Abstract
The 5′-AMP-activated protein kinase (AMPK) is considered “a metabolic master-switch” in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (∼4 month) or old (∼18 month) wild type and muscle specific α2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional α2AMPK in muscle. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle.
Highlights
Insulin resistance in peripheral tissues is a hallmark characteristic of obesity-related type 2 diabetes (T2D)
The AMPK Ki mice on chow diet in that study showed a tendency towards impaired insulin action (,50% reduction vs. wild type (WT), p = 0.07) whereas normal insulin action has previously been reported in AMPK Ki mice after only 15 weeks of chow diet [13]
This suggests that acute lack of a2AMPK activation may not directly trigger impaired insulin action, but rather lack of a2AMPK activity over time leads to a muscle phenotype that is more susceptible for insulin resistance
Summary
Insulin resistance in peripheral tissues is a hallmark characteristic of obesity-related type 2 diabetes (T2D). AMPK is referred to as ‘‘a metabolic master-switch’’ due to its general ability to reduce ATP consuming anabolic processes while alternative pathways for ATP regeneration are stimulated [9], including stimulation of lipid oxidation in muscle [10,11] This has led to the speculation that AMPK activation may protect muscle from high fat feeding induced insulin resistance. The AMPK Ki mice on chow diet in that study showed a tendency towards impaired insulin action (,50% reduction vs wild type (WT), p = 0.07) whereas normal insulin action has previously been reported in AMPK Ki mice after only 15 weeks of chow diet [13] This suggests that acute lack of a2AMPK activation may not directly trigger impaired insulin action, but rather lack of a2AMPK activity over time leads to a muscle phenotype that is more susceptible for insulin resistance. This would explain our previous observation that insulin resistance induced by 12 weeks high fat feeding was not exacerbated in young kinase dead a2AMPK mice on a C57BL/6J background (AMPK KD) [14]
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