Cardioprotective Effects of Short-Term Caloric Restriction Are Mediated by Adiponectin via Activation of AMP-Activated Protein Kinase

Abstract

Background-Overeating and obesity are major health problems in developed countries. Caloric restriction (CR) can counteract the deleterious aspects of obesity-related diseases and prolong lifespan. We have demonstrated that short-term CR improves myocardial ischemic tolerance and increases adiponectin levels. Here, we investigated the specific role of adiponectin in CR-induced cardioprotection. Methods and Results-Adiponectin antisense transgenic (Ad-AS) mice and wild-type (WT) mice were randomly assigned to a group fed ad libitum and a CR group (90% of caloric intake of ad libitum for 3 weeks, then 65% for 2 weeks). Isolated perfused mouse hearts were subjected to 25 minutes of ischemia, followed by 60 minutes of reperfusion. CR increased serum adiponectin levels by 84% in WT mice. Gel filtration analysis of the oligomeric complex distribution showed that CR produced a marked increase in the high-molecular-weight complex of adiponectin in WT mice; in contrast, CR did not change serum adiponectin levels or their oligomeric pattern in Ad-AS mice. CR improved the recovery of left ventricular function after ischemia/reperfusion and limited infarct size in WT mice; these effects were completely abrogated in Ad-AS mice. CR also increased the phosphorylated form of AMP-activated protein kinase and acetyl-CoA carboxylase in WT but not in Ad-AS mice. Recombinant adiponectin restored CR-induced cardioprotection in Ad-AS mice, and inhibition of AMP-activated protein kinase phosphorylation completely abrogated CR-induced cardioprotection in WT mice. Conclusion-The cardioprotective effects of short-term CR are mediated by increased production of adiponectin and the associated activation of AMP-activated protein kinase.

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

“…In the third series of the experiments, hearts were subjected to 25 min of ischemia followed by 120 min of reperfusion with or without IPC. Infarct size was identified by triphenyltetrazolium chloride staining and quantitated as previously described (43,44).…”

“…The heart was then quickly excised, and the LV was stored at Ϫ140°C until use. Tissue samples were prepared as previously described (42)(43)(44). For the assessment of the subcellular distribution of Sirt1 protein and cytochrome c, cytosolic and nuclear fractions or cytosolic and mitochondrial fractions were prepared according to the manufacturer's instructions.…”

“…We have demonstrated that short-term CR (4 wk) confers cardioprotection in both young and aged rat hearts and that, in both cases, the protection is independent of the opening of ATP-sensitive K ϩ channels (42). Using adiponectin antisense transgenic mice, we have shown that the increase in circulating adiponectin levels, especially in the high-molecular-weight form of adiponectin, is necessary for the cardioprotective effects of short-term CR (43). We have also found that subsequent activation of AMP-activated protein kinase (AMPK) plays an obligatory role in this cardioprotection.…”

The role of leptin/adiponectin ratio in metabolic syndrome and diabetes

“…The thiazolidinediones, for example, promote an increased secretion of adiponectin by activating PPAR-γ in adipocytes [61,62]. Caloric restriction has also been shown to increase adiponectin levels and, in turn, confer resistance to myocardial ischemia-reperfusion injury [63]. Recently, a novel nonpharmacological therapeutic intervention, aged garlic extract, was found to increase adiponectin levels in individuals with MetS [64].…”

Caloric restriction and heart function: is there a sensible link?

“…Adiponectin is known to promote vascular cell function and survival under stressed condi tions [66,67] . It was recently reported that CR may confer resistance to myocardial ischemia-reperfusion injury by increasing adiponectin levels [68] . Lifelong CR drastically attenuates myocardial oxidative stress during ischemia/reperfusion [23] and post-ischemic inflammatory response [69] .…”