Effect of an NHE3 inhibitor in combination with an NPT2b inhibitor on gastrointestinal phosphate absorption in Rodent models.

Many of the pathological consequences of chronic kidney disease can be attributed to an elevation in serum phosphate levels. Current therapies focused on decreasing intestinal phosphate absorption to treat hyperphosphatemia are inadequate. The most effective therapeutic strategy may be to target multiple absorptive pathways. In this study, the ability of a novel inhibitor of the intestinal sodium hydrogen exchanger 3 (NHE3), LY3304000, which inhibits paracellular, diffusional uptake of phosphate, to work in combination with an inhibitor of the active transporter, sodium dependent phosphate cotransporter 2b (NPT2b), LY3358966, was explored. LY3304000 modestly inhibited the acute uptake of phosphate into plasma of rats, while surprisingly, it doubled the rate of phosphate uptake in mice, an animal model dominated by NPT2b mediated acute phosphate uptake. In rats, LY3004000 and LY3358966 work in concert to inhibit acute phosphate uptake. On top of LY3358966, LY3304000 further decreased the acute uptake of phosphate into plasma. Studies measuring the recovery of radiolabeled phosphate in the intestine demonstrated LY3304000 and LY3358966 synergistically inhibited the absorption of phosphate in rats. We hypothesize the synergism is because the NHE3 inhibitor, LY3304000, has two opposing effects on intestinal phosphate absorption in rats, first it decreases diffusion mediated paracellular phosphate absorption, while second, it simultaneously increases phosphate absorption through the NPT2b pathway. NHE3 inhibition decreases proton export from enterocytes and raises the cell surface pH. In vitro, NPT2b mediated phosphate transport is increased at higher pHs. The increased NPT2b mediated transport induced by NHE3 inhibition is masked in rats which have relatively low levels of NPT2b mediated phosphate transport, by the more robust inhibition of diffusion mediated phosphate absorption. Thus, the inhibition of NPT2b mediated phosphate transport in rats in the presence of NHE3 inhibition has an effect that exceeds its effect in the absence of NHE3 inhibition, leading to the observed synergism on phosphate absorption between NPT2b and NHE3 inhibition.

Development of a long-acting relaxin analogue, LY3540378, for treatment of chronic heart failure.

BACKGROUND AND PURPOSE: Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure. EXPERIMENTAL APPROACH: LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain. KEY RESULTS: LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378. CONCLUSION AND IMPLICATIONS: LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials.

COVID-19 presenting after Elective Off-pump Coronary Artery Bypass Grafting and Lessons Learned.

BACKGROUND: Cases of COVID-19 presenting after elective cardiac surgery are rare. Published literature suggests that such cases have a high morbidity and mortality rate. Here, we report a case of COVID-19 presenting after an elective, isolated off-pump coronary artery bypass (OPCAB). CASE PRESENTATION: A 65-year-old obese, hypertensive, hypothyroid lady, with moderate left ventricular dysfunction, presenting with unstable angina, tested negative for COVID-19 at admission, having undergone thrombolysis for a recent inferior wall myocardial infarction, at an outside centre, and coronary angiography revealing left main triple vessel disease, developed signs and symptoms of COVID-19, four days after OPCAB. She was diagnosed with moderate COVID-19 infection. Subsequent contact tracing revealed that her husband was suffering from mild COVID-19 infection and was managed in home isolation. Isolation and early supportive management with moist oxygen, steroids, intravenous antibiotics, zinc and vitamin C helped the patient recover. She was followed up at one month, six months, one year and at eighteen months and has been doing well. CONCLUSIONS: A strong clinical suspicion and repeat testing for COVID-19 is required as the diagnosis may often be missed with COVID-19 mimicking the signs and symptoms of post-cardiotomy syndrome. Preferentially dealing with such cases off-pump, thereby avoiding cardio pulmonary bypass-related complications, may improve outcomes. Isolation and early supportive management help. Adequate follow-up is required in all such cases as cardiovascular complications are common, alongside known long-term sequelae, like anxiety, depression, cardio-respiratory complications, venous thromboembolism and even postural orthostatic tachycardia syndrome.

