TY - JOUR

T1 - Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice

AU - Choi, Beatrice S-Y

AU - Daniel, Noemie

AU - Houde, Vanessa P.

AU - Ouellette, Adia

AU - Marcotte, Bruno

AU - Varin, Thibault V.

AU - Vors, Cecile

AU - Feutry, Perrine

AU - Ilkayeva, Olga

AU - Stahlman, Marcus

AU - St-Pierre, Philippe

AU - Bäckhed, Fredrik

AU - Tremblay, Angelo

AU - White, Phillip J.

AU - Marette, Andre

PY - 2021

Y1 - 2021

N2 - Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance. Diet-induced changes in the microbiome have been associated with obesity. Here, using a mouse model, the authors show that a mixed protein source found in western diets exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling via microbial production of branched-chain fatty acids (BCFA).

AB - Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance. Diet-induced changes in the microbiome have been associated with obesity. Here, using a mouse model, the authors show that a mixed protein source found in western diets exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling via microbial production of branched-chain fatty acids (BCFA).

KW - PLASMA ACYLCARNITINES

KW - METABOLISM

KW - DIET

KW - IDENTIFICATION

KW - INFLAMMATION

KW - ISOBUTYRATE

KW - POPULATION

KW - OXIDATION

KW - GLUCOSE

KW - THETA

U2 - 10.1038/s41467-021-23782-w

DO - 10.1038/s41467-021-23782-w

M3 - Journal article

C2 - 34099716

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 3377

ER -