Skeletal Muscle Gene Expression in High Fat Diet‐fed LKB1 Knockout Mice.

Abstract

The development of obesity leads to many alterations in skeletal muscle metabolism. Liver kinase B1 (LKB1) is well‐known to regulate skeletal muscle function and metabolism through its phosphorylation and regulation of AMPK activated protein kinase (AMPK) family members. LKB1 and AMPK signaling is known to affect gene expression in skeletal muscle through regulation of transcription factors and epigenetic regulation. The purpose of this study was to determine how the lack of LKB1 affects gene expression in skeletal muscle under high fat diet‐induced obesity (DIO). To test this, skeletal muscle specific LKB1 knockout (skmLKB1‐KO) and littermate LKB1‐floxed (WT) mice were fed high fat diet (HFD) or a standard chow diet (SCD) for 14 weeks. RNA sequencing and RT‐PCR was performed using RNA that was isolated from quadriceps muscles. Western blotting was performed using quadriceps homogenates. Gene ontology (GO) analysis showed 549 terms that were significantly affected by genotype in high fat fed mice. When ranked by p‐value, those GO terms with the highest level of significance were mitochondria/respiration‐related and oxidative stress‐related genes in the skmLKB1‐KO vs. WT muscles. Sixty‐nine genes were differentially expressed when comparing skmLKB1‐KO and WT muscles from HFD fed mice. The most under‐expressed of these in the skmLKB1‐KO vs. WT mice was dickkopf‐related protein 3 (DKK3), a regulator of the Wnt pathway. RT‐PCR confirmed the low level of DKK3 expression in skmLKB1‐KO muscles, but also suggested a potential upregulation by HFD feeding. Western blot analysis of DKK3 likewise showed increased expression in muscles from HFD vs. SCD mice. Intriguingly, when the mice were separated into HFD‐induced obesity resistant and obesity‐prone subgroups, DKK3 was only upregulated by HFD in the obesity resistant animals, suggesting a potential protective role against the development of obesity. In conclusion, skmLKB1‐KO under high‐fat diet conditions is associated with altered mitochondrial and oxidation‐reduction related gene expression, and DKK3 expression is greatly reduced in skmLKB1‐KO muscles.Support or Funding InformationThis work was funded by a BYU Mentoring Environment Grant and Graduate Research Fellowship.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.