Publication Date

8-10-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-25025-4

PMID

34376643

PMCID

PMC8355239

PubMedCentral® Posted Date

8-10-2021

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Adipocytes, Adipose Tissue, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Diet, High-Fat, Dioxoles, Female, Glucose, Glucose Intolerance, Homeostasis, Humans, Hyaluronic Acid, Hypoglycemic Agents, Lipolysis, Male, Mice, Mice, Transgenic, Obesity, Mechanisms of disease, Fat metabolism, Diabetes, Obesity

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.

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