Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia.

Hypoxia manifests in many forms including the short repetitive intermittent hypoxia (IH) of sleep apnoea and the continuous hypoxia (CH) of altitude, both of which may impact metabolic function. Based on our own previous studies and the available literature, we hypothesized that whereas acute exposure to IH and CH would lead to comparable metabolic dysfunction, with longer-term exposure, metabolism would normalize to a greater extent with CH than IH. Studies were conducted in lean C57BL/6J mice exposed to either IH or CH for 1 day or 4 weeks and compared to either intermittent air (IA) or unhandled (UN) controls, respectively. We utilized the frequently sampled intravenous glucose tolerance test and minimal model analyses to determine insulin-dependent (insulin sensitivity; S (I)) and insulin-independent (glucose effectiveness; S (g)) glucose disposal, as well as the insulin response to glucose (acute insulin response to glucose; AIR(g)). Our data show that 1-day exposure impaired the glucose tolerance and caused reductions in S (g) and AIR(g) in both the IH and CH groups, but only IH caused a significant decrease in S (I) (7.5 ± 2.7 vs. 17.0 ± 5.3 µU ml(-1) min(-1); p < 0.05). After 4-week exposure, there was evidence of metabolic adaptation in both hypoxic groups, however, in the CH group, there was a supranormal increase in S (I) relative to both UN and IH groups. We conclude that in lean mice, the marked metabolic dysfunction that occurs with acute exposure to hypoxia is reversed to a greater extent with chronic CH exposure than chronic IH exposure.

A high leucine diet mitigates cardiac injury and improves survival after acute myocardial infarction.

OBJECTIVE: Evidence suggests that branched chain amino acids (BCAAs) are beneficial in treating human disease. It is unknown, however, what impact BCAAs have on outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that the specific BCAA leucine mitigates cardiac injury and improves survival post-MI. MATERIALS/METHODS: 11-12 week old male C57BL/6 mice were subjected to experimental MI or sham procedure, and provided regular chow (RC; 1.5% leucine) or a high leucine diet (HLD; 5% leucine), and followed for 3½ or 28 days. All mice were studied by echocardiography and cardiac catheterization, and all hearts were collected for histologic measurements of hypertrophy, fibrosis and apoptosis. Inflammation, hypertrophic gene expression, signal transduction, and glucose, palmitate and leucine metabolism were also measured in 3½day hearts. RESULTS: Except for increased leucine and decreased glucose oxidation, an HLD had no effect on measured outcomes in sham mice. With MI, cardiac structure, function, and survival were significantly improved with an HLD. At 3½days post-MI, an HLD increased cardiac hypertrophic signaling and decreased inflammation. Cardiac leucine oxidation was decreased in RC mice post-MI, but significantly increased with an HLD. These changes in metabolism were accompanied by a significant increase in cardiac ATP content in the HLD group. Finally, at both 3½ and 28 days post-MI, an HLD increased compensatory hypertrophy, and attenuated cardiac fibrosis and apoptosis. CONCLUSIONS: An HLD increases compensatory hypertrophy, attenuates fibrosis and apoptosis, and positively modulates oxidative metabolism to improve cardiac structure, function, and survival post-MI.

Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways.

In the normal heart, leptin modulates cardiac metabolism. It is unknown, however, what effect leptin has on cardiac metabolism and outcomes in acute myocardial infarction (MI). This study was performed to test the hypothesis that leptin signaling increases glucose metabolism and attenuates injury in the acutely infarcted heart. Mice with (ObR(+/+)) and without (ObR(-/-)) cardiomyocyte specific expression of leptin receptor (ObR) were randomly assigned to experimental MI or sham procedure, and studied 3 days later. ObR(+/+) and ObR(-/-) sham mice were not significantly different in any measured outcome. However, after MI, ObR(-/-) mice had greater cardiac dysfunction, left ventricular dilation, and levels of oxidative stress. These worse indices of cardiac injury in ObR(-/-) mice were associated with attenuated signal transducer and activator of transcription (STAT) 3, phosphatidylinositol-3-kinase (PI3K), and Akt signaling, decreased malonyl CoA content, and reduced mitochondrial pyruvate dehydrogenase and electron transport Complex I, II and IV activities. Furthermore, ObR(-/-) mice maintained high rates of cardiac fatty acid oxidation after MI, whereas ObR(+/+) mice demonstrated a switch away from fatty acid oxidation to glucose metabolism. Restoration of cardiac STAT3, PI3K and Akt activity and mitochondrial function in ObR(-/-) mice post-MI was accomplished by ciliary neurotrophic factor (CNTF), an established STAT3 activator, administered immediately after MI. Moreover, CNTF therapy resulted in mitigation of cardiac structural and functional injury, attenuated levels of oxidative stress, and rescued glucose metabolism in the infarcted ObR(-/-) heart. These data demonstrate that impaired cardiac leptin signaling results in metabolic inflexibility for glucose utilization in the face of cardiac stress, and greater morbidity after MI. Further, these studies show that cardiac glucose metabolism can be restored in leptin-resistant hearts by CNTF-mediated activation of survival kinases, resulting in multiple improved structural and functional outcomes post-MI.

Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice.

AIMS: the obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin signalling is unknown. Therefore, our objective was to generate a cardiomyocyte-specific leptin receptor knock-out (ObRKO) mouse to determine whether worse cardiac outcomes after MI result from impaired leptin signalling in cardiomyocytes. METHODS AND RESULTS: tamoxifen-inducible ObRKO mice were subjected to experimental MI or sham surgeries and studied after 1 month. After MI, ObRKO mice displayed a loss of cardiac signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate-activated protein kinase (AMPK) signalling. Worse survival and cardiac morbidity were also seen in the ObRKO mouse post-MI, including decreased contractile function and glycolytic metabolism, and increased left ventricular dilation, hypertrophy, collagen deposition, matrix metalloproteinase activity, apoptosis, and inflammation. Treatment of ObRKO mice post-MI with an ObR-independent AMPK activator improved cardiac function and restored many of these maladaptive processes to wild-type levels. CONCLUSION: these data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.