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

Béatrice S.-Y Choi,Adia Ouellette,Thibault V Varin,Philippe St-Pierre,Fredrik Bäckhed,Noëmie Daniel,Vanessa P Houde,Angelo Tremblay,Perrine Feutry,Bruno Marcotte,Phillip J White,Marcus Ståhlman,Olga Ilkayeva,André Marette,Cécile Vors

doi:10.1038/s41467-021-23782-w

Abstract

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.

Highlights

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source
We show here that inclusion of a diversified mix of proteins mirroring the western diet in a high-fat high-sucrose (HFHS) regimen causes early broad changes in the gut microbiota, selectively increases the production of branched-chain fatty acids (BCFA), and induces early alterations in hepatic lipid oxidation which promote hepatic mTORC1/S6K1 activation, liver insulin resistance, and elevated gluconeogenesis
These changes in systemic insulin levels and hepatic lipid oxidation were observed upon altering the source of dietary protein without modifying total protein intake and were coupled with impaired brown adipose tissue (BAT) thermogenesis, leading to higher lipid deposition in adipose tissues and exacerbating HFHS-induced obesity

Summary

Introduction

Animal models of human diseases are classically fed purified diets that contain casein as the unique protein source. Obesity is a complex disease associated with numerous comorbidities, including metabolic syndrome and cardiovascular diseases[1] These pathologies are commonly studied via animal models fed an obesogenic diet that is rich in fat and sucrose to mimic the western diet. We show that a mixture more representative of the complex composition of dietary protein consumed by humans in western societies promotes distinct metabolic perturbations, such as increased weight gain and insulin resistance, compared to a diet containing only casein and we explore the potential role of the gut microbiota in these effects. We show the impact of consuming mixed dietary proteins compared to casein on liver metabolism through incomplete mitochondrial oxidation of fatty acids, as well as the activation of the mTORC1/ S6K1 signaling pathway These findings highlight the importance of considering protein sources in the diet of animal models of diet-induced obesity

Methods

Results

Conclusion