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. 2014 Mar 14;3(4):465-73.
doi: 10.1016/j.molmet.2014.02.005. eCollection 2014 Jul.

Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity

Lindsay E Wu  1 , Dorit Samocha-Bonet  1 , P Tess Whitworth  2 , Daniel J Fazakerley  2 , Nigel Turner  1 , Trevor J Biden  3 , David E James  4 , James Cantley  5
Affiliations

Identification of fatty acid binding protein 4 as an adipokine that regulates insulin secretion during obesity

Lindsay E Wu et al. Mol Metab. .

Abstract

A critical feature of obesity is enhanced insulin secretion from pancreatic β-cells, enabling the majority of individuals to maintain glycaemic control despite adiposity and insulin resistance. Surprisingly, the factors coordinating this adaptive β-cell response with adiposity have not been delineated. Here we show that fatty acid binding protein 4 (FABP4/aP2) is an adipokine released from adipocytes under obesogenic conditions, such as hypoxia, to augment insulin secretion. The insulinotropic action of FABP4 was identified using an in vitro system that recapitulates adipocyte to β-cell endocrine signalling, with glucose-stimulated insulin secretion (GSIS) as a functional readout, coupled with quantitative proteomics. Exogenous FABP4 potentiated GSIS in vitro and in vivo, and circulating FABP4 levels correlated with GSIS in humans. Insulin inhibited FABP4 release from adipocytes in vitro, in mice and in humans, consistent with feedback regulation. These data suggest that FABP4 and insulin form an endocrine loop coordinating the β-cell response to obesity.

Keywords: Adipocyte; Adipokine; BMI, body mass index; Beta-cell; ELISA, enzyme-linked immunosorbant assay; FABP4; GSIS, glucose-stimulated insulin secretion; IBMX, 3-Isobutyl-1-methylxanthine; Insulin secretion; NEFA, non-esterified fatty acid; Obesity; SILAC, stable-isotope labelling by amino acids in cell culture; T2D, type 2 diabetes; cAMP, cyclic-AMP.

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Figures

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Graphical abstract
Figure 1
Figure 1
Identification of FABP4 as a candidate insulinotropic protein released from adipocytes. A, B, Media were conditioned by 18 h culture with 3T3-L1 adipocytes under normoxia (21% O2) or hypoxia (1% O2), before a >10 kDa protein fraction was purified. Pancreatic islets isolated from mice were cultured for 24 h in media enriched with this conditioned media protein fraction, or unconditioned media, before insulin secretion were measured for 1 h. n = 9 batches of conditioned media. C, Relative abundance of proteins released from hypoxic vs normoxic 3T3L1 adipocytes, detected using SILAC labelling and mass spectrometry. D, Fatty acid binding protein 4 (FABP4) and adiponectin spectra. E, Western blots showing increased FABP4 release (extracellular), and stable intracellular FABP4 levels, during hypoxia; n = 6. F, Quantification of FABP4 release by ELISA; n = 5. G, FABP4 and FABP5 were detected by western blotting protein lysates from a range of mouse tissues. FABP4 protein was restricted to brown and white adipose tissue. H, Mice were fed a standard lab diet (chow/lean) or high-fat diet (HFD/obese) for 40 weeks. Serum FABP4 concentrations were significantly increased during obesity. Data presented as mean ± SEM. *P < 0.05, ***P < 0.001 by t-test. See also Table S1 and data file S1.
Figure 2
Figure 2
FABP4 potentiates glucose-stimulated insulin secretion in vitro and in vivo. A, B, Isolated mouse islets were exposed to recombinant FABP4 (rFABP4) for 24 h, with or without the fatty acids palmitate or linoleate, before 20 mM GSIS was assessed for 1 h (A), and islet insulin content assayed after lysis (B); n = 3–4. C–F, Osmotic mini-pumps containing rFABP4–linoleate (1:1) or saline were implanted (subcutaneously) in mice for 7 days providing continuous rFABP4 infusion (1.22 μg/h), before glucose tolerance (C), insulin secretion (D) and body mass (F) were assessed; n = 15 mice. To account for day-to-day variation in insulin assay results, mean insulin levels 30 min post-glucose from each experimental day were presented as paired treatment groups (n = 3) (E). G, Intraperitoneal co-injection of an rFABP4 bolus (80 μg), or PBS control, along with glucose (2 g/kg) revealed that acute administration of FABP4 does not alter glucose tolerance; n = 5 mice. Data presented as mean ± SEM. *P < 0.05 by unpaired (A) or paired (E) t-test. P < 0.01 by 2-way ANOVA for treatment effect indicated in C. See also Figure S1.
Figure 3
Figure 3
Serum FABP4 levels predict the glucose-stimulated insulin secretion response in humans. Non-diabetic participants were stratified based on body mass index <25 (n = 6) or >25 (n = 11) kg/m2. Intravenous glucose tolerance (0.3 g/kg) was tightly regulated (A) whereas glucose-stimulated insulin secretion was highly variable (B, C). Serum FABP4 levels increased with body mass index (D) and positively correlated with both adiposity (E, P < 0.0001) and glucose-stimulated insulin secretion (F, P < 0.05) using Pearson's correlation coefficients (n = 17). Data presented as mean ± SEM. *P < 0.05 by t-test. See also Table S2.
Figure 4
Figure 4
Reciprocal regulation of FABP4 release by insulin. A, In mice, plasma FABP4, NEFA and blood glucose were suppressed 30 min after i.p. insulin injection (0.75 U/kg); n = 12. B, In humans, serum FABP4 was suppressed following 2 h insulin infusion (60 mU/body surface area/min), during a hyperinsulinaemic–euglycaemic clamp; n = 17. C, Western blots showing insulin suppression of FABP4 release from normoxic (21% O2) and hypoxic (1% O2) 3T3-L1 adipocytes during 18 h cultures, with adiponectin secretion enhanced by insulin. D, Western blots of 3T3-L1 adipocytes treated with beta-3 adrenoreceptor agonists (CL316243 or BRL37344; 0.1 μg/ml). E, Western blots of 3T3-L1 adipocytes treated with 3-Isobutyl-1-methylxanthine (IBMX; 500 μmol/l) to enhance cellular cyclic-AMP levels. Data presented as mean ± SEM. **P < 0.01, ***P < 0.001 by paired t-test.
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References

    1. Yach D., Stuckler D., Brownell K.D. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nature Medicine. 2006;12:62–66. - PubMed
    1. Zimmet P., Alberti K.G., Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782–787. - PubMed
    1. Eckel R.H., Grundy S.M., Zimmet P.Z. The metabolic syndrome. Lancet. 2005;365:1415–1428. - PubMed
    1. Alberti K.G.M.M., Eckel R.H., Grundy S.M., Zimmet P.Z., Cleeman J.I., Donato K.A. Harmonizing the metabolic syndrome. Circulation. 2009;120:1640–1645. - PubMed
    1. Calle E.E., Thun M.J. Obesity and cancer. Oncogene. 2004;23:6365–6378. - PubMed

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