation of FFAs. Once lipolysis is initiated, FABP4/aP2 may be released in a compartmentalized fashion through the lysosomal pathway, and to lesser extent through multivesicular bodies (MVBs). How FABP4/aP2 is recruited into these vesicular compartments remains to be explored. AC, adenylyl cyclase; CGI-58, comparative gene identification-58; DAG, diacylglycerol; EE, early endosome; LE, late endosome; LYS, lysosome; MAG, monoacylglycerol; PKA, protein kinase A; TG, triglyceride.