@article{1ec2744ced0a440290f1c72f2ccee571,
title = "Adipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis",
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.",
author = "Yi Zhu and Na Li and Mingyang Huang and Mason Bartels and Sophie Dogn{\'e} and Shangang Zhao and Xi Chen and Clair Crewe and Leon Straub and Lavanya Vishvanath and Zhuzhen Zhang and Mengle Shao and Yongjie Yang and Gliniak, {Christy M.} and Ruth Gordillo and Smith, {Gordon I.} and Holland, {William L.} and Gupta, {Rana K.} and Bingning Dong and Nathalie Caron and Yong Xu and Yucel Akgul and Samuel Klein and Scherer, {Philipp E.}",
note = "Funding Information: We would like to acknowledge UTSW metabolic phenotyping core for their assistance in mouse metabolic phenotyping, UTSW Transgenic Core Facility for generating TRE-Has2 mouse models, and Pathology Core for their assistance in histology and microscopic imaging. Furthermore, we thank Ilja Kruglikov for helpful suggestions during progression of the work presented here. This study was supported by NIH grants R01-DK55758, R01-DK099110, RC2-DK118620, R01-DK127274, and P01-AG051459 (P.E.S.), R00-DK114498 (Y.Z.). P.E.S. was also supported by an unrestricted grant from the Novo Nordisk Research Foundation. S.Z. was supported by an AHA postdoctoral fellowship (No. 825982). L.G.S. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) grant 444933586. This study was also supported by National Institutes of Health grants P30DK56341 (Nutrition Obesity Research Center) and RR024992 (Clinical and Translational Science Award) and support from the Foundation for Barnes-Jewish Hospital and the Pershing Square Foundation. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-25025-4",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}
