The long noncoding RNA ADIPINT is a gatekeeper of pyruvate carboxylase function regulating human fat cell metabolism

Abstract The pleiotrophic function of long noncoding RNAs (lncRNAs) is well recognized, but their direct role in regulating metabolic homeostasis is less understood. Here, we describe a human adipocyte-specific lncRNA, ADIPINT, which regulates pyruvate carboxylase (PC) an enzyme pivotal to lipid/carbohydrate metabolism. With a novel approach, Targeted RNA-protein identification using Orthogonal Organic Phase Separation (TROOPS), we show that ADIPINT binds to PC in vivo. ADIPINT knockdown alters the mitochondrial interactome of the enzyme leading to reduced activity. Decreases in ADIPINT levels reduces adipocyte lipid synthesis and breakdown as well as cellular bioenergetics. In human white adipose tissue, ADIPINT expression is increased in obesity and linked to insulin resistance. Changes in ADIPINT expression tightly correlate with adipose PC activity and variations in fat cell size, insulin sensitivity or the amount of adipose tissue. Thus, we identify ADIPINT as an important regulator of lipid and energy metabolism in human white adipocytes.