Palmitate and ER stress - Glucose and lipid metabolism in human skeletal muscle

Endoplasmic reticulum (ER) stress has recently emerged as a major player in insulin resistance (Ozcan, Cao et al. 2004). Acute exposure of human myotubes to palmitate induced ER stress (Study III). Thus, we examined if palmitate activates ER stress in intact human skeletal muscle. The effect of palmitate on the PERK signaling arm of the UPR was studied by determining phosphorylation of eIF2α (Harding, Zhang et al. 1999; Ma, Brewer et al. 2002). In skeletal muscle strips from lean men, there was no change in the phosphorylation of eIF2α in response to palmitate. However, when muscles from overweight men were exposed to palmitate, the phosphorylation of eIF2α was significantly increased (Figure 10, Skrobuk et al. unpublished). After 4 h exposure to palmitate, there was also a marked increase in chaperon protein BiP/ GRP78 levels in muscle strips from overweight, but not from lean men. These data provide evidence that overweight human skeletal muscle is suspectible to ER stress in response to palmitate, while lean muscle seems to be able to cope with palmitate excess and resolve ER stress.

JNK, which is activated via IRE1(Urano, Wang et al. 2000), phosphorylates IRS at inhibitory serine residues and thus leads to defects in the insulin-signaling pathway(Sabio, Kennedy et al. 2010). Therefore, in the future it will be interesting to test the link between ER stress and insulin signaling pathway in human skeletal muscle.

Figure 10. Phosphorylation of eIF2α and GRP78/BiP expression. Skeletal muscle strips from 5 lean and 10 overweight men were incubated with or without 1 mM palmitate and phosphorylation of eIF2α and GRP78/BiP levels were measured at the end of the glucose transport protocol. Representative blots are presented. For clarity, only basal and palmitate stimulated data are quantified. * p<0.05 vs respective condition w/o palmitate (Skrobuk et al. unpublished).

6 Summary

The results of the studies can be summarised as follows:

1. Acute exposure to globular adiponectin stimulates glucose transport in skeletal muscle from type 2 diabetic men. This is related neither to insulin nor AMPK signaling pathways.

2. Acute exposure to rosiglitazone does not affect glucose transport or insulin signaling in human skeletal muscle. However, rosiglitazone transiently activates AMPK signaling.

3. Palmitate impairs glucose metabolism and increases ER stress in isolated skeletal muscle as well as in human primary muscle cells. Acute exposure to resveratrol inhibits glucose and lipid metabolism, and directly inhibits AMPK activity in human skeletal muscle cells. Resveratrol does not prevent palmitate-induced insulin resistance. Exposure to resveratrol increases and exposure to AICAR reduces ER stress, respectively.

7 Conclusions and future perspectives

Insulin resistance, particularly in skeletal muscle, is the hallmark of type 2 diabetes mellitus. Therefore, it is important to understand at molecular level what are the mechanisms and intracellular events that impair insulin signaling and eventually metabolism, as this may identify novel therapeutical targets to improve insulin action.

Here, we observed a stimulatory effect of globular adiponectin on glucose transport in type 2 diabetic muscle. However, the effect was modest and therefore skeletal muscle may not be the primary target of the insulin-sensitizing effect of adiponectin. Similarly, acute exposure to rosiglitazone, a TZD, failed to impact on glucose transport in human skeletal muscle. These data support the notion that the primary target of TZDs is adipose tissue, and the increase in insulin sensitivity in skeletal muscle and liver would be secondary to improved adipocyte function.

The polyphenolic compound resveratrol acts acutely as a metabolic inhibitor in human skeletal muscle. Therefore, any beneficial effects of resveratrol appear to be secondary, and further human studies on the effects of resveratrol and its mechanisms of action are warranted. Our results add AMPK among the many intracellular kinases that are directly inhibited by resveratrol. Acetylation/deacetylation of proteins may play an important role in the insulin signaling pathway (Pirola, Zerzaihi et al. 2012). Thus, this concept should be tested in future studies using compounds like resveratrol, as protein acetylation/deacetylation might be a promising target to design new pharmacological compounds to treat T2DM. Palmitate induces insulin resistance and ER stress both in primary human myotubes as well as in intact human muscle strips. AICAR reduces ER stress in human muscle cells. Therefore targeting ER stress via the AMPK pathway may be beneficial in treating metabolic diseases. However, more experiments with AMPK activators would be needed to confirm this concept. In addition, to clarify the involvement of ER stress in insulin resistance in skeletal muscle and T2DM, experiments using ER stress alleviating chemical chaperons such as 4-PBA and TUDCA should be tested to combat excess nutrient or cytokine induced insulin resistance.

Acute exposure to palmitate impairs proximal insulin signaling and affects glucose metabolism in skeletal muscle from overweight men. This is associated with sustained ER stress. The negative effect of palmitate is also seen in human primary muscle cells. Thus, more signaling experiments are called for to describe mechanism of palmitate-induced insulin resistance in skeletal muscle, as various intracellular sensors, for example stress kinases such as JNK and inhibitory IRS1-Ser³¹² phosphorylation may play a role. It is interesting to note that in contrast to overweight muscle, lean muscle seems to be able to cope with acute exposure to excess palmitate. Identification of the molecular mechanisms behind this adaptation may provide clues to the pathogenesis of T2DM, as well as insulin resistance induced by excess nutrients such as obesity.

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