Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states

Abstract

(DR) in the sense that MR increases rodent longevity, but without food restriction. We report here that MR also persistently increases total energy expenditure (EE) and limits fat deposition despite increasing weightspecific food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0°C vs. 1.5°C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ϳ0.75) vs. controls (RQ ϳ0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE. We conclude that the hyperphagic response to dietary MR is matched to a coordinated increase in uncoupled respiration, suggesting the engagement of a nutrient-sensing mechanism, which compensates for limited methionine through integrated effects on energy homeostasis. energy expenditure; metabolic efficiency; oxidative metabolism; futile cycles; adipose tissue; dietary restriction DIETARY METHIONINE RESTRICTION (MR) extends lifespan by 30 -35% in rats (28, 31) and mice (27) by delaying all causes of death. The increase in lifespan is accompanied by a reduction in adiposity that occurs despite a paradoxical increase in weight-specific food consumption (25,28,46). Pair-feeding studies comparing rats fed the control diet to the amount of MR diet consumed by the MR group clearly show that dietary MR decreases metabolic efficiency (25, 46), but the underlying basis for the metabolic responses to dietary MR remains poorly understood. Short-(12 wk) and long-term (80 wk) consumption of the MR diet after weaning also reduced circulating triglyceride, insulin, and leptin while increasing plasma adiponectin (25, 29). Collectively, work to date makes a compelling case that limitation of fat deposition by dietary MR is associated with preservation of insulin sensitivity and significant improvements in metabolic markers of lipid metabolism. Using the tools of metabolic phenotyping to examine energy homeostasis and peripheral substrate utilization, we found that dietary MR produced a significant long-term increase in EE that was temporally linked to exaggerated thermogenic responses to feeding and modest increases in resting EE. These physiological responses to MR limited fat deposition and were associated with significant changes in the metabolic and endocrine function of brown and white adipose tissue. MR effectively increas...

Methionine restriction improves renal insulin signalling in aged kidneys

“…Dietary MR offers promise as an intervention for the treatment of metabolic dysfunction due to its ability to reduce body weight and adiposity, despite an increase in food intake (5,19). Moreover, dietary MR improves insulin sensitivity and glucose/lipid homeostasis in rodents and humans (7,19,22,23).…”

“…Moreover, dietary MR improves insulin sensitivity and glucose/lipid homeostasis in rodents and humans (7,19,22,23).…”

“…It has been postulated that the loss of adiposity despite increased consumption of a MR diet is due, at least in part, to elevated energy expenditure driven by UCP-1 nonshivering thermogenesis in adipose tissue (19) and MR has recently been shown to greatly upregulate UCP-1 expressing cells in inguinal WAT leading to increased respiratory capacity (26). However, the function of UCP1 in the kidney is not known.…”

The Methionine Transamination Pathway Controls Hepatic Glucose Metabolism through Regulation of the GCN5 Acetyltransferase and the PGC-1α Transcriptional Coactivator

“…Several studies have demonstrated the benefits of methionine restriction, which include prevention of insulin resistance and obesity (43), increase in energy expenditure (44) and life span extension (45). Interestingly, methionine restriction has also been reported to improve hepatic insulin sensitivity (46), which promotes glucose homeostasis.…”

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

“…Although the initial weight dip has never been reported by others, previous studies did indicate that chronic dietary MR reduces the deposition of adipose tissue [35,36]. A recent study by Hasek et al, (2010) also showed a significant decrease in body weight and adiposity of MR rats relative to the control group after the initial 2 weeks [37]. The authors speculated that this is possibly due to a metabolic inefficiency with higher maintenance requirements induced by MR diet.…”