摘要：SummarylncRAP2 is a conserved cytoplasmic lncRNA enriched in adipose tissue and required for adipogenesis. Using purification andin vivointeractome analyses, we show that lncRAP2 forms complexes with proteins that stabilize mRNAs and modulate translation, among them Igf2bp2. Surveying transcriptome-wide Igf2bp2 client mRNAs in white adipocytes reveals selective binding to mRNAs encoding adipogenic regulators and energy expenditure effectors, including adiponectin. These same target proteins are downregulated when either Igf2bp2 or lncRAP2 is downregulated, hindering adipocyte lipolysis. Proteomics and ribosome profiling show this occurs predominantly through mRNA accumulation, as lncRAP2-Igf2bp2 complex binding does not impact translation efficiency. Phenome-wide association studies reveal specific associations of genetic variants within both lncRAP2 and Igf2bp2 with body mass and type 2 diabetes, and both lncRAP2 and Igf2bp2 are suppressed in adipose depots of obese and diabetic individuals. Thus, the lncRAP2-Igf2bp2 complex potentiates adipose development and energy expenditure and is associated with susceptibility to obesity-linked diabetes.Graphical abstractDisplay OmittedHighlights•lncRAP2 is a cytosolic lncRNA conserved in mouse and human needed for adipogenesis•lncRAP2 complexes with mRNA stability and translation regulators, including Igf2bp2•lncRAP2-Igf2bp2 stabilizes lipid metabolism mRNAs to potentiate energy expenditure•lncRAP2-Igf2bp2 genetic and expression variation is linked to BMI, type 2 diabetesBiological sciences; Molecular physiology; Molecular biology; Omics
