Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota

Abstract

Elucidating the mechanisms by which short chain fatty acids (SCFA) reduce body weight may assist in the development of an effective weight control strategy. Dietary supplementation of acetate, propionate, butyrate or their admixture was shown to significantly inhibit the body weight gain induced by high-fat diet feeding. Supplementation of SCFAs caused significant changes in the expressions of G-protein coupled receptor 43 (GPR43) and GPR41 characterized by increases in the adipose tissue and reductions in the colon. Additionally, they influenced the bacterial community structure in feces, with a reduction in the proportion of Firmicutes and an increase in the proportion of Bacteroidetes. The effects of dietary SCFAs on the GPR expression and gut microbiota composition may further result in body weight reduction by enhancing triglyceride hydrolysis and FFA oxidation in the adipose tissue, promoting beige adipogenesis and mitochondrial biogenesis, and inhibiting chronic inflammation.

Figure 1. SCFAs protect against the high-fat diet induced increases in body weight.

Three- to four-week-old C57BL/6 J male mice were fed a HFD diet and four SCFA-containing HFD diets—HFD-A, HFD-P, HFD-B and HFD-SCFA—with a low-fat diet as the control (C). (A) Body weight changes during the sixteen weeks of feeding (n = 15). (B and C) Food and energy intake per mouse at 2, 8 and 12 weeks of feeding (n = 15). Data are shown as the mean ± SD. *Compared to the lean control (C) group, P < 0.05; #compared to the HFD group, P < 0.05.

Figure 2. SCFAs regulate mRNA expressions of GRP43, GPR41, gut hormone peptides and adipokines in DIO mice.

Three- to four-week-old C57BL/6 J male mice were fed different diets for 16 weeks, the mice were sacrificed and the epididymal fat and intestine were dissected in order to measure mRNA expressions of the genes investigated. (A–E) mRNA expressions in the adipose tissue; (F–I) mRNA expressions in the colon; (J–N) correlation between GPR43 and related genes. n = 8–10 in each group. *Compared to the lean control (C) group, P < 0.05; #compared to the HFD group, P < 0.05.

Figure 3. SCFAs regulate lipid metabolism.

Three- to four-week-old C57BL/6 J male mice were fed different diets for 16 weeks, the mice were sacrificed and the epididymal fat, liver, intestine and muscle were dissected for measuring mRNA expressions of related genes. Blood samples were harvested by heart puncture and plasma was separated. mRNA expressions of cpt1 and cpt2 in the adipose tissue (A–C), liver (D–F) and muscle (G–I); mRNA expressions of LPL, Fiaf and HSL in the adipose tissue (J–L); plasma FFA concentration (M); ACC mRNA in the adipose tissue (N) and liver (O); correlation between fat GRP43 and cpts (P–R). n = 8–10 in each group. *Compared to the lean control (C) group, P < 0.05; #compared to the HFD group, P < 0.05.

Figure 4. SCFAs regulate beige adipocyte differentiation and mitochondrial biogenesis.

Three- to four-week-old C57BL/6 J male mice were fed different diets for 16 weeks, the mice were sacrificed and the epididymal fat was dissected for measuring mRNA expressions of related genes. (A–F) Mitochondrial biogenesis-related genes (PGC-1a, NRF-1, Tfam, β-F1-ATPase, COX IV and cyt-c); G: mtDNA quantity; (H–J) beige adipocyte markers (Tbx1, Tmem26, CD137). (K–M) correlation between fat GRP43 and related genes. n = 8–10 in each group. *Compared to the lean control (C) group, P < 0.05; #compared to the HFD group, P < 0.05.

Figure 5. SCFAs alter gut microbiota in DIO mice.

(A–E) 454 pyrosequencing analysis of the fecal microbiota composition from mice fed different diets at the levels of the phylum, class, order, family and genus. (H–K) Bacterial communities based on weighted UniFrac distance. (F and G) Correlation between the ratio of Firmicutes to Bacteroidetes and the GPR43 expression levels in the adipose tissue and colon. n = 15 in each group.