Chronic GLP1 therapy reduces postprandial IL6 in obese humans with prediabetes.

Single-dose glucagon-like peptide 1 (GLP1) therapy increases postprandial plasma IL6 levels in prediabetic, obese humans. GLP1-IL6 interactions underly multiple antidiabetic effects, but these may differ after acute versus chronic therapy. This study examines postprandial effects of GLP1 after chronic therapy. Seven humans (six Black) with prediabetes and obesity completed 6 weeks of exenatide extended release therapy. Then subjects returned for pre- and post-meal measurements of plasma IL6, GLP1, glucagon, and related inflammatory markers. Weight, which was measured before and after therapy, did not change. Plasma IL6 decreased from baseline to postmeal state ( = 0.016), with decreases in free fatty acids (P < 0.001) and increases in insulin (P = 0.002), glucose (P < 0.0001), triglycerides (P = 0.0178), and glucagon (P = 0.018). Baseline GLP1 levels matched 6 weeks of therapy. The fall in postprandial plasma IL6, which contrasts with the increase after acute therapy, highlights the need for more investigation regarding the mechanisms of acute versus chronic GLP1-IL6 signaling.

Augmenting Mitochondrial Respiration in Immature Smooth Muscle Cells with an ACTA2 Pathogenic Variant Mitigates Moyamoya-like Cerebrovascular Disease.

ACTA2 pathogenic variants altering arginine 179 cause childhood-onset strokes due to moyamoya disease (MMD)-like occlusion of the distal internal carotid arteries. A smooth muscle cell (SMC)-specific knock-in mouse model (Acta2SMC-R179C/+) inserted the mutation into 67% of aortic SMCs, whereas explanted SMCs were uniformly heterozygous. Acta2R179C/+ SMCs fail to fully differentiate and maintain stem cell-like features, including high glycolytic flux, and increasing oxidative respiration (OXPHOS) with nicotinamide riboside (NR) drives the mutant SMCs to differentiate and decreases migration. Acta2SMC-R179C/+ mice have intraluminal MMD-like occlusive lesions and strokes after carotid artery injury, whereas the similarly treated WT mice have no strokes and patent lumens. Treatment with NR prior to the carotid artery injury attenuates the strokes, MMD-like lumen occlusions, and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice. These data highlight the role of immature SMCs in MMD-associated occlusive disease and demonstrate that altering SMC metabolism to drive quiescence of Acta2R179C/+ SMCs attenuates strokes and aberrant vascular remodeling in the Acta2SMC-R179C/+ mice.

A Two-Step Transcriptome Analysis of the Human Heart Reveals Broad and Disease-Responsive Expression of Ectopic Olfactory Receptors.

G-protein-coupled receptors (GPCRs) are critical regulators of cardiac physiology and a key therapeutic target for the treatment of heart disease. Ectopic olfactory receptors (ORs) are GPCRs expressed in extra-nasal tissues which have recently emerged as new mediators in the metabolic control of cardiac function. The goals of this study were to profile OR gene expression in the human heart, to identify ORs dysregulated by heart failure caused by ischemic cardiomyopathy, and to provide evidence suggestive of a role for those altered ORs in the pathogenesis of heart failure. Left ventricular tissue from heart failure patients (n = 18) and non-failing heart samples (n = 4) were subjected to a two-step transcriptome analysis consisting of the quantification of 372 distinct OR transcripts on real-time PCR arrays and simultaneous determination of global cardiac gene expression by RNA sequencing. This strategy led to the identification of >160 ORs expressed in the human heart, including 38 receptors differentially regulated with heart failure. Co-expression analyses predicted the involvement of dysregulated ORs in the alteration of mitochondrial function, extracellular matrix remodeling, and inflammation. We provide this dataset as a resource for investigating roles of ORs in the human heart, with the hope that it will assist in the identification of new therapeutic targets for the treatment of heart failure.

Fetal metabolic adaptations to cardiovascular stress in twin-twin transfusion syndrome.

Monochorionic-diamniotic twin pregnancies are susceptible to unique complications arising from a single placenta shared by two fetuses. Twin-twin transfusion syndrome (TTTS) is a constellation of disturbances caused by unequal blood flow within the shared placenta giving rise to a major hemodynamic imbalance between the twins. Here, we applied TTTS as a model to uncover fetal metabolic adaptations to cardiovascular stress. We compared untargeted metabolomic analyses of amniotic fluid samples from severe TTTS cases vs. singleton controls. Amniotic fluid metabolites demonstrated alterations in fatty acid, glucose, and steroid hormone metabolism in TTTS. Among TTTS cases, unsupervised principal component analysis revealed two distinct clusters of disease defined by levels of glucose metabolites, amino acids, urea, and redox status. Our results suggest that the human fetal heart can adapt to hemodynamic stress by modulating its glucose metabolism and identify potential differences in the ability of individual fetuses to respond to cardiovascular stress.

The Lure of Cardiac Metabolism in the Diagnosis, Prevention, and Treatment of Heart Failure.

Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart failure. In this Review Topic of the Month, the authors focus on concepts and brevity to provide a strategic overview of cardiac metabolism in the diagnosis, prevention, and treatment of nonischemic heart failure.

Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.

Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced increase in thermogenesis and glucose utilization. We show that adipose IL-6R knockout mice still display liraglutide-induced weight loss but lack thermogenic adipocyte browning and metabolism activation. We conclude that the anti-diabetic effects of GLP1 analogs are mediated by transient upregulation of IL-6, which activates canonical IL-6R signaling and thermogenesis.

Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice.

Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40 days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.

Cardio-Onco-Metabolism - Metabolic vulnerabilities in cancer and the heart.

Cancer and cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic remodeling is a hallmark of both cancer and the failing heart. Tumors reprogram metabolism to optimize nutrient utilization and meet increased demands for energy provision, biosynthetic pathways, and proliferation. Shared risk factors for cancer and CVDs suggest intersecting mechanisms for disease pathogenesis and progression. In this review, we aim to highlight the role of metabolic remodeling in cancer and its potential to impair cardiac function. Understanding these mechanisms will help us develop biomarkers, better therapies, and identify patients at risk of developing heart disease after surviving cancer.

SIRPα Mediates IGF1 Receptor in Cardiomyopathy Induced by Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling. METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes. RESULTS: We demonstrate that SIRPα regulates myocardial insulin/IGF1R (insulin growth factor-1 receptor) signaling in CKD. First, in the serum of both mice and patients, SIRPα was robustly secreted in response to CKD. Second, cardiac muscle upregulation of SIRPα was associated with impaired insulin/IGF1R signaling, myocardial dysfunction, and fibrosis. However, both global and cardiac muscle-specific SIRPα KO mice displayed improved cardiac function when compared with control mice with CKD. Third, both muscle-specific or cardiac muscle-specific SIRPα KO mice did not significantly activate fetal genes and maintained insulin/IGF1R signaling with suppressed fibrosis despite the presence of CKD. Importantly, SIRPα directly interacted with IGF1R. Next, rSIRPα (recombinant SIRPα) protein was introduced into muscle-specific SIRPα KO mice reestablishing the insulin/IGF1R signaling activity. Additionally, overexpression of SIRPα in myoblasts and cardiomyocytes impaired pAKT (phosphorylation of AKT) and insulin/IGF1R signaling. Furthermore, myotubes and cardiomyocytes, but not adipocytes treated with high glucose or cardiomyocytes treated with uremic toxins, stimulated secretion of SIRPα in culture media, suggesting these cells are the origin of circulating SIRPα in CKD. Both intracellular and extracellular SIRPα exert biologically synergistic effects impairing intracellular myocardial insulin/IGF1R signaling. CONCLUSIONS: Myokine SIRPα expression impairs insulin/IGF1R functions in cardiac muscle, affecting cardiometabolic signaling pathways. Circulating SIRPα constitutes an important readout of insulin resistance in CKD-induced cardiomyopathy.

Strategies for Imaging Metabolic Remodeling of the Heart in Obesity and Heart Failure.

PURPOSE OF REVIEW: Define early myocardial metabolic changes among patients with obesity and heart failure, and to describe noninvasive methods and their applications for imaging cardiac metabolic remodeling. RECENT FINDINGS: Metabolic remodeling precedes, triggers, and sustains functional and structural remodeling in the stressed heart. Alterations in cardiac metabolism can be assessed by using a variety of molecular probes. The glucose tracer analog, 18F-FDG, and the labeled tracer 11C-palmitate are still the most commonly used tracers to assess glucose and fatty acid metabolism, respectively. The development of new tracer analogs and imaging agents, including those targeting the peroxisome proliferator-activated receptor (PPAR), provides new opportunities for imaging metabolic activities at a molecular level. While the use of cardiac magnetic resonance spectroscopy in the clinical setting is limited to the assessment of intramyocardial and epicardial fat, new technical improvements are likely to increase its usage in the setting of heart failure. Noninvasive imaging methods are an effective tool for the serial assessment of alterations in cardiac metabolism, either during disease progression, or in response to treatment.

Homeostasis Disrupted and Restored-A Fresh Look at the Mechanism and Treatment of Obesity During COVID-19.

The prevalence of obesity in the United States approaches half of the adult population. The COVID-19 pandemic endangers the health of obese individuals. In addition, the metabolic syndrome poses a challenge to the health of obese adults. Bariatric surgery and diet restore metabolic homeostasis in obese individuals; however, it is still unclear which strategy is most effective. For example, intermittent fasting improves insulin sensitivity and diet alone decreases visceral adipose tissue at a disproportionately high rate compared to weight loss. Bariatric surgery causes rapid remission of type 2 diabetes and increases incretins for long-term remission of insulin resistance before meaningful weight loss has occurred. Malabsorptive surgeries have provided insight into the mechanism of altering metabolic parameters, but strong evidence to determine the duration of their effects is yet to be established. When determining the best method of weight loss, metabolic parameters, target weight loss, and risk-benefit analysis must be considered carefully. In this review, we address the pros and cons for the optimal way to restore metabolic homeostasis.

Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy.

RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.

Obesity and Heart Failure with Preserved Ejection Fraction.

Obese heart failure with preserved ejection fraction (HFpEF) is a distinct HFpEF phenotype. Sodium retention, high circulating neurohormone levels, alterations in energy substrate metabolism, group 3 pulmonary hypertension, pericardial restraint, and systemic inflammation are central pathophysiologic mechanisms. Confirming the diagnosis may be challenging and high suspicion is required. Reduction of visceral adipose tissue, via caloric restriction and/or bariatric surgery, may improve outcomes in obese HFpEF patients. Furthermore, mineralocorticoid receptor inhibition, neprilysin inhibition, and sodium-glucose cotransporter 2 inhibition can ameliorate the effects of adiposity on the cardiovascular system, allowing for promising new treatment targets for the obese HFpEF phenotype.