Metabolic functions of fabps—mechanisms and therapeutic implications

KEY POINTS * Fatty acid-binding proteins (FABPs) are versatile proteins that can modulate lipid fluxes, trafficking, signalling and metabolism * Fatty acid-binding protein, adipocyte (FABP4)

regulates metabolic and inflammatory pathways, and in mouse models its inhibition can improve type 2 diabetes mellitus and atherosclerosis * FABP4 is actively secreted by adipocytes and its

levels are increased in obesity; in humans, elevated circulating FABP4 levels are associated with obesity, metabolic disease and cardiac dysfunction * Circulating FABP4 is secreted through

a vesicular pathway and has pleiotropic roles that include the stimulation of hepatic glucose production * Targeting FABP4 offers a novel therapeutic approach for the treatment of many

metabolic diseases * The signalling components of hormonal FABP4 and determinants of FABP-mediated functions in the context of specific lipid or other cargo are issues that must be addressed

in future research ABSTRACT Intracellular and extracellular interactions with proteins enables the functional and mechanistic diversity of lipids. Fatty acid-binding proteins (FABPs) were

originally described as intracellular proteins that can affect lipid fluxes, metabolism and signalling within cells. As the functions of this protein family have been further elucidated, it

has become evident that they are critical mediators of metabolism and inflammatory processes, both locally and systemically, and therefore are potential therapeutic targets for

immunometabolic diseases. In particular, genetic deficiency and small molecule-mediated inhibition of FABP4 (also known as aP2) and FABP5 can potently improve glucose homeostasis and reduce

atherosclerosis in mouse models. Further research has shown that in addition to their intracellular roles, some FABPs are found outside the cells, and FABP4 undergoes regulated, vesicular

secretion. The circulating form of FABP4 has crucial hormonal functions in systemic metabolism. In this Review we discuss the roles and regulation of both intracellular and extracellular

FABP actions, highlighting new insights that might direct drug discovery efforts and opportunities for management of chronic metabolic diseases. Access through your institution Buy or

subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online

access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which

are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS

THE MEASUREMENT, REGULATION AND BIOLOGICAL ACTIVITY OF FAHFAS Article 28 January 2025 PHYSIOLOGICAL AND PATHOLOGICAL ROLES OF LIPOGENESIS Article 04 May 2023 A HORMONE COMPLEX OF FABP4 AND

NUCLEOSIDE KINASES REGULATES ISLET FUNCTION Article 08 December 2021 ACCESSION CODES ACCESSIONS GENBANK/EMBL/DDBJ * CAJ18597.1 REFERENCES * Poveda, J. A. _ et al_. Lipid modulation of ion

channels through specific binding sites. _Biochim. Biophys. Acta_ 1838, 1560–1567 (2014). Article  CAS  PubMed  Google Scholar  * Wahli, W. & Michalik, L. PPARs at the crossroads of

lipid signaling and inflammation. _Trends Endocrinol. Metab._ 23, 351–363 (2012). Article  CAS  PubMed  Google Scholar  * Shimizu, T. Lipid mediators in health and disease: enzymes and

receptors as therapeutic targets for the regulation of immunity and inflammation. _Annu. Rev. Pharmacol. Toxicol._ 49, 123–150 (2009). Article  CAS  PubMed  Google Scholar  * Dresner, A. _

et al_. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. _J. Clin. Invest._ 103, 253–259 (1999). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Cho, H. _ et al_. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB β). _Science_ 292, 1728–1731 (2001).

Article  CAS  PubMed  Google Scholar  * Kim, J. K. _ et al_. Prevention of fat-induced insulin resistance by salicylate. _J. Clin. Invest._ 108, 437–446 (2001). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Solinas, G., Naugler, W., Galimi, F., Lee, M. S. & Karin, M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated

phosphorylation of insulin-receptor substrates. _Proc. Natl Acad. Sci. USA_ 103, 16454–16459 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Nguyen, M. T. _ et al_. JNK and

tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. _J. Biol. Chem._ 280, 35361–35371 (2005). Article  CAS  PubMed  Google Scholar  * Shi, H. _

et al_. TLR4 links innate immunity and fatty acid-induced insulin resistance. _J. Clin. Invest._ 116, 3015–3025 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Severeid, L.,

Connor, W. E. & Long, J. P. The depressant effect of fatty acids on the isolated rabbit heart. _Proc. Soc. Exp. Biol. Med._ 131, 1239–1243 (1969). Article  CAS  PubMed  Google Scholar  *

Gordon, G. B. Saturated free fatty acid toxicity. II. Lipid accumulation, ultrastructural alterations, and toxicity in mammalian cells in culture. _Exp. Mol. Pathol._ 27, 262–276 (1977).

Article  CAS  PubMed  Google Scholar  * Ockner, R. K., Manning, J. A., Poppenhausen, R. B. & Ho, W. K. A binding protein for fatty acids in cytosol of intestinal mucosa, liver,

myocardium, and other tissues. _Science_ 177, 56–58 (1972). Article  CAS  PubMed  Google Scholar  * Ockner, R. K. & Manning, J. A. Fatty acid-binding protein in small intestine.

Identification, isolation, and evidence for its role in cellular fatty acid transport. _J. Clin. Invest._ 54, 326–338 (1974). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Furuhashi, M. & Hotamisligil, G. S. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. _Nat. Rev. Drug Discov._ 7, 489–503 (2008). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Ockner, R. K. & Manning, J. A. Fatty acid binding protein. Role in esterification of absorbed long chain fatty acid in rat intestine. _J. Clin.

Invest._ 58, 632–641 (1976). Article  CAS  PubMed  PubMed Central  Google Scholar  * Li, L. O., Klett, E. L. & Coleman, R. A. Acyl-CoA synthesis, lipid metabolism and lipotoxicity.

