Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment

Abstract

The molecular mechanisms of obesity-associated insulin resistance are becoming increasingly clear, and the effects of various lipid molecules, such as diacylglycerol and ceramide, on the insulin signal are being actively explored. To better understand the divergent response to lipid exposure between lean and obese, we incubated primary human muscle cells from lean [body mass index (BMI) <25 kg/m(2)] and morbidly obese (BMI >40 kg/m(2)) subjects with the saturated fatty acid palmitate. Additionally, given that AMPK-activating drugs are widely prescribed for their insulin-sensitizing effects, we sought to determine whether 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR)-stimulated AMPK activation could prevent or reverse the deleterious effects of lipid on insulin signaling. We found that a 1-h palmitate incubation in lean myotubes reduced (P < 0.05) insulin-stimulated phosphoprotein kinase B (Akt), Akt substrate 160 (AS160), and inhibitory factor kappaBalpha (IkappaBalpha) mass, all of which were prevented with AICAR inclusion. With a longer incubation, we observed that myotubes from morbidly obese individuals appear to be largely resistant to the detrimental effects of 16 h lipid exposure as was evident, in contrast to the lean, by the absence of a reduction in insulin-stimulated insulin receptor substrate (IRS)-1 Tyr phosphorylation, phospho-Akt, and phospho-AS160 (P < 0.05). Furthermore, 16 h lipid exposure significantly reduced IkappaBalpha levels and increased phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and IRS1-Ser(312) in lean myotubes only (P < 0.05). Despite a divergent response to lipid between lean and obese myotubes, AICAR inclusion improved insulin signaling in all myotubes. These findings suggest an important role for regular exercise in addition to offering a potential mechanism of action for oral AMPK-activating agents, such as thiazolidinediones and metformin.

Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance

“…For example, in a study by Bruce et al, obese humans who participated in 8 weeks of exercise training showed a decrease of approximately 40% in skeletal muscle ceramide content and an associated improvement in insulin sensitivity [44]. One potential contributing factor to exerciseinduced suppression of ceramide generation may involve the activation of AMP-activated protein kinase (AMPK) [71]. AMPK activation by pharmacological means has been shown to prevent palmitate-induced SPT activity [72], thereby suggesting the possibility of a similar response to exercise-stimulated AMPK in vivo [73].…”

Are cultured human myotubes far from home?

“…Interestingly, AS160 phosphorylation was also reduced after 72 h fasting, and AS160 may be a better intracellular signaling molecule reflecting insulin-stimulated glucose uptake (Vendelbo, et al, 2012). After inducing insulin resistance by palmitic acid in myotubes, phosphorylation of AS160, as well as other signaling proteins, was correspondingly reduced (Bikman, et al, 2010). These are only a few examples of reported signaling defects in myotubes from obese and insulin resistant subject showing that results from myotubes reflect the in vivo situation.…”

Ceramides as modulators of cellular and whole-body metabolism

“…The beneficial metabolic effects of the adipocyte-derived hormone adiponectin were previously thought to be mediated by AMPK (59,60), a serine/threonine kinase that promotes glucose uptake and lipid oxidation. However, the AMPK-centric theory of adiponectin action is challenged by recent findings revealing that liver kinase B1 (LKB1), which is required for AMPK activation, is dispensable for the hormone's effects (46,61).…”