Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization

Toshiharu Onodera, May-Yun Wang, Joseph M. Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S. Balzer, Dae-Seok Kim, Xuenan Sun, Yu A. An, Bianca C. Field, Charlotte Lee, Ei-ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M. Kusminski, Ruth Gordillo, Laurent Gautron, Denise K. Marciano, Ming Chang Hu, Shawn C. Burgess, Katalin Susztak, Orson W. Moe and Philipp E. Scherer ()
Additional contact information
Toshiharu Onodera: The University of Texas Southwestern Medical Center
May-Yun Wang: The University of Texas Southwestern Medical Center
Joseph M. Rutkowski: Texas A&M University College of Medicine
Stanislaw Deja: University of Texas Southwestern Medical Center
Shiuhwei Chen: The University of Texas Southwestern Medical Center
Michael S. Balzer: University of Pennsylvania Perelman School of Medicine
Dae-Seok Kim: The University of Texas Southwestern Medical Center
Xuenan Sun: The University of Texas Southwestern Medical Center
Yu A. An: The University of Texas Southwestern Medical Center
Bianca C. Field: The University of Texas Southwestern Medical Center
Charlotte Lee: University of Texas Southwestern Medical Center
Ei-ichi Matsuo: Solutions COE, Analytical & Measuring Instruments Division, Shimadzu Corporation
Monika Mizerska: University of Texas Southwestern Medical Center
Ina Sanjana: Solutions COE, Analytical & Measuring Instruments Division, Shimadzu Corporation
Naoto Fujiwara: University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd
Christine M. Kusminski: The University of Texas Southwestern Medical Center
Ruth Gordillo: The University of Texas Southwestern Medical Center
Laurent Gautron: University of Texas Southwestern Medical Center
Denise K. Marciano: University of Texas Southwestern Medical Center
Ming Chang Hu: University of Texas Southwestern Medical Center
Shawn C. Burgess: University of Texas Southwestern Medical Center
Katalin Susztak: University of Pennsylvania Perelman School of Medicine
Orson W. Moe: University of Texas Southwestern Medical Center
Philipp E. Scherer: The University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-42188-4

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