Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis

Yi Zhu, Na Li, Mingyang Huang, Mason Bartels, Sophie Dogné, Shangang Zhao, Xi Chen, Clair Crewe, Leon Straub, Lavanya Vishvanath, Zhuzhen Zhang, Mengle Shao, Yongjie Yang, Christy M. Gliniak, Ruth Gordillo, Gordon I. Smith, William L. Holland, Rana K. Gupta, Bingning Dong, Nathalie Caron, Yong Xu, Yucel Akgul, Samuel Klein and Philipp E. Scherer ()
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Yi Zhu: The University of Texas Southwestern Medical Center at Dallas
Na Li: The University of Texas Southwestern Medical Center at Dallas
Mingyang Huang: Baylor College of Medicine
Mason Bartels: The University of Texas Southwestern Medical Center at Dallas
Sophie Dogné: University of Namur
Shangang Zhao: The University of Texas Southwestern Medical Center at Dallas
Xi Chen: Baylor College of Medicine
Clair Crewe: The University of Texas Southwestern Medical Center at Dallas
Leon Straub: The University of Texas Southwestern Medical Center at Dallas
Lavanya Vishvanath: The University of Texas Southwestern Medical Center at Dallas
Zhuzhen Zhang: The University of Texas Southwestern Medical Center at Dallas
Mengle Shao: The University of Texas Southwestern Medical Center at Dallas
Yongjie Yang: Baylor College of Medicine
Christy M. Gliniak: The University of Texas Southwestern Medical Center at Dallas
Ruth Gordillo: The University of Texas Southwestern Medical Center at Dallas
Gordon I. Smith: Washington University School of Medicine in St. Louis.
William L. Holland: The University of Texas Southwestern Medical Center at Dallas
Rana K. Gupta: The University of Texas Southwestern Medical Center at Dallas
Bingning Dong: Baylor College of Medicine
Nathalie Caron: University of Namur
Yong Xu: Baylor College of Medicine
Yucel Akgul: The University of Texas Southwestern Medical Center at Dallas
Samuel Klein: Washington University School of Medicine in St. Louis.
Philipp E. Scherer: The University of Texas Southwestern Medical Center at Dallas

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.

Date: 2021
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DOI: 10.1038/s41467-021-25025-4

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