Targeting ketone body metabolism to treat fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disorder marked by excessive accumulation of lipids within the liver. If untreated, this condition can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Given the liver's pivotal role in glucose and fatty acid metabolism, disruptions in these processes are commonly observed in MASLD.

Transcriptional regulation of the postnatal cardiac conduction system heterogeneity.

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes that coordinates electrical impulse generation and propagation for synchronized heart contractions. Although the components of the CCS, including the sinoatrial node, atrioventricular node, His bundle, bundle branches, and Purkinje fibers, were anatomically discovered more than 100 years ago, their molecular constituents and regulatory mechanisms remain incompletely understood. Here, we demonstrate the transcriptomic landscape of the postnatal mouse CCS at a single-cell resolution with spatial information.

KDM8 epigenetically controls cardiac metabolism to prevent initiation of dilated cardiomyopathy.

Cardiac metabolism is deranged in heart failure, but underlying mechanisms remain unclear. Here, we show that lysine demethylase 8 (Kdm8) maintains an active mitochondrial gene network by repressing , thus preventing dilated cardiomyopathy leading to lethal heart failure. Deletion of in mouse cardiomyocytes increased H3K36me2 with activation of and repression of target genes in the NAD pathway before dilated cardiomyopathy initiated.

Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, modulates glucose production, and when absent influences NAFLD progression.

Elevated circulating dipeptidyl peptidase-4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease progression remains unclear. Here, we identified that DPP4 in hepatocytes but not TEK receptor tyrosine kinase-positive endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis.

Insulin-like growth factor-binding protein-7 (IGFBP7) links senescence to heart failure.

Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model.

Deficiency of Irx5 protects mice from obesity and associated metabolic abnormalities.

Objective: Obesity, a leading cause of several metabolic abnormalities, is mainly caused by imbalanced energy homeostasis. IRX3 and IRX5 have been suggested as genetic determinants of obesity in connection with the intronic variants of the FTO gene, the strongest genetic risk factor of polygenic obesity in humans. Although the causal effects of Irx3 and its cooperation with Irx5 in obesity and associated metabolic abnormalities have been demonstrated in vivo, the function of Irx5 in energy homeostasis remains unclear.

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk.

Heart disease is the leading cause of morbidity and mortality worldwide. Due to their low cost, ease of handling, and abundance of transgenic strains, rodents have become essential models for cardiovascular research. However, spontaneous lethal cardiac arrhythmias that often cause mortality in heart disease patients are rare in rodent models of heart disease.

Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis.

Objective: Aberrant ketogenesis is correlated with the degree of steatosis in non-alcoholic fatty liver disease (NAFLD) patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease.

Methods: Loss- and gain-of-ketogenic function models, achieved by Hmgcs2 knockout and overexpression, respectively, were utilized to investigate the role of ketogenesis in the hepatic lipid accumulation during postnatal development and in a high-fat diet-induced NAFLD mouse model.

Irx5 and transient outward K currents contribute to transmural contractile heterogeneities in the mouse ventricle.

Previous studies have established that transmural gradients of the fast transient outward K current () correlate with regional differences in action potential (AP) profile and excitation-contraction coupling (ECC) with high expression in the epimyocardium (EPI) being associated with short APs and low contractility and vice versa. Herein, we investigated the effects of altering the gradients on transmural contractile properties using mice lacking (Irx5-KO) or lacking (K4.2-KO) or both.

Quantification of murine myocardial infarct size using 2-D and 4-D high-frequency ultrasound.

Ischemic heart disease is the leading cause of death in the United States, Canada, and worldwide. Severe disease is characterized by coronary artery occlusion, loss of blood flow to the myocardium, and necrosis of tissue, with subsequent remodeling of the heart wall, including fibrotic scarring. The current study aims to demonstrate the efficacy of quantitating infarct size via two-dimensional (2-D) echocardiographic akinetic length and four-dimensional (4-D) echocardiographic infarct volume and surface area as in vivo analysis techniques.

