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bioRxiv · 10.64898/2025.12.11.693656

Free fatty acids increase basal glucose uptake by adipocytes leveling it to insulin stimulated uptake

Podkuychenko, N. V.·Bogdanova, P. A.·Perelygina, V. S.·Tikhonov, A. V.·Badun, G. A.·Sudnitsyna, M. V.·Vorotnikov, A. V.
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Abstract

Increased free fatty acids (FFA) are considered a key factor in the development of insulin resistance in muscle and liver; however, their role in regulating glucose uptake in adipocytes remains controversial. Here, the effects of palmitate (PA) and oleate (OA) were studied in 3T3-L1 adipocytes with a focus on lipid accumulation and glucose uptake. We found that glucose rather than FFA availability promotes adipocyte maturation and fat accumulation associated with increased basal glucose uptake and altered expression of fatty acid oxidation markers (CPT-1 isoforms and UCP-1) toward lipid storage phenotype. Neither PA, nor OA altered insulin-stimulated glucose uptake by immature or mature adipocytes. Adipogenic differentiation of preadipocytes in the presence of rosiglitazone led to appearance of double effect of PA on glucose uptake by differentiated adipocytes, i.e. (1) PA dose-dependently increased basal glucose uptake, and (2) at high concentration PA suppressed insulin-stimulated glucose uptake. The effect of PA on basal glucose uptake was independent of mTORC1-mediated feedback in insulin signaling and persisted even when insulin signaling was inhibited by high-dose PA. Nonetheless, it was associated with GLUT4 exposure at the plasma membrane as reported by PA-induced, insulin-independent translocation of cMyc-GLUT4-mCherry chimera expressed in 3T3-L1 adipocytes. Thus, we conclude that only excessive FFA may context-dependently trigger classic insulin resistance in adipocytes, but otherwise FFA increase glucose uptake in adipocytes via GLUT4 mobilization.

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Podkuychenko, N. V., Bogdanova, P. A., Perelygina, V. S., Tikhonov, A. V., Badun, G. A., Sudnitsyna, M. V., Vorotnikov, A. V.. 2025-12-13. Free fatty acids increase basal glucose uptake by adipocytes leveling it to insulin stimulated uptake. https://doi.org/10.64898/2025.12.11.693656

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