Regulation of mitochondrial metabolism in murine skeletal muscle by the medium‐chain fatty acid receptor Gpr84

Abstract

Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium‐chain fatty acid (MCFA) receptor G‐protein‐coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue. Mice with global deletion of Gpr84 [Gpr84 knockout (KO)] exhibit a mild impairment in glucose tolerance when fed a MCFA‐enriched diet. Studies in mice and pancreatic islets suggest that glucose intolerance is accompanied by a defect in insulin secretion. MCFA‐fed KO mice also exhibit a significant impairment in the intrinsic respiratory capacity of their skeletal muscle mitochondria, but at the same time also exhibit a substantial increase in mitochondrial content. Changes in canonical pathways of mitochondrial biogenesis and turnover are unable to explain these mitochondrial differences. Our results show that Gpr84 plays a crucial role in regulating mitochondrial function and quality control.—Montgomery, M. K., Osborne, B., Brandon, A. E., O'Reilly, L., Fiveash, C. E., Brown, S. H. J., Wilkins, B. P., Samsudeen, A., Yu, J., Devanapalli, B., Hertzog, A., Tolun, A. A., Kavanagh, T., Cooper, A. A., Mitchell, T. W., Biden, T. J., Smith, N. J., Cooney, G. J., Turner, N. Regulation of mitochondrial metabolism in murine skeletal muscle by the medium‐chain fatty acid receptor Gpr84. FASEB J. 33, 12264‐12276 (2019). http://www.fasebj.org

20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

“…Gpr84 upregulation in the brain, bone marrow, and kidney in NOD mice, and in the aortae of ApoE -/high-fat diet mice suggests an involvement in inflammation associated with diabetes and atherosclerosis. Mice fed a MCFAenriched high-fat diet for 8 weeks did not reveal a significant increase of GPR84 in quadriceps muscle, but mice on methionine-and choline-deficient diets and choline-deficient, l-amino acid-defined, high-fat diets showed higher GPR84 expression in the liver (Montgomery et al, 2019;Puengel et al, 2020). These studies imply GPR84 has a role in inflammatory processes underlying various chronic noncommunicable conditions such as diabetes, atherosclerosis, and nonalcoholic fatty liver disease, and that long-term GPR84 expression might be relevant under pathological conditions.…”

“…Gpr84 was undetected in a direct analysis of the four chambers of hearts in mice (Moore-Morris et al, 2009). In skeletal muscle, Montgomery et al (2019) highlight that Gpr84 transcripts are present across more mouse tissue types, including skeletal muscle, when considered relative to total RNA rather than normalized to Gapdh. Despite repeated doubts about GPR84 antibody specificity (Recio et al, 2018), Western blots indicated receptor protein was present in skeletal muscle and adipose tissue, and at low levels in the heart (Montgomery et al, 2019).…”

“…Both the high-fat diets caused an increase in body mass and impaired glucose tolerance, but these changes were not affected by genetic deletion of Gpr84. The global Gpr84 KO utilized by Montgomery et al (2019) showed no genotype effect in MCFA-diet induced body weight and fat mass increases, but KO mice did have mild impairments in glucose tolerance. This can be contrasted with experiments on FFARs in mice; FFA3 KO mice have an increased body fat content (Bellahcene et al, 2013), as do FFA4 KO mice on a high-fat diet (Oh et al, 2010;Ichimura et al, 2012).…”

“…In skeletal muscle, Montgomery et al (2019) highlight that Gpr84 transcripts are present across more mouse tissue types, including skeletal muscle, when considered relative to total RNA rather than normalized to Gapdh. Despite repeated doubts about GPR84 antibody specificity (Recio et al, 2018), Western blots indicated receptor protein was present in skeletal muscle and adipose tissue, and at low levels in the heart (Montgomery et al, 2019). Moreover, radiolabeling studies detected specific binding to GPR84 in mouse liver, but not in mouse heart (Köse et al, 2019).…”

Experimental Babesia Rossi Infection Induces Hemolytic, Metabolic, and Viral Response Pathways in the Canine Host

“…Many lipid metabolism-related genes were in cluster 2 in both inoculum cohorts. This includes: PLA2G4A, which encodes a phospholipase involved in membrane lipid remodeling and biosynthesis of lipid mediators of the in ammatory response (32,33); GPR84, which serves as a receptor for free fatty acid (34); CD5L, which encodes a regulator of lipid synthesis that in turn regulates in ammatory response mechanisms and T cell activities (35); and ALOX15, which encodes a lipoxygenase that catalyzes the deoxygenation of polyunsaturated fatty acids and has known roles in red cell maturation and the in ammatory immune response (36). Several lipid metabolism-related genes that were in cluster 2 in the low inoculum cohort were in cluster 3 in the high, indicating that they continued to increase expression levels throughout infection and recovery.…”