UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity

Abstract

Dietary methionine restriction (MR) by 80% increases energy expenditure (EE), reduces adiposity, and improves insulin sensitivity. We propose that the MRinduced increase in EE limits fat deposition by increasing sympathetic nervous system-dependent remodeling of white adipose tissue and increasing uncoupling protein 1 (UCP1) expression in both white and brown adipose tissue. In independent assessments of the role of UCP1 as a mediator of MR's effects on EE and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1 2/2 mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25% in WT mice. In contrast, MR failed to increase EE or reduce adiposity in Ucp1 2/2 mice. However, MR was able to increase overall insulin sensitivity by 2.2-fold in both genotypes. Housing temperatures used to minimize (28°C) or increase (23°C) sympathetic nervous system activity revealed temperature-independent effects of the diet on EE. Metabolomics analysis showed that genotypic and dietary effects on white adipose tissue remodeling resulted in profound increases in fatty acid metabolism within this tissue. These findings establish that UCP1 is required for the MR-induced increase in EE but not insulin sensitivity and suggest that diet-induced improvements in insulin sensitivity are not strictly derived from dietary effects on energy balance

Metabolic Responses to Dietary Protein Restriction Require an Increase in FGF21 that Is Delayed by the Absence of GCN2

“…Long-term protein restriction significantly increased both UCP1 and Cidea mRNA within iWAT in association with morphological changes consistent with browning, and these effects were absent in FGF21-KO mice. Whether these effects on WAT and BAT are required for the persistent increase in EE and reduction in body weight gain observed with long-term dietary protein restriction remains unclear, as recent reports suggest that the effects of FGF21 on EE may not require UCP1 or WAT browning (Bernardo et al, 2015; Samms et al, 2015; Veniant et al, 2015), although UCP1 appears contribute to the metabolic effects induced by dietary restriction of just the amino acid methionine (Wanders et al, 2015). …”

FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism

“…The most prominent physiological responses are coordinated increases in energy intake and expenditure (2), with the larger effect on energy expenditure (EE) limiting net increases in fat deposition and accumulation of body weight (BW) (4). The MR diet also increases in vivo insulin sensitivity through a combination of direct and indirect effects on the liver, adipose tissue, and muscle (5).…”

“…Although progress has been made in identifying the molecular sensors that detect MR (6–13), a full accounting of the specific mechanisms linking reduced methionine to its metabolic phenotype remains incomplete. The MR-induced improvement in insulin sensitivity is partly due to reductions in adiposity, but the MR diet also increases tissue-specific insulin sensitivity through mechanisms that are independent of differences in adiposity (4). For example, MR-dependent reductions in hepatic glutathione significantly enhance insulin signaling by slowing glutathione-dependent degradation of PIP3 (5).…”

“…To date, the biological responses to FGF21 have been cataloged in studies where FGF21 was infused at high doses or increased via transgenic overexpression, so whether the physiological increases produced by MR are sufficient to elicit all of the responses produced by pharmacological modulation of FGF21 is unclear (23). However, many if not most of the metabolic, transcriptional, and signaling effects attributed to FGF21 are fully reproduced by dietary MR (1,2,4,5,24). Using Fgf21 −/− mice and dietary MR in both low-fat and high-fat (HF) contexts, we report here that FGF21 is an essential mediator of the effects of MR on EE and energy intake but not overall energy balance due to a paradoxical decrease in intake of the MR diet in Fgf21 −/− mice.…”

Cutting back on the essentials: Can manipulating intake of specific amino acids modulate health and lifespan?

“…Enhanced metabolic flexibility (i.e., effectiveness of substrate switching between fasting and fed states; fat to carbohydrate utilization) may be linked to improvement in glucose metabolism for fatty acid oxidation appears to be downregulated in methionine restriction (Plaisance et al, 2010; Hasek et al, 2010; Anthony and Gietzen, 2013; Orgeron et al, 2014; Wanders et al, 2015). Increased metabolic rate of methionine-restricted mice is however not observed in mice lacking uncoupling protein (UCP1; Wanders et al, 2015), suggesting that methionine-restricted mice exhibit higher levels of thermogenesis and possibly may have higher body temperatures. Increased thermogenesis rather than ATP formation may be causally linked to the observed decline in oxidative damage in methionine-restricted rats (Maddineni et al, 2013; Sanchez-Roman et al, 2012).…”