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

Lindsay E Wu; Dorit Samocha-Bonet; P Tess Whitworth; Daniel J Fazakerley; Nigel Turner; Trevor J Biden; David E James; James Cantley

doi:10.1016/j.molmet.2014.02.005

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

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

Authors

Lindsay E Wu¹, Dorit Samocha-Bonet¹, P Tess Whitworth², Daniel J Fazakerley², Nigel Turner¹, Trevor J Biden³, David E James⁴, James Cantley⁵

Affiliations

¹ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; School of Medical Sciences, University of New South Wales, New South Wales 2052, Australia.
² Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
³ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
⁴ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; The Charles Perkins Centre, School of Molecular Biosciences, School of Medicine, University of Sydney, New South Wales 2006, Australia.
⁵ Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia ; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, New South Wales 2010, Australia ; Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.

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.