GLUT1 mediates the therapeutic benefits of FGF21 by facilitating futile lipid cycling in adipocytes

Abstract

Fibroblast growth factor 21 (FGF21) is a stress-induced peptide hormone that is mainly derived from hepatocytes and regulates glucose-lipid metabolism and energy homeostasis. It is a promising drug candidate for hyperlipidemia, fatty liver, and obesity-related metabolic dysfunction, considering the favorable results from both pre-clinical studies and clinical trials with FGF21 analogs. FGF21 acts on its target organs by binding the receptor complex consisting of FGFR1 and the obligatory co-receptor β-Klotho, which is highly expressed in the liver, adipose tissues, pancreas, and hypothalamus. Adipose tissues have been confirmed as the critical target organs of FGF21 by using adipocyte-specific β-Klotho knockout mouse model and mediate the therapeutic benefits of FGF21 via multiple pathways.

FGF21 promotes glucose uptake in adipocytes in an insulin-independent manner, accompanied with robust upregulation of glucose transporter 1 (GLUT1) expression. However, whether adipocyte GLUT1 mediates FGF21-induced glucose uptake and systemic therapeutic benefits remain unknown. This project focuses on the key scientific question whether and how the GLUT1 in adipocytes mediates the therapeutic effects of FGF21 in treating diet-induced obesity. Adipocyte-specific Glut1 knockout mice were utilized to investigate the complex interplay between GLUT1 and FGF21 involved in the regulation of glucose-lipid metabolism and energy homeostasis in adipose tissues and the entire body under the context of obesity. Through a series of in vivo and in vitro experiments, we demonstrated that GLUT1 in adipocytes mediates the effect of FGF21 in promoting glucose uptake in adipose tissue, as well as improving glucose and lipid homeostasis. In addition, GLUT1 in adipocytes mediates the therapeutic effects of FGF21 in weight loss, increased energy expenditure, and amelioration of fatty liver. Therefore, our study highlights the essential role of GLUT1 in adipocytes for the efficacy of FGF21 therapeutic benefits in the body. Mechanically, our results demonstrated that adipocyte GLUT1 mediates the therapeutic benefits of FGF21 by enhancing “futile lipid cycle”, referring to a continuous cycle of lipolysis and re-esterification that consumes excessive FFA and utilizes more energy. The completion of this project helps to elucidate the mechanism of FGF21 in improving diabetes and related metabolic syndrome, contributing to the clinical translation and application of new anti-diabetic drugs targeting FGF21.