How do mobility restrictions and social distancing during COVID-19 affect oil price?

This paper provides an analysis of the effect of the COVID-19 outbreak on the crude oil price. Using a newly developed air mobility index and Apple's driving trends index, we assess the effect of human mobility restrictions and social distancing during the COVID-19 pandemic on the crude oil price. We apply a quantile regression model, which evaluates different quantiles of the crude oil price. We also conduct an extreme value modeling, which examines the lower tail of the crude oil price distribution. We find that both the air mobility index and driving trends index significantly influence lower and upper quantiles of the WTI crude oil price. The extreme value models suggest that there is a potential risk of a negative crude oil price for a sudden extreme fall of air mobility.

Effects of pharmacological inhibition of the sodium-dependent phosphate cotransporter 2b (NPT2b) on intestinal phosphate absorption in mouse and rat models.

An excess phosphate burden in renal disease has pathological consequences for bone, kidney, and heart. Therapies to decrease intestinal phosphate absorption have been used to address the problem, but with limited success. Here, we describe the in vivo effects of a novel potent inhibitor of the intestinal sodium-dependent phosphate cotransporter NPT2b, LY3358966. Following treatment with LY3358966, phosphate uptake into plasma 15 min following an oral dose of radiolabeled phosphate was decreased 74% and 22% in mice and rats, respectively, indicating NPT2b plays a much more dominant role in mice than rats. Following the treatment with LY3358966 and radiolabeled phosphate, mouse feces were collected for 48 h to determine the ability of LY3358966 to inhibit phosphate absorption. Compared to vehicle-treated animals, there was a significant increase in radiolabeled phosphate recovered in feces (8.6% of the dose, p < .0001). Similar studies performed in rats also increased phosphate recovered in feces (5.3% of the dose, p < .05). When used in combination with the phosphate binder sevelamer in rats, there was a further small, but not significant, increase in fecal phosphate. In conclusion, LY3358966 revealed a more prominent role for NPT2b on acute intestinal phosphate uptake into plasma in mice than rats. However, the modest effects on total intestinal phosphate absorption observed in mice and rats with LY3359866 when used alone or in combination with sevelamer highlights the challenge to identify new more effective therapeutic targets and/or drug combinations to treat the phosphate burden in patients with renal disease.

Impacts of COVID-19 local spread and Google search trend on the US stock market.

We develop a novel temporal complex network approach to quantify the US county level spread dynamics of COVID-19. We use both conventional econometric and Machine Learning (ML) models that incorporate the local spread dynamics, COVID-19 cases and death, and Google search activities to assess if incorporating information about local spreads improves the predictive accuracy of models for the US stock market. The results suggest that COVID-19 cases and deaths, its local spread, and Google searches have impacts on abnormal stock prices between January 2020 to May 2020. Furthermore, incorporating information about local spread significantly improves the performance of forecasting models of the abnormal stock prices at longer forecasting horizons.

Topological clustering of multilayer networks.

Multilayer networks continue to gain significant attention in many areas of study, particularly due to their high utility in modeling interdependent systems such as critical infrastructures, human brain connectome, and socioenvironmental ecosystems. However, clustering of multilayer networks, especially using the information on higher-order interactions of the system entities, still remains in its infancy. In turn, higher-order connectivity is often the key in such multilayer network applications as developing optimal partitioning of critical infrastructures in order to isolate unhealthy system components under cyber-physical threats and simultaneous identification of multiple brain regions affected by trauma or mental illness. In this paper, we introduce the concepts of topological data analysis to studies of complex multilayer networks and propose a topological approach for network clustering. The key rationale is to group nodes based not on pairwise connectivity patterns or relationships between observations recorded at two individual nodes but based on how similar in shape their local neighborhoods are at various resolution scales. Since shapes of local node neighborhoods are quantified using a topological summary in terms of persistence diagrams, we refer to the approach as clustering using persistence diagrams (CPD). CPD systematically accounts for the important heterogeneous higher-order properties of node interactions within and in-between network layers and integrates information from the node neighbors. We illustrate the utility of CPD by applying it to an emerging problem of societal importance: vulnerability zoning of residential properties to weather- and climate-induced risks in the context of house insurance claim dynamics.

