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

Adipocyte fatty acid binding protein 4, aP2, contributes to the pathogenesis of several common diseases including type 2 diabetes, atherosclerosis, fatty liver disease, asthma, and cancer. Although the biological functions of aP2 have classically been attributed to its intracellular action, recent studies demonstrated that aP2 acts as an adipokine to regulate systemic metabolism. However, the mechanism and regulation of aP2 secretion remain unknown. Here, we demonstrate a specific role for lipase activity in aP2 secretion from adipocytes in vitro and ex vivo. Our results show that chemical inhibition of lipase activity, genetic deficiency of adipose triglyceride lipase and, to a lesser extent, hormone-sensitive lipase blocked aP2 secretion from adipocytes. Increased lipolysis and lipid availability also contributed to aP2 release as determined in perilipin1-deficient adipose tissue explants ex vivo and upon treatment with lipids in vivo and in vitro. In addition, we identify a nonclassical route for aP2 secretion in exosome-like vesicles and show that aP2 is recruited to this pathway upon stimulation of lipolysis. Given the effect of circulating aP2 on glucose metabolism, these data support that targeting aP2 or the lipolysis-dependent secretory pathway may present novel mechanistic and translational opportunities in metabolic disease. Adipocyte fatty acid binding protein 4, aP2, contributes to the pathogenesis of several common diseases including type 2 diabetes, atherosclerosis, fatty liver disease, asthma, and cancer. Although the biological functions of aP2 have classically been attributed to its intracellular action, recent studies demonstrated that aP2 acts as an adipokine to regulate systemic metabolism. However, the mechanism and regulation of aP2 secretion remain unknown. Here, we demonstrate a specific role for lipase activity in aP2 secretion from adipocytes in vitro and ex vivo. Our results show that chemical inhibition of lipase activity, genetic deficiency of adipose triglyceride lipase and, to a lesser extent, hormone-sensitive lipase blocked aP2 secretion from adipocytes. Increased lipolysis and lipid availability also contributed to aP2 release as determined in perilipin1-deficient adipose tissue explants ex vivo and upon treatment with lipids in vivo and in vitro. In addition, we identify a nonclassical route for aP2 secretion in exosome-like vesicles and show that aP2 is recruited to this pathway upon stimulation of lipolysis. Given the effect of circulating aP2 on glucose metabolism, these data support that targeting aP2 or the lipolysis-dependent secretory pathway may present novel mechanistic and translational opportunities in metabolic disease. Adipose 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 (1Kershaw E.E. Flier J.S. Adipose tissue as an endocrine organ.J. Clin. Endocrinol. Metab. 2004; 89: 2548-2556Crossref PubMed Scopus (3679) Google Scholar, 2Scherer P.E. Adipose tissue: from lipid storage compartment to endocrine organ.Diabetes. 2006; 55: 1537-1545Crossref PubMed Scopus (828) Google Scholar). Such signals converge on target tissues, for example on liver to regulate glucose production, and on β 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 (3Furuhashi M. Hotamisligil G.S. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets.Nat. Rev. Drug Discov. 2008; 7: 489-503Crossref PubMed Scopus (1125) Google Scholar, 4Hertzel A.V. Bernlohr D.A. The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function.Trends Endocrinol. Metab. 2000; 11: 175-180Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). Since its identification, aP2 has been studied primarily for its intracellular functions in lipid metabolism and inflammation (3Furuhashi M. Hotamisligil G.S. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets.Nat. Rev. Drug Discov. 2008; 7: 489-503Crossref PubMed Scopus (1125) Google Scholar, 4Hertzel A.V. Bernlohr D.A. The mammalian fatty acid-binding protein multigene family: molecular and genetic insights into function.Trends Endocrinol. Metab. 2000; 11: 175-180Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar). 