Paracrine FGFs target skeletal muscle to exert potent anti-hyperglycemic effects

Lei Ying, Luyao Wang, Kaiwen Guo, Yushu Hou, Na Li, Shuyi Wang, Xingfeng Liu, Qijin Zhao, Jie Zhou, Longwei Zhao, Jianlou Niu, Chuchu Chen, Lintao Song, Shaocong Hou, Lijuan Kong, Xiaokun Li, Jun Ren (), Pingping Li (), Moosa Mohammadi () and Zhifeng Huang ()
Additional contact information
Lei Ying: Wenzhou Medical University
Luyao Wang: Wenzhou Medical University
Kaiwen Guo: Wenzhou Medical University
Yushu Hou: Wenzhou Medical University
Na Li: Wenzhou Medical University
Shuyi Wang: Fudan University
Xingfeng Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Qijin Zhao: Chinese Academy of Medical Sciences and Peking Union Medical College
Jie Zhou: Wenzhou Medical University
Longwei Zhao: Wenzhou Medical University
Jianlou Niu: Wenzhou Medical University
Chuchu Chen: Wenzhou Medical University
Lintao Song: Wenzhou Medical University
Shaocong Hou: Chinese Academy of Medical Sciences and Peking Union Medical College
Lijuan Kong: Chinese Academy of Medical Sciences and Peking Union Medical College
Xiaokun Li: Wenzhou Medical University
Jun Ren: Fudan University
Pingping Li: Chinese Academy of Medical Sciences and Peking Union Medical College
Moosa Mohammadi: New York University School of Medicine
Zhifeng Huang: Wenzhou Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Several members of the FGF family have been identified as potential regulators of glucose homeostasis. We previously reported that a low threshold of FGF-induced FGF receptor 1c (FGFR1c) dimerization and activity is sufficient to evoke a glucose lowering activity. We therefore reasoned that ligand identity may not matter, and that besides paracrine FGF1 and endocrine FGF21, other cognate paracrine FGFs of FGFR1c might possess such activity. Indeed, via a side-by-side testing of multiple cognate FGFs of FGFR1c in diabetic mice we identified the paracrine FGF4 as a potent anti-hyperglycemic FGF. Importantly, we found that like FGF1, the paracrine FGF4 is also more efficacious than endocrine FGF21 in lowering blood glucose. We show that paracrine FGF4 and FGF1 exert their superior glycemic control by targeting skeletal muscle, which expresses copious FGFR1c but lacks β-klotho (KLB), an obligatory FGF21 co-receptor. Mechanistically, both FGF4 and FGF1 upregulate GLUT4 cell surface abundance in skeletal muscle in an AMPKα-dependent but insulin-independent manner. Chronic treatment with rFGF4 improves insulin resistance and suppresses adipose macrophage infiltration and inflammation. Notably, unlike FGF1 (a pan-FGFR ligand), FGF4, which has more restricted FGFR1c binding specificity, has no apparent effect on food intake. The potent anti-hyperglycemic and anti-inflammatory properties of FGF4 testify to its promising potential for use in the treatment of T2D and related metabolic disorders.

Date: 2021
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DOI: 10.1038/s41467-021-27584-y

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