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

Abstract

Purpose of review: Peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1alpha) has been extensively described as a master regulator of mitochondrial biogenesis. However, PGC-1alpha activity is not constant and can be finely tuned in response to different metabolic situations. From this point of view, PGC-1alpha could be described as a mediator of the transcriptional outputs triggered by metabolic sensors, providing the idea that these sensors, together with PGC-1alpha, 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-1alpha 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-1alpha 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-1alpha, 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.

Figure 1. A metabolic sensor network regulating energy expenditure

Situations of energy depletion and/or decreased catabolic rates can be sensed by different enzymes, such as AMPK and SIRT1, whose activation enhance PGC-1α-dependent transcription. Upon calorie rich diets or situations when energy is not limited, AMPK activity is shut down by the high intracellular ATP levels. Similarly, high fat diets increase SRC-3, who positively regulates the protein levels of the acetyltransferase GCN5, which, in turn, plays the opposite role of SIRT1 action on PGC-1α acetylation, hence diminishing PGC-1α transcriptional activity. Perturbations in this metabolic network controlling PGC-1α activity may importantly contribute to whole-body metabolic complications.