Helix-Loop-Helix Factor Id3 (Inhibitor of Differentiation 3)

Objective: The aim of this study was to unravel mechanisms whereby deficiency of the transcription factor Id3 (inhibitor of differentiation 3) leads to metabolic dysfunction in visceral obesity. We investigated the impact of loss of Id3 on hyaluronic acid (HA) production by the 3 HAS isoenzymes (HA synthases; -1, -2, and -3) and on obesity-induced adipose tissue (AT) accumulation of proinflammatory B cells. Approach and Results: MaleId3 −/− mice and respective wild-type littermate controls were fed a 60% high-fat diet for 4 weeks. An increase in inflammatory B2 cells was detected inId3 −/− epididymal AT. HA accumulated in epididymal AT of high-fat diet–fedId3 −/− mice and circulating levels of HA were elevated.Has2 mRNA expression was increased in epididymal AT ofId3 −/− mice. Luciferase promoter assays showed that Id3 suppressedHas2 promoter activity, while loss ofId3 stimulatedHas2 promoter activity. Functionally, HA strongly promoted B2 cell adhesion in the AT and on cultured vascular smooth muscle cells ofId3 −/− mice, an effect sensitive to hyaluronidase.Conclusions: Our data demonstrate that loss ofId3 increasesHas2 expression in the epididymal AT, thereby promoting HA accumulation. In turn, elevated HA content promotes HA-dependent binding of B2 cells and an increase in the B2 cells in the AT, which contributes to AT inflammation.