MRP4 deficiency drives lipid metabolism dysregulation and adipose tissue inflammation through cAMP-CREB-CRTC2 activation

Multidrug resistance-associated protein 4 (MRP4/ABCC4), a plasma membrane transporter, plays a critical role in the efflux of endogenous metabolites and xenobiotics. Recent studies have also implicated MRP4 in adipogenesis and fatty acid metabolism. Our previous work using MRP4 knockout (MRP4^-/-) mice demonstrated a strong association between MRP4 deficiency and the development of obesity and diabetes. However, the underlying mechanisms through which MRP4 regulates adipose tissue function remain unclear.

Aim

To investigate the role of MRP4 in adipose tissue dysfunction and metabolic regulation under high-fat, high-sucrose (HFHS) diet conditions.

Materials and methods

MRP4 knockout (MRP4^-/-) and wild-type (WT) mice were fed either a regular chow or HFHS diet for 24 weeks. Body weight, plasma glucose, cholesterol, insulin secretion, glucose tolerance, and insulin sensitivity were assessed. Body composition, physical activity, and energy expenditure were measured. Epididymal adipose tissue (EA) was analyzed for gene expression (adipogenic, lipogenic, fibrotic, and inflammatory markers), histology, cAMP levels, and protein expression of phosphorylated CREB (P-CREB) and CRTC2.

Key findings

MRP4^-/- mice showed greater body weight gain than WT controls, even on a chow diet. Under HFHS conditions, they exhibited exacerbated metabolic dysfunction, including elevated glucose and cholesterol levels, increased adiposity, adipocyte hypertrophy, and altered leptin levels. These mice also showed impaired insulin secretion, reduced glucose tolerance, and decreased insulin sensitivity. Body composition analysis revealed higher fat mass, lower lean mass, and increased water retention. MRP4^-/- mice displayed reduced physical activity, altered energy expenditure, and upregulation of adipogenic, fibrotic, and inflammatory genes in EA. Histological analysis confirmed inflammation and fibrosis. Elevated cAMP levels, along with increased P-CREB and CRTC2 expression, indicated activation of the cAMP-CREB-CRTC2 signaling pathway.

Significance

MRP4 deficiency promotes adipose tissue inflammation, fibrosis, and metabolic dysfunction through activation of the cAMP-CREB-CRTC2 signaling axis. These findings reveal a novel regulatory role for MRP4 in maintaining adipose tissue homeostasis and protecting against diet-induced metabolic disease.