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 deficient 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 (5Hotamisligil G.S. Johnson R.S. Distel R.J. Ellis R. Papaioannou V.E. Spiegelman B.M. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein.Science. 1996; 274: 1377-1379Crossref PubMed Scopus (651) Google Scholar, 6Uysal K.T. Scheja L. Wiesbrock S.M. Bonner-Weir S. Hotamisligil G.S. Improved glucose and lipid metabolism in genetically obese mice lacking aP2.Endocrinology. 2000; 141: 3388-3396Crossref PubMed Scopus (0) Google Scholar, 7Boord J.B. 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Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.Cell. 2008; 134: 933-944Abstract Full Text Full Text PDF PubMed Scopus (818) Google Scholar, 11Erbay E. Babaev V.R. Mayers J.R. Makowski L. Charles K.N. Snitow M.E. Fazio S. Wiest M.M. Watkins S.M. Linton M.F. et al.Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.Nat. Med. 2009; 15: 1383-1391Crossref PubMed Scopus (393) Google Scholar, 12Makowski L. Boord J.B. Maeda K. Babaev V.R. Uysal K.T. Morgan M.A. Parker Fazio S. Hotamisligil G.S. et of macrophage fatty-acid-binding protein aP2 mice deficient in apolipoprotein atherosclerosis.Nat. Med. 7: PubMed Scopus Google Scholar). The aP2 and metabolic disease is also by genetic studies in metabolic and cardiovascular in a mutation in the aP2 the of this pathway in disease G. E. H. Hotamisligil G.S. 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In addition, recent studies have potential for aP2 Adipocyte fatty acid-binding protein a obesity and 2009; PubMed Scopus Google Scholar, Identification of fatty acid binding protein as an adipokine that insulin secretion during Metab. PubMed Scopus Google Scholar). the that aP2 is a hormone linking adipose tissue to systemic metabolism and that targeting circulating aP2 may have potential for a of the that and regulate its secretion is of critical is the for hormones as insulin and aP2 secretion from adipose tissue is by and also with lipolysis H. M. M. M.F. Mayers J.R. K. M. et lipid chaperone aP2 is a adipokine glucose Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). is that lipolysis is increased in the context of as as insulin and diabetes Adipocyte linking obesity to insulin resistance and type 2 Rev. 2008; PubMed Scopus Google Scholar, in lipid and insulin Endocrinol. Metab. 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Here, we a novel mechanism and route of aP2 hormone secretion from adipocytes through a nonclassical secretory pathway to activity and the availability of fatty demonstrate that adipocyte lipase and, to a lesser extent, in the secretion of aP2, and genetic deletion or chemical inhibition of these aP2 secretion from adipocytes. has been in various that and nonclassical hormone secretion H. M. M. K. insulin secretion by an on the pathway of glucose in PubMed Scopus Google Scholar, H. S. M. Charles et of the pathway in the regulation of hormone secretion in 2000; PubMed Scopus Google Scholar, M. M. The role of in Endocrinol. PubMed Scopus Google Scholar, and secretion of and the and Endocrinol. PubMed Scopus Google Scholar). 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S. et tissue exosome-like vesicles activation of insulin 2009; PubMed Scopus Google that may a role in the of The regulation of aP2 secretion by and and its in glucose and insulin with of glucose regulation during the release of and signals from adipose tissue in specific with is A recent has demonstrated that during insulin resistance with lipolysis and increased aP2 and their glucose this E. K. et insulin obese to a insulin resistance during Metab. Full Text PDF PubMed Scopus Google Scholar). In the on fat adipose aP2 and insulin is However, circulating aP2 with this regulation to in adipose tissue to of aP2 release and to increased liver glucose to and aP2 the of a hormone of or is to a in the of liver in obesity that of in a S. Watkins S.M. Hotamisligil G.S. in liver regulation of endoplasmic reticulum by obesity and PubMed Scopus Google Scholar). have been as for inhibiting of lipids from increased lipolysis in with metabolic disease M. M. 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