PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure

By C. Cantó, Johan Auwerx. Current Opinion in Lipidology, 2009

1,559 citations recorded by the source corpus.

Purpose of review Peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC-1α) has been extensively described as a master regulator of mitochondrial biogenesis. However, PGC-1α activity is not constant and can be finely tuned in response to different metabolic situations. From this point of view, PGC-1α could be described as a mediator of the transcriptional outputs triggered by metabolic sensors, providing the idea that these sensors, together with PGC-1α, might be weaving a network controlling cellular energy expenditure. In this review, we will focus on how disorders such as type 2 diabetes and the metabolic syndrome might be related to an abnormal and improper function of this network. Recent findings Two metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1 have been described to directly affect PGC-1α activity through phosphorylation and deacetylation, respectively. Although the physiological relevance of these modifications and their molecular consequences are still largely unknown, recent insight from different in-vivo transgenic models clearly suggests that AMPK, SIRT1 and PGC-1α might act as an orchestrated network to improve metabolic fitness. Summary Metabolic sensors such as AMPK and SIRT1, gatekeepers of the activity of the master regulator of mitochondria, PGC-1α, are vital links in a regulatory network for metabolic homeostasis. Together, these players explain many of the beneficial effects of physical activity and dietary interventions in our battle against type 2 diabetes and related metabolic disorders. Hence, understanding the mechanisms by which they act could guide us to identify and improve preventive and therapeutic strategies for metabolic diseases.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/91ff89d296bcbb2fc5d767e1b5f17424db0998ae

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In Physiology

1. J. Little
2. M. Gibala

Citations in the corpus

• Sirtuin Regulation of Mitochondria - Energy Production, Apoptosis, and Signaling (2010, neutral): “Indeed, changes in the NAD+:NADH ratio can change the redox state of the cell and alter the activity of enzymes such as poly-ADP-ribose polymerases and sirtuins, with subsequent effects on signaling cascades and gene expression [59-61].”
• Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “353 Conversely, the mTORC1, a sensor of nutrient and growth factor availability, exerts a suppressive effect on mitochondrial biogenesis under conditions rich in nutrients.”
• Metabolic Syndrome: Updates on Pathophysiology and Management in 2021 (2022, background): “Mitochondrial biogenesis pathways are activated in response to high-energy requirements translated by increased AMP:ADP/ATP and NAD+:NADH ratios, which are mediated by AMPactivated protein kinase (AMPK) and Sirtuin-1 pathways, respectively [107].”
• Kisspeptins and reproduction: physiological roles and regulatory mechanisms. (2012, background): “Several systems have been identified during the last years as key elements for sensing the cellular energy status, thus allowing the coupling of energy availability of any cell and its functional activity (45, 84, 263, 295, 394, 478, 502).”
• The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis. (2020, background): “proliferator-activated receptor γ coactivator-1 (PGC-1) through deacetylation and phosphorylation, respectively (Cantó and Auwerx, 2009).”
• A practical model of low‐volume high‐intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms (2010, background): “…that total SIRT1 protein content may not be entirely reflective of its deacetylase activity; rather SIRT1 activity may be primarily regulated by metabolic factors such as the NAD+:NADH ratio, intracellular nicotinamide levels, and several post-translational modifications (Cantó & Auwerx, 2009).”
• Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010, neutral): “States of energy depletion, such as reduced caloric intake and exercise, result in an increase in the ratio of AMP to ATP, thereby activating AMPK (41, 52, 266).”