Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

Abstract

Journal of Lipid Research Volume 56, 2015 423Adipose tissue is an endocrine organ whose products orchestrate the metabolic functions of various tissues, including brain, pancreas, and liver, to maintain systemic homeostasis. Adipocytes respond to metabolic and immune cues by mobilizing their fat stores through lipolysis and by secreting a variety of hormones and cytokines ( 1, 2 ). Such signals converge on target tissues, for example on liver to regulate glucose production, and on ␤ cells to modulate insulin production. A critical molecule for the integration of adipocyte biology with systemic metabolic regulation is aP2 [fatty acid binding protein (FABP) 4], a lipid binding protein that is upregulated during differentiation of adipocytes and upon macrophage activation ( 3, 4 ). Since its identifi cation, aP2 has been studied primarily for its intracellular functions in lipid metabolism and infl ammation ( 3,4 ). Genetic deletion models demonstrated that this FABP plays a critical role in the pathogenesis of several chronic metabolic diseases, including diabetes, atherosclerosis, and fatty liver. Mice defi cient in aP2 or aP2 and the related protein FABP5/mal1 together have improved adipose and liver function, increased insulin sensitivity, and reduced fatty liver and cardiovascular disease in the context of high-fat diet and genetic mouse models of obesity and atherosclerosis ( 5-12 ). The link between aP2 and metabolic disease is also supported by genetic association studies in multiple populations demonstrating metabolic and cardiovascular benefi ts in individuals carrying a rare haploinsuffi ciency mutation in the aP2 locus, validating the relevance of this pathway in human disease ( 13,14 ).

Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

“…For example, lipolysis has been linked to increased FABP4 secretion from adipose tissue via a nonclassical mechanism (59,60,187,188). FABP4 secretion is regulated by ATGL and hormone-sensitive lipase activity and subsequent increase in fatty acid availability (60). Interestingly, there is strong correlation between circulating FABP4 levels and metabolic disease in preclinical models and in humans (59,(189)(190)(191)(192)(193)(194)(195)(196)(197)(198)(199).…”

“…Reciprocally, pro-inflammatory cytokines such as TNF regulate lipid metabolism in adipocytes via increasing lipolysis (58), which continuously exposes the organs to fatty acids. Increased lipolysis from adipose tissue is also linked to secretion of the adipokine, aP2 (FABP4) (59,60), which is an important mediator of immunometabolic responses locally at the adipose tissue, and links the lipolytic state to glucose metabolism in the liver and elsewhere (61)(62)(63). Overall, while adipocytes are the specialized site for neutralizing fatty acids, this capacity is not infinite and these cells are not impervious to excess lipid accumulation, which drives inflammatory responses locally and at distant tissues.…”

“…Further understanding of the lipolytic pathway and the details and molecular components of its contribution to signaling and metabolism will help determine if and how lipolysis can be pharmacologically targeted in a more specific and restricted manner toward treatment of diabetes. For example, lipolysis has been linked to increased FABP4 secretion from adipose tissue via a nonclassical mechanism (59,60,187,188). FABP4 secretion is regulated by ATGL and hormone-sensitive lipase activity and subsequent increase in fatty acid availability (60).…”

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

“…Exosomes are membrane vesicles that carry a cargo of proteins, lipids and nuclear acids, which may differ based on adipogenic stages and/or under pathological conditions [120,121,122]. Adipocyte-secreted exosomes are demonstrated to contain specific transcripts (such as adiponectin [123] and aP2 [124]) and miRNAs [119,99], which are transported into recipient cells and are involved in modulating gene expression as well as energy metabolism. Several studies demonstrated that adipocyte derived exosomes mediate cell-cell communication that might play a role in controlling lipogenesis and cell size [121], obesity related disease [120] and nonalcoholic fatty liver disease [125].…”

Circulating AFABP promotes insulin secretion

“…, and James Cantley 3 Dear Editor: We read with interest the recent paper "Circulating Adipocyte Fatty Acid-Binding Protein Induces Insulin Resistance in Mice In Vivo" by Kralisch and Kl€ oting et al (1). The authors concluded that exogenous administration of the adipokine Adipocyte Fatty Acid Binding Protein (AFABP/FABP4/aP2) for 8 weeks caused insulin resistance in mice, measured indirectly using the HOMA-IR score, which is based on a composite of circulating glucose and insulin levels.…”