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.

A century after the identification of a coenzymatic activity for NAD⁺, NAD⁺ metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD⁺ have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD⁺-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD⁺ provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD⁺-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD⁺ production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD⁺; and 3) novel data that show how modulation of NAD⁺-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.