Selective Phosphodiesterase 1 Inhibitor BTTQ Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats: Role of Peripheral Vasodilation.

Regulation of the peripheral vascular resistance via modulating the vessel diameter has been considered as a main determinant of the arterial blood pressure. Phosphodiesterase enzymes (PDE1-11) hydrolyse cyclic nucleotides, which are key players controlling the vessel diameter and, thus, peripheral resistance. Here, we have tested and reported the effects of a novel selective PDE1 inhibitor (BTTQ) on the cardiovascular system. Normal Sprague Dawley, spontaneously hypertensive (SHR), and Dahl salt-sensitive rats were used to test in vivo the efficacy of the compound. Phosphodiesterase radiometric enzyme assay revealed that BTTQ inhibited all three isoforms of PDE1 in nanomolar concentration, while micromolar concentrations were needed to induce effective inhibition for other PDEs. The myography study conducted on mesenteric arteries revealed a potent vasodilatory effect of the drug, which was confirmed in vivo by an increase in the blood flow in the rat ear arteriols reflected by the rise in the temperature. Furthermore, BTTQ proved a high efficacy in lowering the blood pressure about 9, 36, and 24 mmHg in normal Sprague Dawley, SHR and, Dahl salt-sensitive rats, respectively, compared to the vehicle-treated group. Moreover, additional blood pressure lowering of about 22 mmHg could be achieved when BTTQ was administered on top of ACE inhibitor lisinopril, a current standard of care in the treatment of hypertension. Therefore, PDE1 inhibition induced efficient vasodilation that was accompanied by a significant reduction of blood pressure in different hypertensive rat models. Administration of BTTQ was also associated with increased heart rate in both models of hypertension as well as in the normotensive rats. Thus, PDE1 appears to be an attractive therapeutic target for the treatment of resistant hypertension, while tachycardia needs to be addressed by further compound structural optimization.

What network motifs tell us about resilience and reliability of complex networks.

Network motifs are often called the building blocks of networks. Analysis of motifs has been found to be an indispensable tool for understanding local network structure, in contrast to measures based on node degree distribution and its functions that primarily address a global network topology. As a result, networks that are similar in terms of global topological properties may differ noticeably at a local level. This phenomenon of the impact of local structure has been recently documented in network fragility analysis and classification. At the same time, many studies of networks still tend to focus on global topological measures, often failing to unveil hidden mechanisms behind vulnerability of real networks and their dynamic response to malfunctions. In this paper, a study of motif-based analysis of network resilience and reliability under various types of intentional attacks is presented, with the goal of shedding light on local dynamics and vulnerability of networks. These methods are demonstrated on electricity transmission networks of 4 European countries, and the results are compared with commonly used resilience and reliability measures.

Visual Impairment Registry of Patients from North Kolkata, Eastern India: A Hospital-based Study.

PURPOSE: To study the demographic profile, severity and causes of visual impairment among registered patients in a tertiary care hospital in north Kolkata, eastern India, and to assess the magnitude of under-registration in that population. METHODS: This is a retrospective analytical study. A review of all visually impaired patients registered at our tertiary care hospital during a ten-year period from January 2005 to December 2014, which is entitled for certification of people of north Kolkata, eastern India (with a population denominator of 1.1 million), was performed. Overall, 2472 eyes of 1236 patients were analyzed in terms of demographic characteristics, cause of visual impairment, and percentage of visual disability as per the guidelines established by the government of India. RESULTS: Male patients (844, 68.28%; 95% confidence interval [CI], 65.69-70.87) registered more often than female patients (392; 31.72%, P = 0.0004). The registration rate for visual impairment was 11.24 per 100,000 per annum; this is not the true incidence rate, as both new patients and those visiting for renewal of certification were included in the study. Optic atrophy was the most common cause of visual impairment (384 eyes, 15.53%; 95% CI, 14.1-16.96). CONCLUSION: Commonest cause of visual impairment was optic atrophy followed by microphthalmos. Under-registration is a prevalent problem as the registration system is voluntary rather than mandatory, and female patients are more likely to be unregistered in this area.

