Deletion of CD44 promotes adipogenesis by regulating PPARγ and cell cycle-related pathways

J Endocrinol. 2024 May 20;262(1):e240079. doi: 10.1530/JOE-24-0079. Print 2024 Jul 1.

Abstract

CD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type-specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressing Pparg expression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. These data were further supported by increased preadipocyte proliferation rates in CD44-deficient cells and re-expression of CD44 diminished this effect. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPARγ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.

Keywords: CD44; PPARγ; adipogenesis; cell cycle; insulin signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells*
  • Adipocytes* / metabolism
  • Adipogenesis* / genetics
  • Adipogenesis* / physiology
  • Adipose Tissue / cytology
  • Adipose Tissue / metabolism
  • Animals
  • Cell Cycle* / genetics
  • Cell Cycle* / physiology
  • Cell Differentiation / genetics
  • Gene Deletion
  • Humans
  • Hyaluronan Receptors* / genetics
  • Hyaluronan Receptors* / metabolism
  • Mice
  • PPAR gamma* / genetics
  • PPAR gamma* / metabolism
  • Signal Transduction / physiology

Substances

  • CD44 protein, human
  • Cd44 protein, mouse
  • Hyaluronan Receptors
  • PPAR gamma