_Biochim. Biophys. Acta_ 1801, 246–251 (2010). Article  CAS  PubMed  Google Scholar  * Ockner, R. K., Manning, J. A. & Kane, J. P. Fatty acid binding protein. Isolation from rat liver,

characterization, and immunochemical quantification. _J. Biol. Chem._ 257, 7872–7878 (1982). Article  CAS  PubMed  Google Scholar  * Gordon, J. I., Alpers, D. H., Ockner, R. K. &

Strauss, A. W. The nucleotide sequence of rat liver fatty acid binding protein mRNA. _J. Biol. Chem._ 258, 3356–3363 (1983). Article  CAS  PubMed  Google Scholar  * Bass, N. M., Raghupathy,

E., Rhoads, D. E., Manning, J. A. & Ockner, R. K. Partial purification of molecular weight 12,000 fatty acid binding proteins from rat brain and their effect on synaptosomal

Na+-dependent amino acid uptake. _Biochemistry_ 23, 6539–6544 (1984). Article  CAS  PubMed  Google Scholar  * Haq, R. U., Shrago, E., Christodoulides, L. & Ketterer, B. Purification and

characterization of fatty acid binding protein in mammalian lung. _Exp. Lung Res._ 9, 43–55 (1985). Article  CAS  PubMed  Google Scholar  * Sweetser, D. A., Lowe, J. B. & Gordon, J. I.

The nucleotide sequence of the rat liver fatty acid-binding protein gene. Evidence that exon 1 encodes an oligopeptide domain shared by a family of proteins which bind hydrophobic ligands.

_J. Biol. Chem._ 261, 5553–5561 (1986). Article  CAS  PubMed  Google Scholar  * Sacchettini, J. C., Said, B., Schulz, H. & Gordon, J. I. Rat heart fatty acid-binding protein is highly

homologous to the murine adipocyte 422 protein and the P2 protein of peripheral nerve myelin. _J. Biol. Chem._ 261, 8218–8223 (1986). Article  CAS  PubMed  Google Scholar  * Madsen, P.,

Rasmussen, H. H., Leffers, H., Honore, B. & Celis, J. E. Molecular cloning and expression of a novel keratinocyte protein (psoriasis-associated fatty acid-binding protein [PA-FABP]) that

is highly up-regulated in psoriatic skin and that shares similarity to fatty acid-binding proteins. _J. Invest. Dermatol._ 99, 299–305 (1992). Article  CAS  PubMed  Google Scholar  * Kurtz,

A. _ et al_. The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. _Development_ 120, 2637–2649 (1994).

Article  CAS  PubMed  Google Scholar  * Watanabe, R. _ et al_. Molecular cloning of a cDNA encoding a novel fatty acid-binding protein from rat skin. _Biochem. Biophys. Res. Commun._ 200,

253–259 (1994). Article  CAS  PubMed  Google Scholar  * Spiegelman, B. M. & Green, H. Control of specific protein biosynthesis during the adipose conversion of 3T3 cells. _J. Biol.

Chem._ 255, 8811–8818 (1980). Article  CAS  PubMed  Google Scholar  * Bernlohr, D. A., Angus, C. W., Lane, M. D., Bolanowski, M. A. & Kelly, T. J. Jr. Expression of specific mRNAs during

adipose differentiation: identification of an mRNA encoding a homologue of myelin P2 protein. _Proc. Natl Acad. Sci. USA_ 81, 5468–5472 (1984). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Haq, R. U., Christodoulides, L., Ketterer, B. & Shrago, E. Characterization and purification of fatty acid-binding protein in rat and human adipose tissue. _Biochim. Biophys.

Acta_ 713, 193–198 (1982). Article  CAS  PubMed  Google Scholar  * LaLonde, J. M., Bernlohr, D. A. & Banaszak, L. J. The up-and-down β-barrel proteins. _FASEB J._ 8, 1240–1247 (1994).

Article  CAS  PubMed  Google Scholar  * Storch, J. & Thumser, A. E. Tissue-specific functions in the fatty acid-binding protein family. _J. Biol. Chem._ 285, 32679–32683 (2010). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Zezulak, K. M. & Green, H. Specificity of gene expression in adipocytes. _Mol. Cell Biol._ 5, 419–421 (1985). CAS  PubMed  PubMed Central

  Google Scholar  * Bernlohr, D. A., Doering, T. L., Kelly, T. J. Jr & Lane, M. D. Tissue specific expression of p422 protein, a putative lipid carrier, in mouse adipocytes. _Biochem.

Biophys. Res. Commun._ 132, 850–855 (1985). Article  CAS  PubMed  Google Scholar  * Matarese, V. & Bernlohr, D. A. Purification of murine adipocyte lipid-binding protein.

Characterization as a fatty acid- and retinoic acid-binding protein. _J. Biol. Chem._ 263, 14544–14551 (1988). Article  CAS  PubMed  Google Scholar  * Blake, W. L. & Clarke, S. D.

Induction of adipose fatty acid binding protein (a-FABP) by insulin-like growth factor-1 (IGF-1) in 3T3-L1 preadipocytes. _Biochem. Biophys. Res. Commun._ 173, 87–91 (1990). Article  CAS 

PubMed  Google Scholar  * Amri, E. Z., Ailhaud, G. & Grimaldi, P. Regulation of adipose cell differentiation. II. Kinetics of induction of the aP2 gene by fatty acids and modulation by

dexamethasone. _J. Lipid Res._ 32, 1457–1463 (1991). Article  CAS  PubMed  Google Scholar  * Amri, E. Z., Bertrand, B., Ailhaud, G. & Grimaldi, P. Regulation of adipose cell

differentiation. I. Fatty acids are inducers of the aP2 gene expression. _J. Lipid Res._ 32, 1449–1456 (1991). Article  CAS  PubMed  Google Scholar  * Distel, R. J., Robinson, G. S. &

Spiegelman, B. M. Fatty acid regulation of gene expression. Transcriptional and post-transcriptional mechanisms. _J. Biol. Chem._ 267, 5937–5941 (1992). Article  CAS  PubMed  Google Scholar

  * Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ 2, a lipid-activated transcription factor. _Cell_ 79, 1147–1156 (1994). Article  CAS 

PubMed  Google Scholar  * Pelton, P. D., Zhou, L., Demarest, K. T. & Burris, T. P. PPARγ activation induces the expression of the adipocyte fatty acid binding protein gene in human

monocytes. _Biochem. Biophys. Res. Commun._ 261, 456–458 (1999). Article  CAS  PubMed  Google Scholar  * Shum, B. O. _ et al_. The adipocyte fatty acid-binding protein aP2 is required in

allergic airway inflammation. _J. Clin. Invest._ 116, 2183–2192 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wootan, M. G., Bass, N. M., Bernlohr, D. A. & Storch, J.