Identification of 4-Aminopyrazolopyrimidine Metabolite That May Contribute to the Hypolipidemic Effects of LY2584702 in Long Evans Diet-Induced Obese Rats.

LY2584702 is an inhibitor of p70 S6 kinase-1 previously developed for the treatment of cancer. In two phase 1 trials in oncology patients, significant reductions of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride were observed. In the current study, we sought to understand the potential mechanism of action of this compound in regulating lipid metabolism. In Long Evans diet-induced obese (DIO) rats, oral administration of LY2584702 for 3-4 weeks led to robust reduction of LDL-C up to 60%. An unexpected finding of liver triglyceride (TG) increase implicated a metabolite of LY2584702, 4-aminopyrazolo[3,4-day]pyrimidine (4-APP), in modulation of lipid metabolism in these rats. We showed that low-dose 4-APP, when administered orally for 3-4 weeks to Long Evans DIO rats, produced lipoprotein profile changes that were strikingly similar to LY2584702. Kinetic studies suggested that both LY2584702 and 4-APP had no effect on chylomicron-TG secretion and only exerted a modest effect on hepatic very low-density lipoprotein (VLDL)-TG secretion. In human hepatoma HepG2 cells, 4-APP, but not LY2584702, increased LDL uptake. We hypothesize that generation of the 4-APP metabolite may contribute to the efficacy of LY2584702 in lowering LDL-C in rats and potentially in humans as well. This mechanism of LDL-C lowering may include inhibition of VLDL production and increase in LDL clearance.

Ocular manifestations in children with cerebral palsy.

To evaluate the prevalence of ocular abnormalities among children with cerebral palsy, 140 patients with age between 6 months and 16 years were selected and the overall incidence of ocular abnormalities in this study was 42.1%. Two major ocular abnormalities identified in these cases were strabismus in 36.4%. Myopia was detected in 12.9% children while hypermetropia in 8.6% and astigmatism in 3.6% cases. Non-glaucomatous optic atrophy was present in 10.7% cases and nystagmus in 9.3% cases. Raised intra-ocular pressure was detected in 2.1% cases. Cortical visual impairment was seen in 20.7% children. Ocular abnormalities are frequent manifestations in cerebral palsy patients. Therefore, evaluation of all cerebral palsy cases emphasises the need for a full ophthalmological examination in order to detect ocular problems and to institute necessary therapy of the abnormalities for better livelihood of these physically challenged patients.

Sustained hemodynamic stress disrupts normal circadian rhythms in calcineurin-dependent signaling and protein phosphorylation in the heart.

RATIONALE: Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling. OBJECTIVE: To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts. METHODS AND RESULTS: We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice. Calcineurin-dependent transcript levels and nuclear occupancy of the NFAT (nuclear factor of activated T cells) regularly fluctuated as much as 20-fold over the course of a day, peaking in the morning when mice enter a period of rest. Phosphorylation of the protein phosphatase 1 inhibitor 1 (I-1), a direct calcineurin substrate, and phospholamban, an indirect target, oscillated directly out of phase with calcineurin-dependent signaling. Using a surgical model of cardiac pressure overload, we found that although calcineurin-dependent activities were markedly elevated, the circadian pattern of activation was maintained, whereas, oscillations in phospholamban and I-1 phosphorylation were lost. Changes in the expression of fetal gene markers of heart failure did not mirror the rhythm in calcineurin/NFAT activation, suggesting that these may not be direct transcriptional target genes. Cardiac function in mice subjected to pressure overload was significantly lower in the morning than in the evening when assessed by echocardiography. CONCLUSIONS: Normal, opposing circadian oscillations in calcineurin-dependent activities and phosphorylation of proteins that regulate contractility are disrupted in heart failure.

Rare association of retinitis pigmentosa and Marfan's syndrome--a case report.

