Elsevier

Molecular Metabolism

Available online 24 June 2017
open access
Molecular Metabolism
Original Article

Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution

Under a Creative Commons license

Highlights

Dietary PD reduces serum BCAAs in humans and mice.

Repletion of dietary BCAAs reverses somatic mTORC1 but not hepatic ISR signaling.

Glucose control during dietary PD is unperturbed by BCAA repletion in diabetic mice.

Abstract

Objective

Dietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance. We tested whether replenishment of dietary BCAAs to an AA-diluted (AAD) diet is sufficient to reverse the glucoregulatory benefits of dietary PD.

Methods

We conducted AA profiling of serum from healthy humans and lean and high fat-fed or New Zealand obese (NZO) mice following dietary PD. We fed wildtype and NZO mice one of three amino acid defined diets: control, total AAD, or the same diet with complete levels of BCAAs (AAD + BCAA). We quantified serum AAs and characterized mice in terms of metabolic efficiency, body composition, glucose homeostasis, serum FGF21, and tissue markers of the integrated stress response (ISR) and mTORC1 signaling.

Results

Serum BCAAs, while elevated in serum from hyperphagic NZO, were consistently reduced by dietary PD in humans and murine models. Repletion of dietary BCAAs modestly attenuated insulin sensitivity and metabolic efficiency in wildtype mice but did not restore hyperglycemia in NZO mice. While hepatic markers of the ISR such as P-eIF2α and FGF21 were unabated by dietary BCAA repletion, hepatic and peripheral mTORC1 signaling were fully or partially restored, independent of changes in circulating glucose or insulin.

Conclusions

Repletion of BCAAs in dietary PD is sufficient to oppose changes in somatic mTORC1 signaling but does not reverse the hepatic ISR nor induce insulin resistance in type 2 diabetes during dietary PD.

Keywords

BCAA
Dietary protein
FGF21
mTORC1
Diabetes

Abbreviations

PD
protein dilution
AA
amino acid
BCAA
branched chain amino acid
AAD
amino acid diluted
mTORC1
mammalian target of rapamycin complex 1
ISR
integrated stress response
HF
high fat
NZB
New Zealand black
NZO
New Zealand obese
FGF21
fibroblast growth factor 21
T2D
type 2 diabetes