Fatty acid binding sites of rodent adipocyte and heart fatty acid binding proteins: characterization using fluorescent fatty acids. _Biochemistry_ 29, 9305–9311 (1990). Article  CAS  PubMed

  Google Scholar  * Xu, Z., Bernlohr, D. A. & Banaszak, L. J. The adipocyte lipid-binding protein at 1.6-A resolution. Crystal structures of the apoprotein and with bound saturated and

unsaturated fatty acids. _J. Biol. Chem._ 268, 7874–7884 (1993). Article  CAS  PubMed  Google Scholar  * Richieri, G. V., Ogata, R. T. & Kleinfeld, A. M. Equilibrium constants for the

binding of fatty acids with fatty acid-binding proteins from adipocyte, intestine, heart, and liver measured with the fluorescent probe ADIFAB. _J. Biol. Chem._ 269, 23918–23930 (1994).

Article  CAS  PubMed  Google Scholar  * Wootan, M. G., Bernlohr, D. A. & Storch, J. Mechanism of fluorescent fatty acid transfer from adipocyte fatty acid binding protein to membranes.

_Biochemistry_ 32, 8622–8627 (1993). Article  CAS  PubMed  Google Scholar  * Gericke, A., Smith, E. R., Moore, D. J., Mendelsohn, R. & Storch, J. Adipocyte fatty acid-binding protein:

interaction with phospholipid membranes and thermal stability studied by FTIR spectroscopy. _Biochemistry_ 36, 8311–8317 (1997). Article  CAS  PubMed  Google Scholar  * Herr, F. M.,

Matarese, V., Bernlohr, D. A. & Storch, J. Surface lysine residues modulate the collisional transfer of fatty acid from adipocyte fatty acid binding protein to membranes. _Biochemistry_

34, 11840–11845 (1995). Article  CAS  PubMed  Google Scholar  * LiCata, V. J. & Bernlohr, D. A. Surface properties of adipocyte lipid-binding protein: response to lipid binding, and

comparison with homologous proteins. _Proteins_ 33, 577–589 (1998). Article  CAS  PubMed  Google Scholar  * Banaszak, L. _ et al_. Lipid-binding proteins: a family of fatty acid and retinoid

transport proteins. _Adv. Protein Chem._ 45, 89–151 (1994). Article  CAS  PubMed  Google Scholar  * Jenkins-Kruchten, A. E. _ et al_. Fatty acid-binding protein-hormone-sensitive lipase

interaction. Fatty acid dependence on binding. _J. Biol. Chem._ 278, 47636–47643 (2003). Article  CAS  PubMed  Google Scholar  * Hellberg, K. _ et al_. X-ray crystallographic analysis of

adipocyte fatty acid binding protein (aP2) modified with 4-hydroxy-2-nonenal. _Protein Sci._ 19, 1480–1489 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Borchers, T. &

Spener, F. Involvement of arginine in the binding of heme and fatty acids to fatty acid-binding protein from bovine liver. _Mol. Cell Biochem._ 123, 23–27 (1993). Article  CAS  PubMed 

Google Scholar  * Jenkins, A. E., Hockenberry, J. A., Nguyen, T. & Bernlohr, D. A. Testing of the portal hypothesis: analysis of a V32G, F57G, K58G mutant of the fatty acid binding

protein of the murine adipocyte. _Biochemistry_ 41, 2022–2027 (2002). Article  CAS  PubMed  Google Scholar  * Sha, R. S., Kane, C. D., Xu, Z., Banaszak, L. J. & Bernlohr, D. A.

Modulation of ligand binding affinity of the adipocyte lipid-binding protein by selective mutation. Analysis _in vitro_ and _in situ_. _J. Biol. Chem._ 268, 7885–7892 (1993). Article  CAS 

PubMed  Google Scholar  * Grimsrud, P. A., Picklo, M. J. Sr, Griffin, T. J. & Bernlohr, D. A. Carbonylation of adipose proteins in obesity and insulin resistance: identification of

adipocyte fatty acid-binding protein as a cellular target of 4-hydroxynonenal. _Mol. Cell Proteomics_ 6, 624–637 (2007). Article  CAS  PubMed  Google Scholar  * Chabowski, A., Gorski, J.,

Luiken, J. J., Glatz, J. F. & Bonen, A. Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane. _Prostaglandins Leukot. Essent.

Fatty Acids_ 77, 345–353 (2007). Article  CAS  PubMed  Google Scholar  * Glatz, J. F., Luiken, J. J. & Bonen, A. Membrane fatty acid transporters as regulators of lipid metabolism:

implications for metabolic disease. _Physiol. Rev._ 90, 367–417 (2010). Article  CAS  PubMed  Google Scholar  * Spitsberg, V. L., Matitashvili, E. & Gorewit, R. C. Association and

coexpression of fatty-acid-binding protein and glycoprotein CD36 in the bovine mammary gland. _Eur. J. Biochem._ 230, 872–878 (1995). Article  CAS  PubMed  Google Scholar  * Woodford, J. K.,

Jefferson, J. R., Wood, W. G., Hubbell, T. & Schroeder, F. Expression of liver fatty acid binding protein alters plasma membrane lipid composition and structure in transfected L-cell

fibroblasts. _Biochim. Biophys. Acta_ 1145, 257–265 (1993). Article  CAS  PubMed  Google Scholar  * Iso, T. _ et al_. Capillary endothelial fatty acid binding proteins 4 and 5 play a

critical role in fatty acid uptake in heart and skeletal muscle. _Arterioscler. Thromb. Vasc. Biol._ 33, 2549–2557 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Murphy, E.

