Insulin signaling requires glucose to promote lipid anabolism in adipocytes

Krycer, James R., Quek, Lake-Ee, Francis, Deanne, Zadoorian, Armella, Weiss, Fiona C., Cooke, Kristen C., Nelson, Marin E., Diaz-Vegas, Alexis, Humphrey, Sean J., Scalzo, Richard, Hirayama, Akiyoshi, Ikeda, Satsuki, Shoji, Futaba, Suzuki, Kumi, Huynh, Kevin, Giles, Corey, Varney, Bianca, Nagarajan, Shilpa R., Hoy, Andrew J., Soga, Tomoyoshi, Meikle, Peter J., Cooney, Gregory J., Fazakerley, Daniel J., and James, David E. (2020) Insulin signaling requires glucose to promote lipid anabolism in adipocytes. Journal of Biological Chemistry, 295 (38). pp. 13250-13266.

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Abstract

Adipose tissue is essential for metabolic homeostasis, balancing lipid storage and mobilization based on nutritional status. This is coordinated by insulin, which triggers kinase signaling cascades to modulate numerous metabolic proteins, leading to increased glucose uptake and anabolic processes like lipogenesis. Given recent evidence that glucose is dispensable for adipocyte respiration, we sought to test whether glucose is necessary for insulin-stimulated anabolism. Examining lipogenesis in cultured adipocytes, glucose was essential for insulin to stimulate the synthesis of fatty acids and glyceride–glycerol. Importantly, glucose was dispensable for lipogenesis in the absence of insulin, suggesting that distinct carbon sources are used with or without insulin. Metabolic tracing studies revealed that glucose was required for insulin to stimulate pathways providing carbon substrate, NADPH, and glycerol 3-phosphate for lipid synthesis and storage. Glucose also displaced leucine as a lipogenic substrate and was necessary to suppress fatty acid oxidation. Together, glucose provided substrates and metabolic control for insulin to promote lipogenesis in adipocytes. This contrasted with the suppression of lipolysis by insulin signaling, which occurred independently of glucose. Given previous observations that signal transduction acts primarily before glucose uptake in adipocytes, these data are consistent with a model whereby insulin initially utilizes protein phosphorylation to stimulate lipid anabolism, which is sustained by subsequent glucose metabolism. Consequently, lipid abundance was sensitive to glucose availability, both during adipogenesis and in Drosophila flies in vivo. Together, these data highlight the importance of glucose metabolism to support insulin action, providing a complementary regulatory mechanism to signal transduction to stimulate adipose anabolism.

Item ID: 73610
Item Type: Article (Research - C1)
ISSN: 1083-351X
Copyright Information: © 2020 Krycer et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article under the CC BY license.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC Senior Principal Research Fellowship APP1019680, NHMRC Project Grant GNT1061122, NHMRC Project Grant GNT1086851, NHMRC Project Grant GNT1086850, NHMRC Early Career Fellowship APP1072440
Date Deposited: 02 Aug 2022 04:31
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310103 Cell metabolism @ 100%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 100%
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