Post-transcriptional Stabilization of Ucp1 mRNA Protects Mice from Diet-Induced Obesity

Abstract

Uncoupling protein 1 (Ucp1) contributes to thermogenesis, and its expression is regulated at the transcriptional level. Here, we show that Ucp1 expression is also regulated post-transcriptionally. In inguinal white adipose tissue (iWAT) of mice fed a high-fat diet (HFD), Ucp1 level decreases concomitantly with increases in Cnot7 and its interacting partner Tob. HFD-fed mice lacking Cnot7 and Tob express elevated levels of Ucp1 mRNA in iWAT and are resistant to diet-induced obesity. Ucp1 mRNA has an elongated poly(A) tail and persists in iWAT of Cnot7(-/-) and/or Tob(-/-) mice on a HFD. Ucp1 3'-UTR-containing mRNA is more stable in cells expressing mutant Tob that is unable to bind Cnot7 than in WT Tob-expressing cells. Tob interacts with BRF1, which binds to an AU-rich element in the Ucp1 3'-UTR. BRF1 knockdown partially restores the stability of Ucp1 3'-UTR-containing mRNA. Thus, the Cnot7-Tob-BRF1 axis inhibits Ucp1 expression and contributes to obesity.

Adipocyte‐specific disruption of mouse Cnot3 causes lipodystrophy

“…Cnot3, a noncatalytic subunit, is involved in substrate recognition, complex formation, and regulation of deadenylase activity [7][8][9][10]. Cnot3 participates in energy metabolism and senses nutrient states [11,12]. In WAT and liver, the Abbreviations BAT, brown adipose tissue; H&E, hematoxylin and eosin; MEFs, mouse embryonic fibroblasts; MRI, magnetic resonance imaging; ND, normal diet; qPCR, quantitative real-time RT-PCR; Ucp1, uncoupling protein 1; WAT, white adipose tissue.…”

“…Cnot3 participates in energy metabolism and senses nutrient states [11,12]. expression level of Cnot3 decreases upon fasting, and increases in obesity [11,12]. expression level of Cnot3 decreases upon fasting, and increases in obesity [11,12].…”

QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity

“…Takahashi et al showed that the RNA-binding protein BRF1, which binds to an AU-rich element in the UCP1 3 0 UTR, suppresses the stability of UCP1 mRNA and contributes to obesity [18]. First, RNA-binding proteins control target RNA stability.…”

“…Transcriptional factors in the PPAR family, Irf4, Hif1a, Zfp516, CREB and the cofactors Prdm16, PGC1a, and Sirt1, have been shown to promote the browning of white fat to combat obesity. During changes in obesity-induced dynamic gene expression programs, the posttranscriptional mechanisms that promptly alter mRNA availability are critically implicated in modulating fat metabolism balance [18]. During changes in obesity-induced dynamic gene expression programs, the posttranscriptional mechanisms that promptly alter mRNA availability are critically implicated in modulating fat metabolism balance [18].…”

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

“…Biochemical evidence from Drosophila and mammalian cell culture experiments using overexpressed, tagged proteins suggests that components of the CNOT deadenylase complex associate with NOCT [31,35,92]. Like NOCT knockout mice, CNOT3 +/- and CNOT7 -/- mice resist high-fat diet-induced obesity [33,93]; however, it is difficult to assess the extent of phenotypic similarity among these mice as they have not been directly compared under common conditions. The structural basis for any potential interaction between NOCT and members of the CNOT complex is also unclear, because NOCT lacks the leucine-rich repeats that mediate interaction of other CCR4 orthologs with the CNOT complex [11,94] (Fig.…”