A long-non-coding RNA, LINC00473, confers the human adipose tissue thermogenic phenotype through enhanced cAMP responsiveness

Abstract

SummarySpecialized adipocytes localized in distinct depots mediate the many physiological functions of adipose tissue. In humans, paucity of thermogenic adipocytes correlates with high metabolic disease risk, raising much interest in the mechanisms by which these cells arise. Here we report molecular signatures associated with adipocyte development in different human depots and identify a long non-coding RNA, LINC00473, as the transcript most closely associated with enrichment of thermogenic adipocytes.LINC00473 expression is low in subjects with obesity or type-2 diabetes and is highly correlated with cAMP signaling and mitochondrial oxidative phosphorylation pathways. LINC00473 is localized in the nucleus and the cytoplasm, and its knockdown impairs induction of UCP1 and mitochondrial respiration.These results reveal that depot-enriched genes that modulate responsiveness to external stimuli, specifically LINC00473, are important determinants of the adipose tissue thermogenic phenotype, and potential targets for metabolic disease therapy.

Diverse repertoire of human adipocyte subtypes develops from transcriptionally distinct mesenchymal progenitor cells

“…3 C , Lower , arrows). To determine whether cells developing the multilocular phenotype correspond to cluster 2 thermogenic adipocytes, we performed in situ hybridization for the long-noncoding RNA LINC00473 , which is highly enriched in human thermogenic adipose tissue (22) and highly enriched in cluster 2 (Fig. 3 D and E ).…”

“Multiple human adipocyte subtypes and mechanisms of their development”

“…For unknown reasons, UCP1 reads were detected only in a few clones, despite strong RT-PCR signals ( Figure 3a) and accumulation of UCP1 protein (Figure 3a,b). To further test whether Cluster 2 represents "brite/beige" adipocytes, we leveraged recent findings that the levels of the long non-coding RNA, LINC00473, highly correlated with UCP1 levels in "brite/beige" human adipose tissue and in adipocytes derived from this depot [22]. Indeed, we verified this correlation by analyzing the levels of LINC00473 prior to stimulation by Fsk to the levels of UCP1 following stimulation in adipocytes differentiated from non-cloned cells from 3 independent subjects ( Figure 3h).…”