A-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes

Lingling Shu,Lai Yee Cheong,Stefan R Bornstein,Jiao Guo,Ruby L C Hoo,Xiaoping Wu,Aimin Xu,Xianglu Rong,Yong Pan,Ida P C Lee

doi:10.1038/ncomms14147

Abstract

The adipokine adipocyte fatty acid-binding protein (A-FABP) has been implicated in obesity-related cardio-metabolic complications. Here we show that A-FABP increases thermogenesis by promoting the conversion of T4 to T3 in brown adipocytes. We find that A-FABP levels are increased in both white (WAT) and brown (BAT) adipose tissues and the bloodstream in response to thermogenic stimuli. A-FABP knockout mice have reduced thermogenesis and whole-body energy expenditure after cold stress or after feeding a high-fat diet, which can be reversed by infusion of recombinant A-FABP. Mechanistically, A-FABP induces the expression of type-II iodothyronine deiodinase in BAT via inhibition of the nuclear receptor liver X receptor α, thereby leading to the conversion of thyroid hormone from its inactive form T4 to active T3. The thermogenic responses to T4 are abrogated in A-FABP KO mice, but enhanced by A-FABP. Thus, A-FABP acts as a physiological stimulator of BAT-mediated adaptive thermogenesis.

Highlights

The adipokine adipocyte fatty acid-binding protein (A-FABP) has been implicated in obesityrelated cardio-metabolic complications
The authors speculated that A/E-FABP may have a key role in facilitating free fatty acids (FFAs) transport from circulation to brown adipose tissue (BAT) providing energy substrate for thermogenesis[28], this hypothesis was not experimentally validated
We demonstrated that A-FABP is a physiological regulator of adaptive thermogenesis in response to both high-fat diet (HFD) and cold exposure, through its intracellular actions to promote the activation of thyroid hormones and its endocrine actions to transport FFAs released from white adipose tissue (WAT) to BAT for b-oxidation (Fig. 9)

Summary

Introduction

The adipokine adipocyte fatty acid-binding protein (A-FABP) has been implicated in obesityrelated cardio-metabolic complications. We find that A-FABP levels are increased in both white (WAT) and brown (BAT) adipose tissues and the bloodstream in response to thermogenic stimuli. A-FABP induces the expression of type-II iodothyronine deiodinase in BAT via inhibition of the nuclear receptor liver X receptor a, thereby leading to the conversion of thyroid hormone from its inactive form T4 to active T3. Thyroid hormones contribute to adaptive thermogenesis in BAT by coordinating with SNS to induce expression of thermogenic genes[6]. A-FABP knockout (KO) mice are protected against high-fat diet (HFD)-induced metabolic dysfunction but exhibit increased adiposity comparing with their wild-type (WT) littermates[23]. Expression of A-FABP messenger RNA (mRNA) is increased together with other thermogenic genes in BAT and WAT of HFD-induced UCP-1 deficient mice, suggesting that A-FABP might mediate a compensatory mechanism to maintain energy homeostasis[27]. The underlying mechanism whereby A-FABP regulates energy metabolism remains elusive

Methods

Results

Conclusion