Metabolic roles of PGC-1α and its implications for type 2 diabetes

PGC-1 alpha is a transcriptional coactivator expressed in brown adipose tissue, liver, pancreas, kidney, skeletal and cardiac muscles, and the brain. This review presents data illustrating how PGC-1 alpha regulates metabolic adaptations and participates in the aetiology of type 2 diabetes (T2D). Studies in mice have shown that increased PGC-1 alpha expression may be beneficial or deleterious, depending on the tissue: in adipose tissue, it promotes thermogenesis and thus protects against energy overload, such as seen in diabetes and obesity; in muscle, PGC-1 alpha induces a change of phenotype towards oxidative metabolism. In contrast, its role is clearly deleterious in the liver and pancreas, where it induces hepatic glucose production and inhibits insulin secretion, changes that promote diabetes. Previous studies by our group have also demonstrated the role of PGC-1 alpha in the fetal origins of T2D. Overexpression of PGC-1 alpha in beta cells during fetal life in mice is sufficient to induce beta-cell dysfunction in adults, leading to glucose intolerance. PGC-1 alpha also is associated with glucocorticoid receptors in repressing expression of Pdx1, a key beta-cell transcription factor. In conclusion, PGC-1 alpha participates in the onset of diabetes through regulation of major metabolic tissues. Yet, it may not represent a useful target for therapeutic strategies against diabetes as it exerts both beneficial and deleterious actions on glucose homoeostasis, and because PGC-1 alpha modulation is involved in neurodegenerative diseases. However, its role in cellular adaptation shows that greater comprehension of PGC-1 alpha actions is needed. (C) 2015 Elsevier Masson SAS. All rights reserved.