Insulin signaling requires glucose to promote lipid anabolism in adipocytes

James R. Krycer, Lake Ee Quek, Deanne Francis, Armella Zadoorian, Fiona C. Weiss, Kristen C. Cooke, Marin E. Nelson, Alexis Diaz-Vegas, Sean J. Humphrey, Richard Scalzo, Akiyoshi Hirayama, Satsuki Ikeda, Futaba Shoji, Kumi Suzuki, Kevin Huynh, Corey Giles, Bianca Varney, Shilpa R. Nagarajan, Andrew J. Hoy, Tomoyoshi SogaPeter J. Meikle, Gregory J. Cooney, Daniel J. Fazakerley, David E. James

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)13250-13266
Number of pages17
JournalThe Journal of biological chemistry
Volume295
Issue number38
DOIs
Publication statusPublished - 2020 Sep 18

Keywords

  • adipocyte
  • cell metabolism
  • Drosophila
  • fat tissue
  • fatty acid
  • glucose
  • insulin
  • kinase signaling
  • lipid
  • metabolic regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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