Abstract
Resveratrol (RSV) and SRT1720 (SRT) elicit beneficial metabolic effects and are postulated to ameliorate obesity and related metabolic complications. The co-activator, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), has emerged as a major downstream effector responsible for metabolic remodeling of muscle and other metabolic tissues in response to RSV or SRT treatment. However, the requirement of PGC-1α in skeletal muscle for the systemic metabolic effects of these compounds has so far not been demonstrated. Using muscle-specific PGC-1α knock-out mice, we show that PGC-1α is necessary for transcriptional induction of mitochondrial genes in muscle with both RSV and SRT treatment. Surprisingly, the beneficial effects of SRT on glucose homeostasis and of both compounds on energy expenditure occur even in the absence of muscle PGC-1α. Moreover, RSV and SRT treatment elicit differential transcriptional effects on genes involved in lipid metabolism and mitochondrial biogenesis in liver and adipose tissue. These findings indicate that RSV and SRT do not induce analogous metabolic effects in vivo. Our results provide important insights into the mechanism, effects, and organ specificity of the caloric restriction mimetics RSV and SRT. These findings are important for the design of future therapeutic interventions aimed at ameliorating obesity and obesity-related metabolic dysfunction.
Highlights
Resveratrol and SRT1720 elicit beneficial metabolic effects, supposedly through activation of PGC-1␣ in skeletal muscle
In contrast to previous hypotheses implying muscle PGC-1␣ as the common molecular effector of RSV and SRT, we show that skeletal muscle PGC-1␣ is dispensable for the improved metabolic rate of these compounds and the improved glucose homeostasis seen with SRT treatment
PGC-1␣ was required for the induction of mitochondrial gene transcription in muscle with RSV and SRT treatment, whereas it was dispensable for the induction of non-transcriptional changes, such as increased oxidative capacity and enhanced mitochondrial number, in skeletal muscle with SRT treatment
Summary
Resveratrol and SRT1720 elicit beneficial metabolic effects, supposedly through activation of PGC-1␣ in skeletal muscle. Using mice with a skeletal muscle-specific deletion of PGC-1␣, we demonstrate that PGC-1␣ is required for transcriptional induction of mitochondrial genes in muscle, this co-activator in muscle is dispensable for systemic metabolic effects of both RSV and SRT treatment, such as increased energy expenditure. Another important question is whether structurally distinct compounds, such as RSV and SRT, are able to induce similar effects in major metabolic organs. We could reveal several important analogous and differential effects between RSV and SRT on transcriptional regulation of lipid metabolism and mitochondrial biogenesis
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