Autocrine FGF1 signaling promotes glucose uptake in adipocytes

Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2022-10, Vol.119 (40), p.e2122382119
Main Authors: Nies, Vera J M, Struik, Dicky, Liu, Sihao, Liu, Weilin, Kruit, Janine K, Downes, Michael, van Zutphen, Tim, Verkade, Henkjan J, Evans, Ronald M, Jonker, Johan W
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Adipocytes
Adipocytes - metabolism
Adipose tissue
Adipose Tissue, White - metabolism
AKT protein
Animals
Autocrine signalling
Biological Sciences
Diabetes mellitus (non-insulin dependent)
Explants
Fibroblast growth factor 1
Fibroblast Growth Factor 1 - genetics
Fibroblast Growth Factor 1 - metabolism
Glucose
Glucose - metabolism
Glucose transporter
Glucose Transporter Type 1 - genetics
Glucose Transporter Type 1 - metabolism
Glucose Transporter Type 4 - genetics
Glucose Transporter Type 4 - metabolism
Growth factors
Insulin
Insulin - metabolism
Mice
Molecular modelling
Overnutrition
Proto-Oncogene Proteins c-akt - metabolism
Receptors, Fibroblast Growth Factor - metabolism
Signaling
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Summary:Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2122382119