<p>The Long Noncoding RNA Blnc1 Protects Against Diet-Induced Obesity by Promoting Mitochondrial Function in White Fat</p>

Abstract

Introduction: Long noncoding RNAs (lncRNAs) play critical regulatory roles in metabolic disorder. Whereas, the regulatory role of lncRNAs in mitochondrial function of white adipose tissue (WAT) is unknown. Materials and Methods: We investigated the role of Blnc1 in metabolic homeostasis and mitochondrial function of C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks, followed by multi-point injection of adenovirus carrying Blnc1 into epididymal fat (eWAT). In vitro, mitochondrial biogenesis and function were analyzed in 3T3-L1 pre-adipocytes with Blnc1 overexpression or knockdown. Mechanically, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) were used to highlight the molecular mechanism of Blnc1 in pre-adipocytes. Results: Gross eWAT weight was significantly decreased and insulin resistance was improved in HFD-Ad-Blnc1 mice. Mitochondrial biosynthesis was induced by Blnc1 in eWAT, as evidenced by an increased mitochondrial DNA and enhanced Mito-tracker staining. The expression of mitochondria-related genes was increased in eWAT, hepatic fatty acid oxidation was upregulated, and lipid deposition was reduced in HFD-Ad-Blnc1 mice. Knockdown of Blnc1 in 3T3-L1 pre-adipocytes resulted in mitochondrial dysfunction. The mechanistic investigation indicated that Blnc1 stimulated the transcription of Pgc1β via decoying hnRNPA1. Conclusion: Therefore, eWAT-specific overexpression of Blnc1 improves hepatic steatosis and systemic insulin sensitivity, likely by enhancing mitochondrial biogenesis and function.

Involvements of long noncoding RNAs in obesity‐associated inflammatory diseases

“…Transgenic expression of Blnc1 rescues these effects by silencing pro‐inflammatory cytokines interleukin 6 (IL‐6) and CCL5 and promoting lipid metabolism through a ribonucleoprotein complex with ZBTB7B 21 . Additionally, Tang et al find that not only is overexpression of Blnc1 in WAT protective against HFD‐induced obesity but through remodelling of mitochondrial biogenesis is able to improve insulin sensitivity 24 . There is increasing interest in the lipid oxidation‐mediated thermoregulatory properties of BAT, and understanding the role of lncRNAs in this process may be key in harnessing this potential for therapeutic treatment of obesity 20,24 …”

“…24 There is increasing interest in the lipid oxidation-mediated thermoregulatory properties of BAT, and understanding the role of lncRNAs in this process may be key in harnessing this potential for therapeutic treatment of obesity. 20,24 RNA-sequencing analysis of human AT has provided a catalogue of over 3,000 lncRNAs, of which approximately 900 were specifically detected in BAT, which in humans is associated with improved metabolic health. Of these BAT-specific lncRNAs, the expression of lnc-dPRM16 was associated with the expression of BAT-selected markers in vivo and its knockdown impaired differentiation of brown adipocytes.…”

“…Transgenic expression silences proinflammatory cytokines and promotes lipid metabolism, whereas silencing accelerated Zhao et al 21 and Tang et al 24 T A B L E 1 (Continued)…”

“…21 Additionally, Tang et al find that not only is overexpression of Blnc1 in WAT protective against HFD-induced obesity but through remodelling of mitochondrial biogenesis is able to improve insulin sensitivity. 24 There is increasing interest in the lipid oxidation-mediated thermoregulatory properties of BAT, and understanding the role of lncRNAs in this process may be key in harnessing this potential for therapeutic treatment of obesity. 20,24 RNA-sequencing analysis of human AT has provided a catalogue of over 3,000 lncRNAs, of which approximately 900 were specifically detected in BAT, which in humans is associated with improved metabolic health.…”

“…Transgenic expression silences proinflammatory cytokines and promotes lipid metabolism, whereas silencing accelerated Zhao et al 21 and Tang et al 24 T A B L E 1 (Continued) Neppl et al 84 (Continues) distal tissues. With the use of an lncRNA array, a total of 249 lncRNAs were found to be differentially expressed (213 upregulated and 36 downregulated) in the blood of those individuals with obesity, compared with healthy control individuals.…”