Interaction between maternal and postnatal high fat diet leads to a greater risk of myocardial dysfunction in offspring via enhanced lipotoxicity, IRS-1 serine phosphorylation and mitochondrial defects.

Maternal overnutrition is associated with heart diseases in adult offspring. However, combined effect of maternal and postnatal fat intake on cardiac function is unknown. This study was designed to examine the impact of maternal and postnatal fat intake on metabolic, myocardial, insulin and mitochondrial responses in adult offspring. Pregnant FVB mice were fed a low fat (LF) or high fat (HF) diet during gestation and lactation. Weaning male offspring were placed on either LF or HF (calorie-restricted HF-fed mice used as weight control) for 4 months prior to assessment of metabolic indices, myocardial histology, cardiac function, insulin signaling, mitochondrial integrity and reactive oxygen species (ROS) generation. Compared with LF- and HF-fed weight-control mice, postnatal HF intake resulted in obesity, adiposity, dyslipidemia, insulin resistance, cardiac hypertrophy, interrupted cardiac contractile, intracellular Ca(2+) and mitochondrial properties, all of which were significantly accentuated by prenatal fat exposure. Despite the preserved cardiac contractile function, LF offspring from HF-fed dams displayed higher body weights, increased adiposity and glucose intolerance. HF-fed mice with prenatal HF exposure displayed upregulated serine phosphorylation of IRS-1, PTP1B, the rate-limiting fatty acid synthesis enzyme stearoyl-CoA desaturase (SCD1) and hypertrophic markers (calcineurin A, GATA4, ANP, ß-MHC and skeletal α-actin), while suppressing AMP-dependent protein kinase, glucose uptake and PGC-1α levels. Importantly, myocardial and mitochondrial ultrastructural abnormalities were more pronounced in HF-fed offspring with prenatal fat exposure, shown as loss of mitochondrial density and membrane potential, increased ROS generation and apoptosis. Our data suggest that prenatal dietary fat exposure predisposes offspring to postnatal dietary fat-induced cardiac hypertrophy and contractile defect possibly via lipotoxicity, glucose intolerance and mitochondrial dysfunction. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".

Insulin-like growth factor 1 alleviates high-fat diet-induced myocardial contractile dysfunction: role of insulin signaling and mitochondrial function.

Obesity is often associated with reduced plasma insulin-like growth factor 1 (IGF-1) levels, oxidative stress, mitochondrial damage, and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high-fat diet-induced oxidative, myocardial, geometric, and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low- (10%) or high-fat (45%) diet to induce obesity. High-fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin 6, insulin, and triglyceride, as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end-systolic and end-diastolic diameter, increased wall thickness, and cardiac hypertrophy in high-fat-fed FVB mice. High-fat diet promoted reactive oxygen species generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca(2+) dysregulation (including depressed peak shortening and maximal velocity of shortening/relengthening), prolonged duration of relengthening, and dampened intracellular Ca(2+) rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor and postreceptor signaling molecules insulin receptor substrate 1 (tyrosine/serine phosphorylation), Akt, glycogen synthase kinase 3ß, forkhead transcriptional factors, and mammalian target of rapamycin, as well as downregulated expression of mitochondrial proteins peroxisome proliferator-activated receptor-γ coactivator 1α and uncoupling protein 2. Intriguingly, IGF-1 mitigated high-fat-diet feeding-induced alterations in reactive oxygen species, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca(2+) handling, and insulin signaling but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high-fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high-fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly because of preserved cell survival, mitochondrial function, and insulin signaling.

Disulfonic stilbene permeation and block of the anion channel from the sarcoplasmic reticulum of rabbit skeletal muscle.

Block of a sarcoplasmic reticulum anion channel (SCl channel) by disulfonic stilbene derivatives [DIDS, dibenzamidostilbene-2,2'-disulfonic acid (DBDS), and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS)] was investigated in planar bilayers using SO4(2-) as the conducting ion. All molecules caused reversible voltage-dependent channel block when applied to either side of the membrane. DIDS also produced nonreversible channel block from both sides within 1-3 min. Reversible inhibition was associated with a decrease in channel open probability and mean open duration but not with any change in channel conductance. The half inhibitory concentration for cis- and trans-inhibition had voltage dependencies with minima of 190 nM and 33 microM for DBDS and 3.4 and 55 microM for DNDS. Our data supports a permeant blocker mechanism, in which stilbenes block SCl channels by lodging in the permeation pathway, where they may dissociate to either side of the membrane and thus permeate the channel. The stilbenes acted as open channel blockers where the binding of a single molecule occludes the channel. DBDS and DNDS, from opposite sides of the membrane, competed for common sites on the channel. Dissociation rates exhibited biphasic voltage dependence, indicative of two dissociation processes associated with ion movement in opposite directions within the trans-membrane electric field. The kinetics of DNDS and DBDS inhibition predict that there are two stilbene sites in the channel that are separated by 14-24 A and that the pore constriction is approximately 10 A in diameter.