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.
Highlights
The current global obesity epidemic is associated with a cluster of diseases including type 2 diabetes (T2D) [1,2], cardiovascular disease [3,4] and cancer [5,6]
Proteins released from hypoxic adipocytes modulate insulin secretion Recent evidence indicates that nutrient excess in humans and mice is accompanied by a rapid expansion of fat mass that exceeds vascular capacity leading to transient adipose tissue hypoxia [28e30]
We reasoned that this scenario might provide an ideal experimental model system with which to identify insulinotropic adipokines released during obesity
Summary
The current global obesity epidemic is associated with a cluster of diseases including type 2 diabetes (T2D) [1,2], cardiovascular disease [3,4] and cancer [5,6]. Obesity is often accompanied by insulin resistance and enhanced insulin secretion from pancreatic b-cells [7,8]. If GSIS remains tightly coupled to insulin resistance, normal glycaemic control is maintained. The molecular mechanisms that coordinate enhanced GSIS with increased adiposity to maintain glycaemic control in the pre-diabetic state are not understood. A major determinant of insulin secretion, appears largely uncoupled from the pronounced enhancement of insulin secretion in obese mice [10] and humans [8] that display blood glucose levels within the normal range. Non-esterified fatty acids (NEFAs) potentiate GSIS [11], yet increases in adiposity often occur independently from changes in plasma NEFA [12] suggesting that NEFA are not a common driver of compensatory insulin secretion
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