A 25 years old male patient presented with long stature with disproportionately long limbs and digits (arachnodactyly). Examination of cardiovascular system showed mitral regurgitation and dilatation of aortic root. Slit lamp examination showed bilateral superotemporal dislocation of lens. Ophthalmoscopy revealed waxy pallor of optic disc, arteriolar attenuation and bone-spicule like pigments in the retina. The diagnosis of retinitis pigmentosa was confirmed by electroretinogram.

The CCAAT/enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4.

Regulator of calcineurin 1 (RCAN1) inhibits the protein phosphatase calcineurin and is required for appropriate immune responses, synaptic plasticity, vascular tone, angiogenesis, and cardiac remodeling. Expression of the RCAN1-4 isoform is under the control of the calcineurin-responsive transcription factor NFAT. Typically, NFATs act in cooperation with other transcription factors to achieve maximal activation of gene expression. In this study, we identify the CCAAT/enhancer binding protein beta (C/EBPbeta) as an NFAT binding partner that cooperates with NFAT to regulate RCAN1-4 expression. Numerous C/EBPbeta binding sites are conserved in the RCAN1-4 proximal promoter. Overexpression of C/EBPbeta increased activity of both the endogenous mouse Rcan1-4 gene and a human RCAN1-4 luciferase reporter. Binding of C/EBPbeta to multiple sites in the promoter was verified using electrophoretic mobility shift assays and chromatin immunoprecipitation. A direct interaction between C/EBPbeta and NFAT was demonstrated by co-immunoprecipitation of proteins and complex formation at NFAT-C/EBPbeta composite sites. Depletion of endogenous C/EBPbeta decreased maximal activation of RCAN1-4 expression by calcineurin, whereas inhibition of calcineurin did not alter the ability of C/EBPbeta to activate RCAN1-4 expression. Together, these findings suggest that calcineurin/NFAT activation of RCAN1-4 expression is in part dependent upon C/EBPbeta, whereas activation by C/EBPbeta is not dependent on calcineurin and may provide a calcineurin-independent pathway for regulating RCAN1-4 expression. Importantly, nuclear localization, C/EBPbeta DNA binding activity and occupancy of the Rcan1-4 promoter increased in mouse models of heart failure demonstrating in vivo activation of this pathway to regulate Rcan1-4 expression and ultimately shape the dynamics of calcineurin-dependent signaling.

A prospective evaluation of anterior chamber contamination following cataract surgery.

Anterior chamber aspirate cultures were done in 57 patients who underwent uncomplicated manual small incision cataract surgery with posterior chamber intra-ocular lens implantation. The aspirates were collected at the time of wound closures. The specimens were immediately inoculated into blood agar, chocolate agar and thioglycolate broth. The cultures were incubated at 37 degrees C with 5% CO2 and held for 5 days. Out of 57 patients 8 (14%) had culture positive anterior chamber aspirates. Coagulase negative staphylococcus was the commonest (62%). No anaerobic organism was detected. None of the eyes developed endophthalmitis. The study concluded that the strict aseptic measures, the antimicrobial property of the aqueous humour or small inoculum size could be the possible factors to prevent fulminating infection.

The Down syndrome critical region protein RCAN1 regulates long-term potentiation and memory via inhibition of phosphatase signaling.

Regulator of calcineurin 1 (RCAN1/MCIP1/DSCR1) regulates the calmodulin-dependent phosphatase calcineurin. Because it is located on human chromosome 21, RCAN1 has been postulated to contribute to mental retardation in Down syndrome and has been reported to be associated with neuronal degeneration in Alzheimer's disease. The studies herein are the first to assess the role of RCAN1 in memory and synaptic plasticity by examining the behavioral and electrophysiological properties of RCAN1 knock-out mice. These mice exhibit deficits in spatial learning and memory, reduced associative cued memory, and impaired late-phase long-term potentiation (L-LTP), phenotypes similar to those of transgenic mice with increased calcineurin activity. Consistent with this, the RCAN1 knock-out mice display increased enzymatic calcineurin activity, increased abundance of a cleaved calcineurin fragment, and decreased phosphorylation of the calcineurin substrate dopamine and cAMP-regulated phosphoprotein-32. We propose a model in which RCAN1 plays a positive role in L-LTP and memory by constraining phosphatase signaling.

