Adipocyte-Specific Hnrnpa1 Knockout Aggravates Obesity-Induced Metabolic Dysfunction via Upregulation of CCL2

Abstract

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is involved in lipid and glucose metabolism via mRNA processing. However, whether and how HNRNPA1 alters adipocyte function in obesity remain obscure. Here, we found that the obese state downregulated HNRNPA1 expression in white adipose tissue (WAT). The depletion of adipocyte HNRNPA1 promoted markedly increased macrophage infiltration and expression of proinflammatory and fibrosis genes in WAT of obese mice, eventually leading to exacerbated insulin sensitivity, glucose tolerance, and hepatic steatosis. Mechanistically, HNRNPA1 interacted with Ccl2 and regulated its mRNA stability. Intraperitoneal injection of CCL2-CCR2 signaling antagonist improved adipose tissue inflammation and systemic glucose homeostasis. Furthermore, HNRNPA1 expression in human WAT was negatively correlated with BMI, fat percentage, and subcutaneous fat area. Among individuals with 1-year metabolic surgery follow-up, HNRNPA1 expression was positively related to percentage of total weight loss. These findings identify adipocyte HNRNPA1 as a link between adipose tissue inflammation and systemic metabolic homeostasis, which might be a promising therapeutic target for obesity-related disorders.

Article Highlights

• Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) is decreased during obesity, but the specific role in adipose tissue remains unclear.

• Adipocyte-specific depletion of Hnrnpa1 accelerates adipose tissue inflammation and systemic metabolic disorders via enhancing mRNA stability of chemokine CCL2.

• CCL2 receptor antagonist rescues metabolic dysfunction elicited by Hnrnpa1 depletion.

• HNRNPA1 expression in human adipose tissue is closely related to BMI, fat percentage, and subcutaneous fat area and is positively associated with percentage of total weight loss 1 year after bariatric surgery.