J., Prows, D. R., Stiles, T. & Schroeder, F. Liver and intestinal fatty acid-binding protein expression increases phospholipid content and alters phospholipid fatty acid composition in

L-cell fibroblasts. _Lipids_ 35, 729–738 (2000). Article  CAS  PubMed  Google Scholar  * Maeda, K. _ et al_. Adipocyte/macrophage fatty acid binding proteins control integrated metabolic

responses in obesity and diabetes. _Cell Metab._ 1, 107–119 (2005). Article  CAS  PubMed  Google Scholar  * Coe, N. R., Simpson, M. A. & Bernlohr, D. A. Targeted disruption of the

adipocyte lipid-binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels. _J. Lipid Res._ 40, 967–972 (1999). Article  CAS  PubMed  Google

Scholar  * Shaughnessy, S., Smith, E. R., Kodukula, S., Storch, J. & Fried, S. K. Adipocyte metabolism in adipocyte fatty acid binding protein knockout mice (aP2−/−) after short-term

high-fat feeding: functional compensation by the keratinocyte [correction of keritinocyte] fatty acid binding protein. _Diabetes_ 49, 904–911 (2000). Article  CAS  PubMed  Google Scholar  *

Scheja, L. _ et al_. Altered insulin secretion associated with reduced lipolytic efficiency in aP2−/− mice. _Diabetes_ 48, 1987–1994 (1999). Article  CAS  PubMed  Google Scholar  * Hertzel,

A. V. _ et al_. Lipid metabolism and adipokine levels in fatty acid-binding protein null and transgenic mice. _Am. J. Physiol. Endocrinol. Metab._ 290, E814–E823 (2006). Article  CAS  PubMed

  Google Scholar  * Storch, J. & Thumser, A. E. The fatty acid transport function of fatty acid-binding proteins. _Biochim. Biophys. Acta_ 1486, 28–44 (2000). Article  CAS  PubMed 

Google Scholar  * Schroeder, F. _ et al_. Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription. _Lipids_ 43, 1–17 (2008).

Article  CAS  PubMed  Google Scholar  * Huang, H., Starodub, O., McIntosh, A., Kier, A. B. & Schroeder, F. Liver fatty acid-binding protein targets fatty acids to the nucleus. Real time

confocal and multiphoton fluorescence imaging in living cells. _J. Biol. Chem._ 277, 29139–29151 (2002). Article  CAS  PubMed  Google Scholar  * Yu, S., Levi, L., Siegel, R. & Noy, N.

Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor β/δ (PPARβ/δ). _J. Biol. Chem._ 287, 42195–42205 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Yu, S., Levi, L., Casadesus, G., Kunos, G. & Noy, N. Fatty acid-binding protein 5 (FABP5) regulates cognitive function both by

decreasing anandamide levels and by activating the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in the brain. _J. Biol. Chem._ 289, 12748–12758 (2014). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Tan, N. S. _ et al_. Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating

transcription. _Mol. Cell Biol._ 22, 5114–5127 (2002). Article  CAS  PubMed  PubMed Central  Google Scholar  * Adida, A. & Spener, F. Adipocyte-type fatty acid-binding protein as

inter-compartmental shuttle for peroxisome proliferator activated receptor γ agonists in cultured cell. _Biochim. Biophys. Acta_ 1761, 172–181 (2006). Article  CAS  PubMed  Google Scholar  *

Ayers, S. D., Nedrow, K. L., Gillilan, R. E. & Noy, N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARγ by FABP4. _Biochemistry_ 46, 6744–6752

(2007). Article  CAS  PubMed  Google Scholar  * Makowski, L., Brittingham, K. C., Reynolds, J. M., Suttles, J. & Hotamisligil, G. S. The fatty acid-binding protein, aP2, coordinates

macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor γ and IκB kinase activities. _J. Biol. Chem._

280, 12888–12895 (2005). Article  CAS  PubMed  Google Scholar  * Hotamisligil, G. S. _ et al_. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte

fatty acid binding protein. _Science_ 274, 1377–1379 (1996). Article  CAS  PubMed  Google Scholar  * Bernlohr, D. A., Coe, N. R., Simpson, M. A. & Hertzel, A. V. Regulation of gene

expression in adipose cells by polyunsaturated fatty acids. _Adv. Exp. Med. Biol._ 422, 145–156 (1997). Article  CAS  PubMed  Google Scholar  * Uysal, 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_ 141, 3388–3396 (2000). Article  CAS  PubMed  Google

Scholar  * Maeda, K. _ et al_. Role of the fatty acid binding protein mal1 in obesity and insulin resistance. _Diabetes_ 52, 300–307 (2003). Article  CAS  PubMed  Google Scholar  * Cao, H. _

et al_. Regulation of metabolic responses by adipocyte/macrophage fatty acid-binding proteins in leptin-deficient mice. _Diabetes_ 55, 1915–1922 (2006). Article  CAS  PubMed  Google Scholar

  * Cao, H. _ et al_. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. _Cell_ 134, 933–944 (2008). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Erbay, E. _ et al_. Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. _Nat. Med._ 15, 1383–1391 (2009). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Oh, D. Y. _ et al_. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. _Cell_ 142, 687–698 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Ichimura, A. _ et al_. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. _Nature_ 483, 350–354 (2012).

Article  CAS  PubMed  Google Scholar  * Shen, W. J., Sridhar, K., Bernlohr, D. A. & Kraemer, F. B. Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein.

_Proc. Natl Acad. Sci. USA_ 96, 5528–5532 (1999). Article  CAS  PubMed  PubMed Central  Google Scholar  * Smith, A. J. _ et al_. Physical association between the adipocyte fatty acid-binding

protein and hormone-sensitive lipase: a fluorescence resonance energy transfer analysis. _J. Biol. Chem._ 279, 52399–52405 (2004). Article  CAS  PubMed  Google Scholar  * Hampton, M. _ et

al_. Deep sequencing the transcriptome reveals seasonal adaptive mechanisms in a hibernating mammal. _PLoS ONE_ 6, e27021 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Tontonoz, P., Nagy, L., Alvarez, J. G., Thomazy, V. A. & Evans, R. M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. _Cell_ 93, 241–252 (1998). Article 

CAS  PubMed  Google Scholar  * Fu, Y., Luo, N., Lopes-Virella, M. F. & Garvey, W. T. The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1

macrophages. _Atherosclerosis_ 165, 259–269 (2002). Article  CAS  PubMed  Google Scholar  * Liu, Q. Y. & Nambi, P. Sirolimus upregulates aP2 expression in human monocytes and

macrophages. _Transplant Proc._ 36, 3229–3231 (2004). Article  CAS  PubMed  Google Scholar  * Liu, Q. Y., Quinet, E. & Nambi, P. Adipocyte fatty acid-binding protein (aP2), a newly

identified LXR target gene, is induced by LXR agonists in human THP-1 cells. _Mol. Cell Biochem._ 302, 203–213 (2007). Article  CAS  PubMed  Google Scholar  * Babaev, V. R. _ et al_.

Macrophage Mal1 deficiency suppresses atherosclerosis in low-density lipoprotein receptor-null mice by activating peroxisome proliferator-activated receptor-γ-regulated genes. _Arterioscler.

Thromb. Vasc. Biol._ 31, 1283–1290 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Garin-Shkolnik, T., Rudich, A., Hotamisligil, G. S. & Rubinstein, M. FABP4 attenuates

PPARγ and adipogenesis and is inversely correlated with PPARγ in adipose tissues. _Diabetes_ 63, 900–911 (2014). Article  CAS  PubMed  Google Scholar  * Zimmer, J. S., Dyckes, D. F.,

Bernlohr, D. A. & Murphy, R. C. Fatty acid binding proteins stabilize leukotriene A4: competition with arachidonic acid but not other lipoxygenase products. _J. Lipid Res._ 45, 2138–2144

(2004). Article  CAS  PubMed  Google Scholar  * Dickinson Zimmer, J. S., Voelker, D. R., Bernlohr, D. A. & Murphy, R. C. Stabilization of leukotriene A4 by epithelial fatty acid-binding

protein in the rat basophilic leukemia cell. _J. Biol. Chem._ 279, 7420–7426 (2004). Article  PubMed  CAS  Google Scholar  * Spite, M. _ et al_. Deficiency of the leukotriene B4 receptor,

BLT-1, protects against systemic insulin resistance in diet-induced obesity. _J. Immunol._ 187, 1942–1949 (2011). Article  CAS  PubMed  Google Scholar  * Layne, M. D. _ et al_. Role of

macrophage-expressed adipocyte fatty acid binding protein in the development of accelerated atherosclerosis in hypercholesterolemic mice. _FASEB J._ 15, 2733–2735 (2001). Article  CAS 

PubMed  Google Scholar  * Chan, K. L. _ et al_. Palmitoleate reverses high fat-induced pro-inflammatory macrophage polarization via AMPK. _J. Biol. Chem._

http://dx.doi.org/10.1074/jbc.M115.646992. * Xu, H. _ et al_. Uncoupling lipid metabolism from inflammation through fatty acid binding protein-dependent expression of UCP2. _Mol. Cell Biol._

35, 1055–1065 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Thompson, B. R., Mazurkiewicz-Munoz, A. M., Suttles, J., Carter-Su, C. & Bernlohr, D. A. Interaction of

adipocyte fatty acid-binding protein (AFABP) and JAK2: AFABP/aP2 as a regulator of JAK2 signaling. _J. Biol. Chem._ 284, 13473–13480 (2009). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Semenkovich, C. F. Insulin resistance and atherosclerosis. _J. Clin. Invest._ 116, 1813–1822 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Perrella, M. A. _ et

al_. Absence of adipocyte fatty acid binding protein prevents the development of accelerated atherosclerosis in hypercholesterolemic mice. _FASEB J._ 15, 1774–1776 (2001). Article  CAS 

PubMed  Google Scholar  * Makowski, L. _ et al_. Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis. _Nat. Med._ 7, 699–705

(2001). Article  CAS  PubMed  PubMed Central  Google Scholar  * Boord, J. B. _ et al_. Adipocyte fatty acid-binding protein, aP2, alters late atherosclerotic lesion formation in severe

hypercholesterolemia. _Arterioscler. Thromb. Vasc. Biol._ 22, 1686–1691 (2002). Article  CAS  PubMed  PubMed Central  Google Scholar  * Furuhashi, M. _ et al_. Treatment of diabetes and

atherosclerosis by inhibiting fatty-acid-binding protein aP2. _Nature_ 447, 959–965 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Boord, J. B. _ et al_. Combined

adipocyte-macrophage fatty acid-binding protein deficiency improves metabolism, atherosclerosis, and survival in apolipoprotein E-deficient mice. _Circulation_ 110, 1492–1498 (2004). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Rolph, M. S. _ et al_. Regulation of dendritic cell function and T cell priming by the fatty acid-binding protein AP2. _J. Immunol._ 177,

7794–7801 (2006). Article  CAS  PubMed  Google Scholar  * Reynolds, J. M. _ et al_. Deficiency of fatty acid-binding proteins in mice confers protection from development of experimental

autoimmune encephalomyelitis. _J. Immunol._ 179, 313–321 (2007). Article  CAS  PubMed  Google Scholar  * Elmasri, H. _ et al_. Fatty acid binding protein 4 is a target of VEGF and a

regulator of cell proliferation in endothelial cells. _FASEB J._ 23, 3865–3873 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Harjes, U., Bridges, E., McIntyre, A.,

Fielding, B. A. & Harris, A. L. Fatty acid-binding protein 4, a point of convergence for angiogenic and metabolic signaling pathways in endothelial cells. _J. Biol. Chem._ 289,

23168–23176 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Daly, C. _ et al_. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription

factor FKHR (FOXO1). _Genes Dev._ 18, 1060–1071 (2004). Article  CAS  PubMed  PubMed Central  Google Scholar  * Elmasri, H. _ et al_. Endothelial cell-fatty acid binding protein 4 promotes

angiogenesis: role of stem cell factor/c-kit pathway. _Angiogenesis_ 15, 457–468 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ghelfi, E. _ et al_. Fatty acid binding

protein 4 regulates VEGF-induced airway angiogenesis and inflammation in a transgenic mouse model: implications for asthma. _Am. J. Pathol._ 182, 1425–1433 (2013). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Saint-Geniez, M. _ et al_. Fatty acid binding protein 4 deficiency protects against oxygen-induced retinopathy in mice. _PLoS ONE_ 9, e96253 (2014). Article

  PubMed  PubMed Central  CAS  Google Scholar  * Nieman, K. M. _ et al_. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. _Nat. Med._ 17, 1498–1503

(2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Cataltepe, O. _ et al_. Fatty acid binding protein 4 is expressed in distinct endothelial and non-endothelial cell populations

in glioblastoma. _Neuropathol. Appl. Neurobiol._ 38, 400–410 (2012). Article  CAS  PubMed  Google Scholar  * Lee, D. _ et al_. Expression of fatty acid binding protein 4 is involved in the

cell growth of oral squamous cell carcinoma. _Oncol. Rep._ 31, 1116–1120 (2014). Article  CAS  PubMed  Google Scholar  * Pelsers, M. M. _ et al_. Liver fatty acid-binding protein as a

sensitive serum marker of acute hepatocellular damage in liver transplant recipients. _Clin. Chem._ 48, 2055–2057 (2002). Article  CAS  PubMed  Google Scholar  * Knowlton, A. A., Apstein, C.

S., Saouf, R. & Brecher, P. Leakage of heart fatty acid binding protein with ischemia and reperfusion in the rat. _J. Mol. Cell Cardiol._ 21, 577–583 (1989). Article  CAS  PubMed 

Google Scholar  * Tanaka, T., Hirota, Y., Sohmiya, K., Nishimura, S. & Kawamura, K. Serum and urinary human heart fatty acid-binding protein in acute myocardial infarction. _Clin.

Biochem._ 24, 195–201 (1991). Article  CAS  PubMed  Google Scholar  * Kleine, A. H., Glatz, J. F., Van Nieuwenhoven, F. A. & Van der Vusse, G. J. Release of heart fatty acid-binding

protein into plasma after acute myocardial infarction in man. _Mol. Cell. Biochem._ 116, 155–162 (1992). Article  CAS  PubMed  Google Scholar  * Kanda, T. _ et al_. Intestinal fatty

acid-binding protein is a useful diagnostic marker for mesenteric infarction in humans. _Gastroenterology_ 110, 339–343 (1996). Article  CAS  PubMed  Google Scholar  * Schellekens, D. H. _

et al_. Plasma intestinal fatty acid-binding protein levels correlate with morphologic epithelial intestinal damage in a human translational ischemia-reperfusion model. _J. Clin.

Gastroenterol._ 48, 253–260 (2014). Article  CAS  PubMed  Google Scholar  * Akbal, E. _ et al_. Liver fatty acid-binding protein is a diagnostic marker to detect liver injury due to chronic

hepatitis C infection. _Arch. Med. Res._ 44, 34–38 (2013). Article  CAS  PubMed  Google Scholar  * Foucaud, L. _ et al_. Output of liver fatty acid-binding protein (L-FABP) in bile.

_Biochim. Biophys. Acta_ 1436, 593–599 (1999). Article  CAS  PubMed  Google Scholar  * Specht, B. _ et al_. Mammary derived growth inhibitor is not a distinct protein but a mix of heart-type

and adipocyte-type fatty acid-binding protein. _J. Biol. Chem._ 271, 19943–19949 (1996). Article  CAS  PubMed  Google Scholar  * Brandt, R. _ et al_. A 13-kilodalton protein purified from

milk fat globule membranes is closely related to a mammary-derived growth inhibitor. _Biochemistry_ 27, 1420–1425 (1988). Article  CAS  PubMed  Google Scholar  * Bronsky, J. _ et al_.

Adiponectin, adipocyte fatty acid binding protein, and epidermal fatty acid binding protein: proteins newly identified in human breast milk. _Clin. Chem._ 52, 1763–1770 (2006). Article  CAS

  PubMed  Google Scholar  * Cao, H. _ et al_. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. _Cell Metab._ 17, 768–778 (2013). Article  PubMed 

PubMed Central  CAS  Google Scholar  * Xu, A. _ et al_. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. _Clin. Chem._ 52,

