Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance

Abstract

PGC-1beta is a transcriptional coactivator that potently stimulates mitochondrial biogenesis and respiration of cells. Here, we have generated mice lacking exons 3 to 4 of the Pgc-1beta gene (Pgc-1beta(E3,4-/E3,4-) mice). These mice express a mutant protein that has reduced coactivation activity on a subset of transcription factors, including ERRalpha, a major target of PGC-1beta in the induction of mitochondrial gene expression. The mutant mice have reduced expression of OXPHOS genes and mitochondrial dysfunction in liver and skeletal muscle as well as elevated liver triglycerides. Euglycemic-hyperinsulinemic clamp and insulin signaling studies show that PGC-1beta mutant mice have normal skeletal muscle response to insulin but have hepatic insulin resistance. These results demonstrate that PGC-1beta is required for normal expression of OXPHOS genes and mitochondrial function in liver and skeletal muscle. Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress

“…Importantly, it has been shown that pharmacological and genetic manipulations that alleviate oxidative stress lead to improvements in insulin sensitivity [10][11][12]. PGC-1α and PGC-1β have both been shown to regulate the production of a range of antioxidant proteins in a variety of cells [14][15][16]. Consistent with these reports, we observed a robust increase in the protein levels of SOD-1 and SOD-2 and in glutathione peroxidase activity in response to Pgc-1β overexpression in muscle.…”

“…We observed that overexpression of Pgc-1β was able to drive a transcriptional programme that increased the capacity for mitochondrial substrate oxidation, improved antioxidant defences and partially protected against HFD-induced insulin resistance. Gain-and loss-of-function studies have shown that PGC-1β regulates the expression of genes involved in mitochondrial function and lipid metabolism [15,16,38,39]. However, although much is known about the physiological stimuli that increase PGC-1α content in muscle, the in vivo regulation of PGC-1β is less well understood.…”

“…However, studies that have manipulated the levels of PGC-1 proteins in mice have yielded unexpected and conflicting results. For example, skeletal muscle insulin action is not impaired in mice with whole body or muscle-specific deletion of PGC-1α or loss of function mutation of PGC-1β, despite these animals displaying the expected reduction in markers of mitochondrial metabolism [16,22]. Furthermore, mice with musclespecific overexpression of PGC-1α display a marked enhancement of oxidative characteristics in muscle, but are also insulin resistant owing to excessive fatty acid delivery to muscle or decreased Glut4 (also known as Slc2a4) expression [23,24].…”

“…In this regard the peroxisome proliferatoractivated receptor, gamma, coactivator 1 (PGC1) family of transcriptional coactivators, which includes PGC-1α, PGC-1β and PGC1-related coactivator 1, are attractive targets. PGC-1α and PGC-1β have been the most extensively characterised proteins in this family, and a number of reports have shown that these two coactivators are both key regulators of mitochondrial oxidative capacity and the expression of several key antioxidant enzymes [13][14][15][16]. However, although PGC-1α and PGC-1β regulate a large number of overlapping genes, studies in rodent models and cell-based systems have also shown distinct effects of these proteins on a number of metabolic variables such as muscle fibre type [17,18], sphingolipid profile [19] and functional properties of mitochondria [15].…”

PGC1β regulates multiple myeloma tumor growth through LDHA‐mediated glycolytic metabolism

“…On the other hand, PGC1β expression also potentiates oxygen consumption with increased mitochondrial DNA copies and intracellular ATP levels. This can be explained because PGC1β is the coactivator of NRF1; it binds and activates mitochondrial transcription factor A (mtTFA) (Lelliott et al ., 2006; Vianna et al ., 2006), which directly regulates mitochondrial DNA replication (Wu et al ., 1999). In addition, we show that PGC1β expression slightly increases ROS formation in MM cells (Gomez de Cedron et al ., 2017).…”