ISM1 regulates white adipose tissue remodelling by dampening adipocyte differentiation and enhancing inflammation

Isthmin-1 (ISM1), a secretory protein predominantly derived from brown adipose tissue, enhances glucose tolerance and attenuates hepatic steatosis. However, its potential involvement in white adipose tissue remodelling remains elusive, which profoundly impacts adipocyte insulin sensitivity and consequently alters systemic metabolic homeostasis. ISM1 expression profiles in human and mouse were systematically characterized using Tabula Sapiens. With the intervention of ISM1 expression, mouse preadipocyte cell lines were employed to observe adipocyte differentiation. Furthermore, inflammatory responses of preadipocytes and macrophages induced by palmitic acid (PA) were also studied in vitro. In vivo, overexpression of ISM1 in white adipose tissue followed by 4 weeks of high-fat diet (HFD) was compared. ISM1 exhibited exclusive expression in adipose stem cells and progenitor cells in white adipose tissue. Stable overexpression of ISM1 in 3T3-F442A could significantly impair the ability to differentiate into adipocytes and promote myofibroblast-like differentiation. Notably, under PA stimuli, ISM1 amplified pro-inflammatory responses elicited by mouse adipocyte progenitors and macrophages with an increase in a couple of inflammatory factors. In mice, ISM1 overexpression could inhibit the differentiation of adipocyte progenitors in inguinal white adipose tissue and enhance macrophage accumulation in epididymal white adipose tissue with a short-term HFD. ISM1 may primarily be derived from stem/progenitor cells in white adipose tissues. ISM1 plays an important role in HFD-induced white adipose tissue remodelling, suggesting its complex potential in improving insulin resistance and treating metabolic disorders.