DOI: 10.5061/dryad.c866t1gg4
title: Data from: Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet

description: Overconsumption of food, especially dietary fat, leads to metabolic
 disorders such as obesity and type 2 diabetes. Long-chain fatty acids,
 such as palmitoleate are recognized as the risk factors for these
 disorders owing to their high-energy content and lipotoxicity. In
 contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however,
 their underlying molecular mechanisms remain unclear. GPR84 is an MCFA
 receptor, particularly for C10:0. Although evidence from in vitro
 experiments and oral administration of C10:0 in mice suggests that GPR84
 is related to the metabolic benefits of MCFAs via glucose metabolism, its
 precise roles in vivo remain unclear. Therefore, the present study
 investigated whether GPR84 affects glucose metabolism and metabolic
 function using Gpr84-deficient mice. Although Gpr84-deficient mice were
 lean and had increased endogenous MCFAs under HFD feeding conditions, they
 exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin
 and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice.
 Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved
 plasma glucose and lipid levels, and increased plasma GLP-1 levels in
 wild-type mice; however, these effects were partially attenuated in
 Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated
 GPR84 activation improves the dysfunction of glucose and lipid
 homeostasis. Our findings may be instrumental for future studies on drug
 development with GPR84 as a potential target, thereby offering new avenues
 for the treatment of metabolic disorders like obesity and type 2 diabetes.
description: # Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic
 homeostasis dysfunction in mice fed high-fat diet
 [https://doi.org/10.5061/dryad.c866t1gg4](https://doi.org/10.5061/dryad.c866t1gg4) ## Description of the data and file structure ### Figure 1: Gpr84−/− mice show reduced weight gain under HFD feeding. (A) Plasma MCFA and LCFA contents determined by LC/MS in wild-type mice (WT) and Gpr84−/− mice fed with NC or HFD for 5 weeks (NC-fed group, n = 8; HFD-fed group, n = 7; independent experiments). (B) Body weight changes in WT and Gpr84−/− mice fed with NC or HFD, and (C) Adipose tissue weight after 5 weeks (NC-fed group, n = 5 from 8 litters; HFD-fed group, n = 9 from 9 litters; independent experiments). Epi, epididymal adipose tissues; peri, perirenal adipose tissues; sub, subcutaneous adipose tissues; WAT, white adipose tissue; BAT, brown adipose tissue. (D) Tissue weight after 5 weeks (NC-fed group, n = 5 from 8 litters; HFD-fed group, n = 9 from 9 litters; independent experiments). (E) Food intake (NC-fed group, n = 4 from 8 litters; HFD-fed group, n = 9 from 9 litters; independent experiments). **P &lt; 0.01; *P &lt; 0.05 (Tukey-Kramer test: A; Mann–Whitney U test: C; two-way ANOVA with the Bonferroni: B). All data are presented as the mean ± SEM. ### Figure 2: Gpr84−/− mice show dysfunction of glucose homeostasis under HFD feeding. (A) Blood glucose, (B) plasma total cholesterol (T-Cho), (C) plasma triglycerides (TGs), and (D) plasma non-esterified fatty acids (NEFAs) (NC-fed group, n = 5 from 8 litters; HFD-fed group, n = 7–9 from 9 litters; independent experiments). (E) Plasma insulin levels, and (F) Plasma GLP-1 levels in WT and Gpr84−/− mice following NC or HFD feeding for 5 weeks (NC-fed group, n = 5; HFD-fed group, n = 8–9; independent experiments). (G) Plasma CCK levels, and (H) Plasma GIP levels in WT and Gpr84−/− mice following NC or HFD feeding for 5 weeks (NC-fed group, n = 4–5; HFD-fed group, n = 