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.
Highlights
Counterregulatory hormones and mediators of the fight-orflight responses are well defined at many levels, how energy stores per se are integrated into this system remains an enigmatic question
This is consistent with in vitro data in primary HUVECs, which have demonstrated that FA binding protein 4 (FABP4) is required for vascular endothelial growth factor signaling and cell proliferation, associated with angiogenesis [17, 18]. This may have particular importance in the context of cancer, as FABP4 in obese individuals is associated with enhanced proliferative and migration capacity of cancer cells [19], contributing to metastasis and reduced survival [20]. These findings suggest that FABP4 governs diverse biology, depending on the tissue source and disease context
FABP4 has emerged as a critical player in immunometabolic diseases, with strong correlations between preclinical models and various human populations supporting the targeting of FABP4 for therapeutic benefit
Summary
Counterregulatory hormones and mediators of the fight-orflight responses are well defined at many levels, how energy stores per se are integrated into this system remains an enigmatic question. In essentially all of the contexts where FABP4 function has been examined, biological consequences have been observed in tissues that do not express FABP4, suggesting that signals or circulating molecules may be downstream of the function of this protein. FABP4 is secreted, and in how circulating levels correlate with disease and how FABP4 interacts with target cells to mediate biological activity.
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