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

Yi Zhu,Sophie Dogné,Gordon I Smith,Christy Gliniak ,Bingning Dong,Samuel Klein,Mengle Shao,Nathalie Caron,Clair Crewe,Yucel Akgul,Meng Huang ,Leon G Straub ,Shangang Zhao,Ruth Gordillo,Na Li,Yongjie Yang,Rana K Gupta,Zhuzhen Zhang,Yong Xu,Mason Bartels,Lavanya Vishvanath,Xi Chen,William L Holland,Philipp E Scherer

doi:10.1038/s41467-021-25025-4

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.

Highlights

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease
Circulating HA inversely correlates with metabolic health
We evaluated plasma HA concentrations before and for 5 h after ingesting a standard meal (50% carbohydrate, 35% fat, 15% protein) containing one-third of their estimated energy requirements[17] in people with obesity and prediabetes (“Obeseprediabetes”) and those with obesity and normal oral glucose tolerance (“Obese-normal)”, who were all matched for body mass index and percent body fat

Summary

Introduction

Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. 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. Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. 9 Department of Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. HA injections have been approved for the treatment of knee pain caused by osteoarthritis in patients[16] All these beneficial aspects of HA prompt many individuals to take HA as nutritional supplements or look for other ways to increase systemic HA levels

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Conclusion