4–5; independent experiments). NC fed group from 8 litters; HFD fed group from 9 litters. (I) Glucose tolerance test (GTT) and (J) insulin tolerance test (ITT) (NC-fed group, n = 5; HFD-fed group, n = 6). **P &lt; 0.01; *P &lt; 0.05 (Mann–Whitney U test: A, E, H; Student’s t test: B–D, F, G; two-way ANOVA with the Bonferroni: I, J). All data are presented as the means ± SEM. ### Figure 3: Gpr84−/− mice show severe dysfunction of glucose homeostasis under long-term HFD feeding. (A) Plasma MCFA and LCFA contents determined by LC/MS in WT mice fed on HFD for 12 weeks (NC-fed group, n = 3–6; HFD-fed group, n = 8; independent experiments). (B) Body weight changes in WT and Gpr84−/− mice during HFD feeding and (C) Adipose tissue weight after 12 weeks (n = 7–8 from 9 litters; independent experiments). Epi, epididymal; peri, perirenal; sub, subcutaneous; BAT, brown adipose tissue; WAT, white adipose tissue. (D) Tissue weight after 12 weeks (n = 6–8 from 9 litters; independent experiments). (E) Food intake (n = 8 from 9 litters; independent experiments). (F) Blood glucose level in WT and Gpr84−/− mice after HFD intervention for 12 weeks (n = 8). (G) Plasma insulin and (H) plasma GLP-1 levels (n = 8 from 9 litters; independent experiments). **P &lt; 0.01, *P &lt; 0.05 (Tukey-Kramer test: A; two-way ANOVA with the Bonferroni: B; Student’s t test: C–H). All data are presented as the mean ± SEM. ### Figure 4: Gpr84−/− mice show improvement in inflammatory response under long-term HFD feeding. (A) Tnf and Adgre1 mRNA expression in WAT (n = 8). (B) Inflammation level in WAT. Scale bar = 100 μm. (C) RNA-Seq transcriptome profiling in WAT of WT and Gpr84−/− mice fed the HFD for 12 weeks. Heatmap shows the results of two-dimensional hierarchical clustering of 77 genes associated with inflammation (n = 4 per group). (D) Top 20 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of differentially expressed genes (DEGs). P-values were adjusted for multiple testing using Bonferroni correction. **P &lt; 0.01, *P &lt; 0.05 (Student’s t-test: A). All data are presented as the mean ± SEM. ### Figure 5: Gpr84−/− mice show dysfunctions of lipid metabolism under long-term HFD feeding. Gpr84−/− mice show dysfunctions of lipid metabolism under long-term HFD feeding. (A) RNA-Seq transcriptome profiling in WAT of WT and Gpr84−/− mice fed the HFD for 12 weeks. Heatmap shows the results of two-dimensional hierarchical clustering of 72 genes associated with lipid metabolism (n = 4 per group). (B) KEGG pathway analysis related to lipid metabolism. (C–E) mRNA expression levels of lipid metabolism-related genes in WAT (C), liver (D), and muscle (E) measured in WT and Gpr84−/− mice during HFD feeding (n = 6–8). **P &lt; 0.01, *P &lt; 0.05 (Student’s t test: C–E). All data are presented as the mean ± SEM. ### Figure 6: Metabolic benefits of MCT intake are partially mediated by GPR84 activation. (A) MCFA concentration in the plasma of mice fed with TriC10-supplemented HFD (n = 8). (B) Body weight gain for 12 weeks in Lard- or MCT diet-fed mice (n = 8). (C) Food intake (n = 4–5). (D) Blood glucose levels in Lard or MCT diet-fed mice at 16 weeks of age were measured after fasting for 5 h (n = 8). (E) Non-esterified fatty acids (NEFAs), and (F) total cholesterol (T-cho) levels in Lard or MCTs diet-fed mice. (G) Plasma insulin and (H) plasma GLP-1 levels (n = 8). **P &lt; 0.01; *P &lt; 0.05 (Mann–Whitney U test: A, F–H; Student’s t test: B–E). All data are presented as the means ± SEM. ## Sharing/Access information Sequence data for RNA sequence has been deposited in DNA Data Bank of Japan (DDBJ) under accession No. DRA018990 and E-GEAD-855.