Gene Expression Profiles Reveal Altered Metabolic Signaling Pathway in Skeletal Muscle With Lipid Sensor Gpr120/Ffar4 Deficiency

ABSTRACT Obesity is driven by a chronic imbalance between energy intake and energy expenditure (EE), and reduced EE has been implicated in its development. We previously demonstrated that deficiency of Gpr120 / Ffar4 , a lipid sensor, led to decreased EE. Since skeletal muscle is a major contributor to EE, we investigated whether Gpr120 is involved in skeletal muscle energy metabolism. We generated gene expression profiles of skeletal muscle in WT mice and Gpr120 ‐deficient (KO) mice under a normal diet (ND) and a high fat diet (HFD) using microarray analysis and found that Gpr120 was associated with mitochondrial gene expression in response to HFD. We also discovered that the enrichment patterns of Gene Ontology (GO) terms in skeletal muscle of Gpr120 ‐deficient mice were common to those of genetically modified mouse models associated with Ampk, Pgc1α , and Errγ , suggesting that these signaling factors may be involved in Gpr120‐mediated signaling. Moreover, analyses including ChIP‐seq of Err γ , morphological evaluation of mitochondria by electron microscopy, and measurements of mtDNA content and muscle strength demonstrated that Gpr120 was involved in regulating mitochondrial structure, gene expression, and skeletal muscle function. Together, our findings suggest that Gpr120 regulates mitochondrial homeostasis and function in skeletal muscle, possibly through signaling from distant organs.