CRISPLD2, a novel insulin-sensitizing adipokine that alters adipocyte size.

Objective: Both obesity and adipose tissue fibrosis are associated with insulin resistance, which can improve with weight loss. We previously found increased adipocyte-specific secretion of the novel adipokine CRISPLD2 during weight loss. In this study, we further explore the function of adipose CRISPLD2, which others suggest may regulate inflammation and fibrosis in a variety of tissues.

Methods: We designed mice with adipose-specific doxycycline-inducible overexpression of CRISPLD2 (CLD2^AD) to assess adipose-specific effects on tissue structure and function on chow or high-fat diets. The effects of prolonged excess CRISPLD2 were determined after 7 months, including stromal vascular fraction analysis by single-cell RNA-seq. CRISPLD2 cell surface signaling was explored in 3T3-L1 adipocytes via transwell assays, and adipocyte binding partners were determined in unbiased binding screening by mass spectrometry.

Results: CLD2^AD mice had decreased adipocyte size but unchanged fat mass. Long-term CRISPLD2 overexpression led to downregulation of collagen transcription and decreased fibrosis. CRISPLD2 induced Ifng transcription in adipocytes in vitro and bound multiple adipocyte cell surface proteins, including nucleolin. Finally, obese CLD2^AD mice had decreased adipocyte size and improved glucose tolerance, with no change in fat mass.

Conclusions: These data suggest a model wherein CRISPLD2 can both regulate adipose tissue fibrosis and improve insulin sensitivity.