Ectopic expression of and in the paraventricular nucleus of the hypothalamus contributes to defects in haploinsufficiency.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of -expressing neurons critical for feeding regulation. haploinsufficiency results in hyperphagic obesity with disruption of PVH neurons, yet the molecular profiles of PVH neurons and the mechanism underlying the defects of haploinsufficiency are not well understood. By single-cell RNA sequencing, we identified two major populations of PVH neurons, which are differentially affected by haploinsufficiency.

Irx3 and Irx5 in Ins2-Cre cells regulate hypothalamic postnatal neurogenesis and leptin response.

Obesity is mainly due to excessive food intake. IRX3 and IRX5 have been suggested as determinants of obesity in connection with the intronic variants of FTO, but how these genes contribute to obesity via changes in food intake remains unclear. Here, we show that mice doubly heterozygous for Irx3 and Irx5 mutations exhibit lower food intake with enhanced hypothalamic leptin response.

Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice.

Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved.

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases.

The global prevalence of metabolic disorders, such as obesity, diabetes and fatty liver disease, is dramatically increasing. Both genetic and environmental factors are well-known contributors to the development of these diseases and therefore, the study of epigenetics can provide additional mechanistic insight. Dietary interventions, including caloric restriction, intermittent fasting or time-restricted feeding, have shown promising improvements in patients' overall metabolic profiles (i.

Single cell and genetic analyses reveal conserved populations and signaling mechanisms of gastrointestinal stromal niches.

Stomach and intestinal stem cells are located in discrete niches called the isthmus and crypt, respectively. Recent studies have demonstrated a surprisingly conserved role for Wnt signaling in gastrointestinal development. Although intestinal stromal cells secrete Wnt ligands to promote stem cell renewal, the source of stomach Wnt ligands is still unclear.

Assessment of the Metabolic Effects of Isocaloric 2:1 Intermittent Fasting in Mice.

Intermittent fasting (IF), a dietary intervention involving periodic energy restriction, has been considered to provide numerous benefits and counteract metabolic abnormalities. So far, different types of IF models with varying durations of fasting and feeding periods have been documented. However, interpreting the outcomes is challenging, as many of these models involve multifactorial contributions from both time- and calorie-restriction strategies.

The impact of sex hormones on genital wound healing in mice: a comparative study.

Introduction And Objective: The effects estrogen and testosterone have on penile wound healing are still uncertain. This study evaluated the effects of these hormones on the wound healing process of penile and non-penile skin in wild-type (Mus musculus species) 4-5-week-old mice.

Methodology: Seventy wild-type Mus musculus species were randomly assigned to four groups control (n = 17), 1-week post-operative topical estrogen (n = 18), 1-week pre-operative testosterone (n = 17), and immediate post-operative testosterone (n = 18).

Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice.

Intermittent fasting (IF) is an effective dietary intervention to counteract obesity-associated metabolic abnormalities. Previously, we and others have highlighted white adipose tissue (WAT) browning as the main underlying mechanism of IF-mediated metabolic benefits. However, whether IF retains its efficacy in different models, such as genetically obese/diabetic animals, is unknown.

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice.

Irx3 is required for postnatal maturation of the mouse ventricular conduction system.

The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43.

Physiological roles of the transient outward current Ito in normal and diseased hearts.

The Ca(2+)-independent transient outward K(+) current (I(to)) plays a critical role in underlying phase 1 of repolarization of the cardiac action potential and, as a result, is central to modulating excitation-contraction coupling and propensity for arrhythmia. Additionally, I(to) and its molecular constituents are consistently reduced in cardiac hypertrophy and heart failure. In this review, we discuss the physiological role of I(to) as well as the molecular basis of this current in human and canine hearts, in which I(to) has been thoroughly studied.

FTO Obesity Variant Circuitry and Adipocyte Browning in Humans.

Background: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive.

Methods: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity.