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Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes.

Burak MF, Inouye KE, White A, Lee A, Tuncman G, Calay ES, Sekiya M, Tirosh A, Eguchi K, Birrane G, Lightwood D, Howells L, Odede G, Hailu H, West S, Garlish R, Neale H, Doyle C, Moore A, Hotamisligil GS
Sci Transl Med 7 319ra205 (2015)
Cited: 42 times
EuropePMC logo PMID: 26702093

Abstract

The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb-mediated therapeutic constitutes a feasible approach for the treatment of diabetes.

Articles - 5d8j mentioned but not cited (2)

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Reviews citing this publication (11)

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Articles citing this publication (29)

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  2. Plasma Levels of Fatty Acid-Binding Protein 4, Retinol-Binding Protein 4, High-Molecular-Weight Adiponectin, and Cardiovascular Mortality Among Men With Type 2 Diabetes: A 22-Year Prospective Study. Liu G, Ding M, Chiuve SE, Rimm EB, Franks PW, Meigs JB, Hu FB, Sun Q. Arterioscler. Thromb. Vasc. Biol. 36 2259-2267 (2016)
  3. Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue. Chen W, Dong J, Plate L, Mortenson DE, Brighty GJ, Li S, Liu Y, Galmozzi A, Lee PS, Hulce JJ, Cravatt BF, Saez E, Powers ET, Wilson IA, Sharpless KB, Kelly JW. J. Am. Chem. Soc. 138 7353-7364 (2016)
  4. A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes. Shu L, Hoo RL, Wu X, Pan Y, Lee IP, Cheong LY, Bornstein SR, Rong X, Guo J, Xu A. Nat Commun 8 14147 (2017)
  5. Circulating level of fatty acid-binding protein 4 is an independent predictor of metabolic dysfunction-associated fatty liver disease in middle-aged and elderly individuals. Tanaka M, Takahashi S, Higashiura Y, Sakai A, Koyama M, Saitoh S, Shimamoto K, Ohnishi H, Furuhashi M. J Diabetes Investig 13 878-888 (2022)
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  7. Transcriptome and Metabolome Analyses in Exogenous FABP4- and FABP5-Treated Adipose-Derived Stem Cells. Yamamoto T, Furuhashi M, Sugaya T, Oikawa T, Matsumoto M, Funahashi Y, Matsukawa Y, Gotoh M, Miura T. PLoS ONE 11 e0167825 (2016)
  8. Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Chung JY, Ain QU, Song Y, Yong SB, Kim YH. Genome Res 29 1442-1452 (2019)
  9. Ectopic Fatty Acid-Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury. Fuseya T, Furuhashi M, Matsumoto M, Watanabe Y, Hoshina K, Mita T, Ishimura S, Tanaka M, Miura T. J Am Heart Assoc 6 (2017)
  10. Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins. Charles KN, Li MD, Engin F, Arruda AP, Inouye K, Hotamisligil GS. Cell Rep 21 393-402 (2017)
  11. Circulating Adipose Fatty Acid Binding Protein Is a New Link Underlying Obesity-Associated Breast/Mammary Tumor Development. Hao J, Zhang Y, Yan X, Yan F, Sun Y, Zeng J, Waigel S, Yin Y, Fraig MM, Egilmez NK, Suttles J, Kong M, Liu S, Cleary MP, Sauter E, Li B. Cell Metab. 28 689-705.e5 (2018)
  12. A hormone complex of FABP4 and nucleoside kinases regulates islet function. Prentice KJ, Saksi J, Robertson LT, Lee GY, Inouye KE, Eguchi K, Lee A, Cakici O, Otterbeck E, Cedillo P, Achenbach P, Ziegler AG, Calay ES, Engin F, Hotamisligil GS. Nature 600 720-726 (2021)
  13. Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice. Lee YS, Kim JY, Oh KS, Chung SW. J Cachexia Sarcopenia Muscle 8 839-850 (2017)
  14. Macrophage FABP4 is required for neutrophil recruitment and bacterial clearance in Pseudomonas aeruginosa pneumonia. Liang X, Gupta K, Quintero JR, Cernadas M, Kobzik L, Christou H, Pier GB, Owen CA, Çataltepe S. FASEB J 33 3562-3574 (2019)
  15. Multiscale engineering of immune cells and lymphoid organs. Kim S, Shah SB, Graney PL, Singh A, Singh A. Nat Rev Mater 4 355-378 (2019)
  16. Serum FABP5 concentration is a potential biomarker for residual risk of atherosclerosis in relation to cholesterol efflux from macrophages. Furuhashi M, Ogura M, Matsumoto M, Yuda S, Muranaka A, Kawamukai M, Omori A, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Harada-Shiba M, Shimamoto K, Miura T. Sci Rep 7 217 (2017)
  17. Treatment with anagliptin, a DPP-4 inhibitor, decreases FABP4 concentration in patients with type 2 diabetes mellitus at a high risk for cardiovascular disease who are receiving statin therapy. Furuhashi M, Sakuma I, Morimoto T, Higashiura Y, Sakai A, Matsumoto M, Sakuma M, Shimabukuro M, Nomiyama T, Arasaki O, Node K, Ueda S. Cardiovasc Diabetol 19 89 (2020)
  18. Comparison of plasma fatty acid binding protein 4 concentration in venous and capillary blood. Numao S, Nagasawa Y, Goromaru N, Tamaki S. PLoS ONE 14 e0226374 (2019)
  19. Contribution of a first-degree family history of diabetes to increased serum adipocyte fatty acid binding protein levels independent of body fat content and distribution. Hu X, Pan X, Ma X, Luo Y, Xu Y, Xiong Q, Xiao Y, Bao Y, Jia W. Int J Obes (Lond) 40 1649-1654 (2016)
  20. Discovery of Cobimetinib as a novel A-FABP inhibitor using machine learning and molecular docking-based virtual screening. Yang S, Li S, Chang J. RSC Adv 12 13500-13510 (2022)
  21. Elevated circulating FABP4 concentration predicts cardiovascular death in a general population: a 12-year prospective study. Saito N, Furuhashi M, Koyama M, Higashiura Y, Akasaka H, Tanaka M, Moniwa N, Ohnishi H, Saitoh S, Ura N, Shimamoto K, Miura T. Sci Rep 11 4008 (2021)
  22. Endothelial-derived FABP4 constitutes the majority of basal circulating hormone and regulates lipolysis-driven insulin secretion. Inouye KE, Prentice KJ, Lee A, Wang ZB, Dominguez-Gonzalez C, Chen MX, Riveros JK, Burak MF, Lee GY, Hotamışlıgil GS. JCI Insight 8 e164642 (2023)
  23. FABP4 blocker attenuates colonic hypomotility and modulates white adipose tissue-derived hormone levels in mouse models mimicking constipation-predominant IBS. Mosińska P, Jacenik D, Sałaga M, Wasilewski A, Cygankiewicz A, Sibaev A, Mokrowiecka A, Małecka-Panas E, Pintelon I, Storr M, Timmermans JP, Krajewska WM, Fichna J. Neurogastroenterol. Motil. 30 e13272 (2018)
  24. High Serum FABP4 Levels are Negatively Associated with the Reversion from Prediabetes to Normal Glucose Tolerance: A 2-Year Retrospective Cohort Community Study. Gu M, Lin Y, Gai X, Wei X, Lu C, Wang Y, Ding X, Peng Y, Ma Y. Diabetes Metab Syndr Obes 15 2217-2225 (2022)
  25. Metabolic Changes in Androgen-Deprived Nondiabetic Men With Prostate Cancer Are Not Mediated by Cytokines or aP2. Gagliano-Jucá T, Burak MF, Pencina KM, Li Z, Edwards RR, Travison TG, Basaria S. J. Clin. Endocrinol. Metab. 103 3900-3908 (2018)
  26. Serum FABP4 concentrations decrease after Roux-en-Y gastric bypass but not after intensive medical management. Jahansouz C, Xu H, Kizy S, Thomas AJ, Josephrajan A, Hertzel AV, Foncea R, Connett JC, Billington CJ, Jensen M, Korner J, Bernlohr DA, Ikramuddin S. Surgery 165 571-578 (2019)
  27. Sympathetic tone dictates the impact of lipolysis on FABP4 secretion. Prentice KJ, Lee A, Cedillo P, Inouye KE, Ertunc ME, Riveros JK, Lee GY, Hotamisligil GS. J Lipid Res 64 100386 (2023)
  28. The adipokine FABP4 is a key regulator of neonatal glucose homeostasis. Ron I, Lerner RK, Rathaus M, Livne R, Ron S, Barhod E, Hemi R, Tirosh A, Strauss T, Ofir K, Goldstein I, Pessach IM, Tirosh A. JCI Insight 6 e138288 (2021)
  29. Unconventional Secretion of Adipocyte Fatty Acid Binding Protein 4 Is Mediated By Autophagic Proteins in a Sirtuin-1-Dependent Manner. Josephrajan A, Hertzel AV, Bohm EK, McBurney MW, Imai SI, Mashek DG, Kim DH, Bernlohr DA. Diabetes 68 1767-1777 (2019)


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