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).

Ämnesord

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)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)