405–413 (2006). Article  CAS  PubMed  Google Scholar  * Schlottmann, I., Ehrhart-Bornstein, M., Wabitsch, M., Bornstein, S. R. & Lamounier-Zepter, V. Calcium-dependent release of

adipocyte fatty acid binding protein from human adipocytes. _Int. J. Obes. (Lond.)_ 38, 1221–1227 (2014). Article  CAS  Google Scholar  * Kaess, B. M. _ et al_. Cardiometabolic correlates

and heritability of fetuin-A, retinol-binding protein 4, and fatty-acid binding protein 4 in the Framingham Heart Study. _J. Clin. Endocrinol. Metab._ 97, E1943–E1947 (2012). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Chow, W. S. _ et al_. Elevated circulating adipocyte-fatty acid binding protein levels predict incident cardiovascular events in a community-based

cohort: a 12-year prospective study. _J. Am. Heart Assoc._ 2, e004176 (2013). Article  PubMed  PubMed Central  CAS  Google Scholar  * von Eynatten, M. _ et al_. Circulating adipocyte fatty

acid-binding protein levels and cardiovascular morbidity and mortality in patients with coronary heart disease: a 10-year prospective study. _Arterioscler. Thromb. Vasc. Biol._ 32, 2327–2335

(2012). Article  CAS  PubMed  Google Scholar  * Tso, A. W. _ et al_. Serum adipocyte fatty acid binding protein as a new biomarker predicting the development of type 2 diabetes: a 10-year

prospective study in a Chinese cohort. _Diabetes Care_ 30, 2667–2672 (2007). Article  CAS  PubMed  Google Scholar  * Ishimura, S. _ et al_. Circulating levels of fatty acid-binding protein

family and metabolic phenotype in the general population. _PLoS ONE_ 8, e81318 (2013). Article  PubMed  PubMed Central  Google Scholar  * Tso, A. W. _ et al_. Serum adipocyte fatty

acid-binding protein associated with ischemic stroke and early death. _Neurology_ 76, 1968–1975 (2011). Article  CAS  PubMed  Google Scholar  * Balci, M. M. _ et al_. Serum levels of

adipocyte fatty acid-binding protein are independently associated with left ventricular mass and myocardial performance index in obstructive sleep apnea syndrome. _J. Investig. Med._ 60,

1020–1026 (2012). Article  PubMed  CAS  Google Scholar  * Hancke, K., Grubeck, D., Hauser, N., Kreienberg, R. & Weiss, J. M. Adipocyte fatty acid-binding protein as a novel prognostic

factor in obese breast cancer patients. _Breast Cancer Res. Treat._ 119, 367–367 (2010). Article  CAS  PubMed  Google Scholar  * Yoo, H. J. _ et al_. Serum adipocyte fatty acid-binding

protein is associated independently with vascular inflammation: analysis with 18F-fluorodeoxyglucose positron emission tomography. _J. Clin. Endocrinol. Metab._ 96, E488–E492 (2011). Article

  CAS  PubMed  Google Scholar  * Schmilovitz-Weiss, H. _ et al_. Serum adipocyte fatty acid binding protein in liver transplant recipients and the metabolic syndrome. _Ann. Hepatol._ 11,

343–349 (2012). Article  CAS  PubMed  Google Scholar  * Haluzikova, D. _ et al_. Serum concentrations of adipocyte fatty acid binding protein in patients with anorexia nervosa. _Physiol.

Res._ 58, 577–581 (2009). Article  CAS  PubMed  Google Scholar  * Comerford, K. B., Buchan, W. & Karakas, S. E. The effects of weight loss on FABP4 and RBP4 in obese women with metabolic

syndrome. _Horm. Metab. Res._ 46, 224–231 (2014). CAS  PubMed  Google Scholar  * Stejskal, D., Karpisek, M. & Bronsky, J. Serum adipocyte-fatty acid binding protein discriminates

patients with permanent and temporary body weight loss. _J. Clin. Lab. Anal._ 22, 380–382 (2008). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tuncman, G. _ et al_. A genetic

variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. _Proc. Natl Acad. Sci. USA_ 103, 6970–6975 (2006).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Saksi, J. _ et al_. Low-expression variant of fatty acid-binding protein 4 favors reduced manifestations of atherosclerotic disease

and increased plaque stability. _Circ. Cardiovasc. Genet._ 7, 588–598 (2014). Article  CAS  PubMed  Google Scholar  * Wang, J. _ et al_. FABP4: a novel candidate gene for polycystic ovary

syndrome. _Endocrine_ 36, 392–396 (2009). Article  CAS  PubMed  Google Scholar  * Bhushan, B. _ et al_. Fatty-acid binding protein 4 gene polymorphisms and plasma levels in children with

obstructive sleep apnea. _Sleep Med._ 12, 666–671 (2011). Article  PubMed  PubMed Central  Google Scholar  * Unger, R. H. & Cherrington, A. D. Glucagonocentric restructuring of diabetes:

a pathophysiologic and therapeutic makeover. _J. Clin. Invest._ 122, 4–12 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wu, L. E. _ et al_. Identification of fatty acid

binding protein 4 as an adipokine that regulates insulin secretion during obesity. _Mol. Metab._ 3, 465–473 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Kralisch, S. _ et

al_. Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice _in vivo_. _Obesity (Silver Spring)_ 23, 1007–1013 (2015). Article  CAS  Google Scholar  * Girona, J.

_ et al_. FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway. _PLoS ONE_ 8, e81914 (2013). Article  PubMed  PubMed Central  CAS  Google

Scholar  * Aragones, G. _ et al_. Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells. _Cardiovasc. Diabetol._ 11, 72 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Lamounier-Zepter, V. _ et al_. Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity

and heart disease. _Circ. Res._ 105, 326–334 (2009). Article  CAS  PubMed  Google Scholar  * Lamounier-Zepter, V. _ et al_. Interaction of epoxyeicosatrienoic acids and adipocyte fatty

acid-binding protein in the modulation of cardiomyocyte contractility. _Int. J. Obes. (Lond.)_ 39, 755–761 (2015). Article  CAS  Google Scholar  * Riquelme, C. A. _ et al_. Fatty acids

identified in the Burmese python promote beneficial cardiac growth. _Science_ 334, 528–531 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ertunc, M. E. _ et al_. Secretion

of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity. _J. Lipid Res._ 56, 423–434 (2015). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Sun, K., Kusminski, C. M. & Scherer, P. E. Adipose tissue remodeling and obesity. _J. Clin. Invest._ 121, 2094–2101 (2011). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Kralisch, S. _ et al_. Adipocyte fatty acid-binding protein is released from adipocytes by a non-conventional mechanism. _Int. J. Obes. (Lond.)_ 38, 1251–1254

(2014). Article  CAS  Google Scholar  * Lee, M. Y. _ et al_. Chronic administration of BMS309403 improves endothelial function in apolipoprotein E-deficient mice and in cultured human

endothelial cells. _Br. J. Pharmacol._ 162, 1564–1576 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hoo, R. L. _ et al_. Pharmacological inhibition of adipocyte fatty acid

binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice. _J. Hepatol._ 58, 358–364 (2013). Article  CAS  PubMed  Google Scholar  * Lehmann, F. _ et al_.

