Hilnc-mediated UCP1 translation repression contributes to thermogenesis and energy expenditure

Background: Beige adipocytes play a critical role in thermoregulation by upregulating uncoupling protein 1 (UCP1) upon stimulation. While the transcriptional regulation of UCP1 in adipose tissue has been extensively investigated, the mechanisms governing its translational control remain largely elusive. Methods: A cold exposure protocol was employed to induce beige adipocyte biogenesis in mouse subcutaneous fat. The overall metabolic rate of mice was monitored by metabolic cage. Primary adipocyte precursors were isolated from the stromal vascular fraction (SVF) of inguinal white adipose tissue (iWAT) and differentiated into beige adipocytes using a standard adipogenic induction cocktail. Transmission electron microscopy (TEM) was utilized to examine mitochondrial morphology. Functional rescue experiments were performed via adenovirus-mediated gene overexpression. Potential binding partners were screened by LC-MS/MS, while RNA immunoprecipitation (RIP) and RNase protection assay (RPA) were applied to evaluate RNA-protein and RNA-RNA interactions, respectively. Additional mechanistic insights were obtained through qPCR, Western blotting, Immunohistochemistry and bioinformatics analyses. Results: In this study, we discovered that Hilnc, a long non-coding RNA (lncRNA), functions in beige adipocytes by suppressing UCP1 translation. Adipocyte-specific Hilnc-deficient mice display increased energy expenditure, elevated body temperature, smaller inguinal white adipose tissue volume and coupling efficiency, and elevated UCP1 protein level. Hilnc binds to the 3' untranslated region of Ucp1 mRNA and recruits insulin-like growth factor 2 binding protein 2 for translational suppression. The previously characterized human Hilnc functional homolog negatively correlates with UCP1 protein levels in human adipose tissues and suppresses UCP1 translation via similar mechanisms. Conclusion: Our findings highlight Hilnc's post-transcriptional role in thermoregulation in beige adipocytes and offer new insights into the variability of thermogenesis among individuals.