Klippel-Feil syndrome: a case report and current understanding of molecular genetic background.

A case of Klippel-Feil syndrome in a 12-year-old boy presentingwith the features of low set posterior hairline, short webbed neck, scoliosis and Sprengel's deformity associated with upper eyelid coloboma and pre-auricular appendages is described. Radiologically there was evidence of maldeveloped cervical and upper thoracic vertebrae associated with elevated scapula. The association of the eyelid defect and pre-auricular appendages has not been documented in the past. The current literatures based on the recent advances in understanding of molecular genetic control over embryonic development of the cervical spines were reviewed.

Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling.

BACKGROUND: Cellular hypertrophy requires coordinated regulation of progrowth and antigrowth mechanisms. In cultured neonatal cardiomyocytes, Foxo transcription factors trigger an atrophy-related gene program that counters hypertrophic growth. However, downstream molecular events are not yet well defined. METHODS AND RESULTS: Here, we report that expression of either Foxo1 or Foxo3 in cardiomyocytes attenuates calcineurin phosphatase activity and inhibits agonist-induced hypertrophic growth. Consistent with these results, Foxo proteins decrease calcineurin phosphatase activity and repress both basal and hypertrophic agonist-induced expression of MCIP1.4, a direct downstream target of the calcineurin/NFAT pathway. Furthermore, hearts from Foxo3-null mice exhibit increased MCIP1.4 abundance and a hypertrophic phenotype with normal systolic function at baseline. Together, these results suggest that Foxo proteins repress cardiac growth at least in part through inhibition of the calcineurin/NFAT pathway. Given that hypertrophic growth of the heart occurs in multiple contexts, our findings also suggest that certain hypertrophic signals are capable of overriding the antigrowth program induced by Foxo. Consistent with this, multiple hypertrophic agonists triggered inactivation of Foxo proteins in cardiomyocytes through a mechanism requiring the PI3K/Akt pathway. In addition, both Foxo1 and Foxo3 are phosphorylated and consequently inactivated in hearts undergoing hypertrophic growth induced by hemodynamic stress. CONCLUSIONS: This study suggests that inhibition of the calcineurin/NFAT signaling cascade by Foxo and release of this repressive action by the PI3K/Akt pathway are important mechanisms whereby Foxo factors govern cell growth in the heart.

Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice.

Type 2 diabetes is a heterogeneous disease characterized by insulin resistance and altered glucose and lipid metabolism in multiple organs. To understand the complex series of events that occur during the development of obesity-associated diabetes, we examined the temporal pattern of changes in insulin action and glucose metabolism in individual organs during chronic high-fat feeding in C57BL/6 mice. Insulin-stimulated cardiac glucose metabolism was significantly reduced after 1.5 weeks of high-fat feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling and GLUT4 levels. Insulin resistance in skeletal muscle, adipose tissue, and liver developed in parallel after 3 weeks of high-fat feeding. Diet-induced whole-body insulin resistance was associated with increased circulating levels of resistin and leptin but unaltered adiponectin levels. High-fat feeding caused insulin resistance in skeletal muscle that was associated with significantly elevated intramuscular fat content. In contrast, diet-induced hepatic insulin resistance developed before a marked increase in intrahepatic triglyceride levels. Cardiac function gradually declined over the course of high-fat feeding, and after 20 weeks of high-fat diet, cardiac dysfunction was associated with mild hyperglycemia, hyperleptinemia, and reduced circulating adiponectin levels. Our findings demonstrate that cardiac insulin resistance is an early adaptive event in response to obesity and develops before changes in whole-body glucose homeostasis. This suggests that obesity-associated defects in cardiac function may not be due to insulin resistance per se but may be attributable to chronic alteration in cardiac glucose and lipid metabolism and circulating adipokines.