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

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. © 2021, The Author(s).

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
NATURVETENSKAP Biologi hsv//swe
NATURAL SCIENCES Biological Sciences hsv//eng
fatty acid
feeding behavior
microbial activity
mitochondrion
obesity
protein
rodent
signaling
Microbiota
mammalian target of rapamycin complex 1
Rps6ka1 protein
mouse
S6 kinase
adverse event
animal
animal food
disease model
fecal microbiota transplantation
germfree animal
gluconeogenesis
human
insulin resistance
intestine flora
lipid diet
liver
liver cell
male
metabolism
mouse
pathology
physiology
protein intake
rat
signal transduction
sugar intake
tumor cell line
Western diet
Animal Feed
Animals
Cell Line
Tumor
Diet
High-Fat
Diet
Western
Dietary Proteins
Dietary Sucrose
Disease Models
Animal
Fatty Acids
Gastrointestinal Microbiome
Germ-Free Life
Hepatocytes
Humans
Mechanistic Target of Rapamycin Complex 1
Mice
Rats
Ribosomal Protein S6 Kinases
90-kDa

Daniel, N. (författare)
Houde, V. P. (författare)
Ouellette, A. (författare)
Marcotte, B. (författare)
Varin, T. V. (författare)
Vors, C. (författare)
Feutry, P. (författare)
Ilkayeva, O. (författare)
Ståhlman, Marcus,1975Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xstahm (författare)
St-Pierre, P. (författare)
Bäckhed, Fredrik,1973Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Wallenberg Laboratory(Swepub:gu)xbafre (författare)
Tremblay, A. (författare)
White, P. J. (författare)
Marette, A. (författare)
Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

Ingår i:Nature Communications: Springer Science and Business Media LLC12:12041-1723

Av författaren/redakt...: Choi, B. S. Y.; Daniel, N.; Houde, V. P.; Ouellette, A.; Marcotte, B.; Varin, T. V.; visa fler...; Vors, C.; Feutry, P.; Ilkayeva, O.; Ståhlman, Marcus ...; St-Pierre, P.; Bäckhed, Fredrik ...; Tremblay, A.; White, P. J.; Marette, A.; visa färre...

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