Abnormal glucose homeostasis in skeletal muscle–specific PGC-1α knockout mice reveals skeletal muscle–pancreatic β cell crosstalk

Abstract

The transcriptional coactivator PPARγ coactivator 1α (PGC-1α) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1α and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1α expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1α knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic β cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1α in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

“…Muscle-derived IL-6, but not IL-8, contributes markedly to systemic levels, where it works in a hormone-like fashion and plays an important role in lipid and glucose metabolism [9,10], principally via activation of AMP-activated protein kinase (AMPK) [10]. Recent studies from others, employing skeletal muscle-specific AKT1 transgenic [11] and muscle-specific peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) knockout [12] mice, have also observed altered metabolism in tissues such as pancreas, liver and adipose tissue. The authors of these respective papers hypothesised that musclederived circulatory factors or myokines may have been responsible for the observed tissue cross-talk.…”

PGC‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice

“…S1). At least in the mTg mice with a reported higher number of oxidative muscle fibers (Handschin, Choi et al., 2007; Lin et al., 2002), this reduction could be based on the exercise‐linked potentiation of the proportion of type IIa and type I muscle fibers, which was not recorded in WT or mKO animals (Figure 2d).…”

“…Mice with muscle ablation (mKO) and overexpression (mTg) of PGC‐1α were described previously (Handschin, Choi et al., 2007; Lin et al., 2002). C57/Bl6 wild‐type (WT) mice were obtained from Janvier (Janvier sas, cs 4105, le genest St‐isle f‐53941, St Berthevin Cedex).…”

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

“…Although the effect of IL-6 on insulin release has not been much studied, a few previous publications have found that IL-6 can increase insulin synthesis and secretion [43,44] and even protect the beta cells [45]. In contrast, it was recently reported that IL-6 reduced insulin secretion at low (3.3 mmol/l) but not at high (11.1 mmol/l) glucose concentrations in isolated islets from some animal models [46]. The reason for this discrepancy is currently unclear.…”