TY - JOUR
T1 - Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis
AU - Zhu, Yi
AU - Li, Na
AU - Huang, Mingyang
AU - Bartels, Mason
AU - Dogné, Sophie
AU - Zhao, Shangang
AU - Chen, Xi
AU - Crewe, Clair
AU - Straub, Leon
AU - Vishvanath, Lavanya
AU - Zhang, Zhuzhen
AU - Shao, Mengle
AU - Yang, Yongjie
AU - Gliniak, Christy M.
AU - Gordillo, Ruth
AU - Smith, Gordon I.
AU - Holland, William L.
AU - Gupta, Rana K.
AU - Dong, Bingning
AU - Caron, Nathalie
AU - Xu, Yong
AU - Akgul, Yucel
AU - Klein, Samuel
AU - Scherer, Philipp E.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112109248&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25025-4
DO - 10.1038/s41467-021-25025-4
M3 - Article
C2 - 34376643
AN - SCOPUS:85112109248
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4829
ER -