Discovery of inhibitors of human adipocyte fatty acid-binding protein, a potential type 2 diabetes target. _Bioorg. Med. Chem. Lett._ 14, 4445–4448 (2004). Article  CAS  PubMed  Google

Scholar  * Barf, T. _ et al_. N.-Benzyl-indolo carboxylic acids: design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors. _Bioorg. Med. Chem.

Lett._ 19, 1745–1748 (2009). Article  CAS  PubMed  Google Scholar  * Liu, X. _ et al_. New aromatic substituted pyrazoles as selective inhibitors of human adipocyte fatty acid-binding

protein. _Bioorg. Med. Chem. Lett._ 21, 2949–2952 (2011). Article  CAS  PubMed  Google Scholar  * Chen, J., Wang, J. & Zhu, W. Binding modes of three inhibitors 8CA, F8A and I4A to

A-FABP studied based on molecular dynamics simulation. _PLoS ONE_ 9, e99862 (2014). Article  PubMed  PubMed Central  CAS  Google Scholar  * Xu, Q. _ et al_. Design, synthesis and biological

evaluation of thiazole- and indole-based derivatives for the treatment of type II diabetes. _Eur. J. Med. Chem._ 52, 70–81 (2012). Article  CAS  PubMed  Google Scholar  * Wang, Y. _ et al_.

Discovery of FDA-approved drugs as inhibitors of fatty acid binding protein 4 using molecular docking screening. _J. Chem. Inf. Model_ 54, 3046–3050 (2014). Article  CAS  PubMed  Google

Scholar  * Cai, H. Y. _ et al_. Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 _in vitro_ and lowers the blood glucose level in _db/db_ mice. _Acta

Pharmacol. Sin._ 34, 1397–1402 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Aouadi, M. _ et al_. Gene silencing in adipose tissue macrophages regulates whole-body

metabolism in obese mice. _Proc. Natl Acad. Sci. USA_ 110, 8278–8283 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Aouadi, M. _ et al_. Orally delivered siRNA targeting

macrophage Map4k4 suppresses systemic inflammation. _Nature_ 458, 1180–1184 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Won, Y. W. _ et al_. Oligopeptide complex for

targeted non-viral gene delivery to adipocytes. _Nat. Mater._ 13, 1157–1164 (2014). Article  CAS  PubMed  Google Scholar  * Miao, X. _ et al_. The mAb against adipocyte fatty acid-binding

protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway. _Mol. Cell. Endocrinol._ 403, 1–9 (2015). Article  CAS  PubMed 

Google Scholar  * Herroon, M. K. _ et al_. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. _Oncotarget_ 4, 2108–2123 (2013). Article  PubMed  PubMed

Central  Google Scholar  * Yore, M. M. _ et al_. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. _Cell_ 159, 318–332 (2014). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Maceyka, M. & Spiegel, S. Sphingolipid metabolites in inflammatory disease. _Nature_ 510, 58–67 (2014). Article  CAS  PubMed  PubMed

Central  Google Scholar  * NCBI. _Fabp4 [Mus musculus] GenBank: CAJ18597.1_ [online], (2005). Download references ACKNOWLEDGEMENTS The authors thank members of the Hotamisligil and Bernlohr

laboratories for helpful discussions. We thank A. P. Arruda for assistance in generating the initial figures, and K. Claiborn for critical reading and editing of the manuscript. The

Hotamisligil laboratory is supported in this area by research funding from the NIH (grant number DK064360) and a sponsored research agreement with Union Chimique Belge. The Bernlohr

laboratory is supported by the NIH (grant number DK053189). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H.

Chan School of Public Health, 677 Huntington Avenue, Boston, 02115, MA, USA Gökhan S. Hotamisligil * Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota,

321 Church Street SE, Minneapolis, 55455, MN, USA David A. Bernlohr Authors * Gökhan S. Hotamisligil View author publications You can also search for this author inPubMed Google Scholar *

David A. Bernlohr View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS Both authors researched data for the article, discussed the content, and

wrote, reviewed and edited the manuscript before submission. CORRESPONDING AUTHORS Correspondence to Gökhan S. Hotamisligil or David A. Bernlohr. ETHICS DECLARATIONS COMPETING INTERESTS

G.S.H. receives research funding under a sponsored agreement with Union Chimique Belge. D.A.B. declares no competing interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FILE 1 The association

of circulating FABP4 with different human diseases.This figure is an adaptation of Figure 3 in the main text, but includes a complete list of references for the association of circulating

FABP4 with different human diseases. Abbreviations: FABP4, fatty acid binding protein 4; NAFLD, nonalcoholic fatty-liver disease. (PDF 96 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1

POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Hotamisligil, G., Bernlohr, D. Metabolic functions of FABPs—mechanisms and therapeutic implications. _Nat Rev Endocrinol_ 11, 592–605 (2015). https://doi.org/10.1038/nrendo.2015.122

Download citation * Published: 11 August 2015 * Issue Date: October 2015 * DOI: https://doi.org/10.1038/nrendo.2015.122 SHARE THIS ARTICLE Anyone you share the following link with will be

able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing

initiative