Mechanisms of Increased In Vivo Insulin Sensitivity by Dietary Methionine Restriction in Mice

Abstract

To understand the physiological significance of the reduction in fasting insulin produced by dietary methionine restriction (MR), hyperinsulinemic-euglycemic clamps were used to examine the effect of the diet on overall and tissue-specific insulin sensitivity in mice. The steady-state glucose infusion rate was threefold higher in the MR group and consistent with the 2.5- to threefold increase in 2-deoxyglucose uptake in skeletal muscle, heart, and white adipose tissue. Dietary MR enhanced suppression of hepatic glucose production by insulin, enhanced insulin-dependent Akt phosphorylation in the liver, and increased hepatic expression and circulating fibroblast growth factor 21 (FGF-21) by fourfold. Limitation of media methionine recapitulated amplification of Akt phosphorylation by insulin in HepG2 cells but not in 3T3-L1 adipocytes or C2C12 myotubes. Amplification of insulin signaling in HepG2 cells by MR was associated with reduced glutathione, where it functions as a cofactor for phosphatase and tensin homolog. In contrast, FGF-21, but not restricting media methionine, enhanced insulin-dependent Akt phosphorylation in 3T3-L1 adipocytes. These findings provide a potential mechanism for the diet-induced increase in insulin sensitivity among tissues that involves a direct effect of methionine in liver and an indirect effect in adipose tissue through MR-dependent increases in hepatic transcription and release of FGF-21.

Macronutrients and caloric intake in health and longevity

“…FGF21 regulates several metabolic functions (gluconeogenesis, mitochondrial activity, ketogenesis, lipid metabolism, energy expenditure) which would be expected to be beneficial for age-related health. Similar effects have been reported in response to dietary methionine restriction (Lees, et al 2014; Stone, et al 2014). Although circulating FGF21 derives primarily from liver, it is also expressed in other metabolically important tissues, including white and brown adipose tissue, skeletal muscle, heart and pancreas (exocrine and β cells).…”

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

“…The connection between dietary AA supply and metabolism has been largely focused upon restriction or deprivation of the EAAs. For example, single EAA restriction (44,45) or deprivation (46,47) has been associated with higher levels of circulating FGF21, alongside elevated energy expenditure and insulin sensitivity. Evidence is emerging, however, that hepatic FGF21 can also be regulated by NEAA supply.…”

The regulation of FGF21 gene expression by metabolic factors and nutrients

“…Serum FGF21 increases on low-protein diets that typically are high in carbohydrates. Singly restricted amino acids, such as methionine [82][83][84][85] or leucine [70], have been shown to increase hepatic expression and circulating levels of FGF21. Serum FGF21 also increases in the context of ketogenic diets that are high in fat, very low in carbohydrate, and moderate to low in protein.…”