Mitochondrial activator BGP-15 protects sperm quality against oxidative damage and improves embryo developmental competence.

Objective: To study the efficacy of mitochondrial activator BGP-15 to preserve sperm quality and competence against cellular damage.

Design: Spermatozoa from mice or humans were treated in vitro with BGP-15 and sperm quality markers assessed. Spermatozoa from young (8-12 weeks old) or reproductively old (>14 months old) mice were treated with BGP-15 for 1h and assessed for sperm quality and pre-implantation embryo development after in vitro fertilization (IVF).

Harnessing the therapeutic potential of exercise in extracellular vesicle-based therapy in metabolic disease associated cardiovascular complications.

Cardiovascular disease (CVD) is a leading cause of mortality, affecting ∼18 million individuals each year. Obesity and type 2 diabetes mellitus in particular, both chronic metabolic disorders, are risk factors for CVD. The salutary effects of physical activity in preventing and ameliorating CVD have long been acknowledged, as it improves glucose and lipid homeostasis, alongside attenuating oxidative damage, increasing mitochondrial function, and ultimately improving cardiac function.

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice.

Background: Regular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood.

Methods: We used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden.

Results: We show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone.

CaMKK2: bridging the gap between Ca2+ signaling and energy-sensing.

Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins.

High-fat feeding drives the intestinal production and assembly of C ceramides in chylomicrons.

Consumption of a diet rich in saturated fat increases lipid absorption from the intestine, assembly into chylomicrons, and delivery to metabolic tissues via the lymphatic and circulatory systems. Accumulation of ceramide lipids, composed of sphingosine and a fatty acid, in metabolic tissues contributes to the pathogenesis of cardiovascular diseases, type 2 diabetes mellitus and cancer. Using a mesenteric lymph duct cannulated rat model, we showed that ceramides are generated by the intestine and assembled into chylomicrons, which are transported via the mesenteric lymphatic system.

Embracing cancer complexity: Hallmarks of systemic disease.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers.

ACAD10 is not required for metformin's metabolic actions or for maintenance of whole-body metabolism in C57BL/6J mice.

Aim: Acyl-coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans.

Impact of voluntary exercise training on the metabolic and behavioral characteristics of the rTg4510 transgenic mouse model of frontotemporal dementia.

Frontotemporal dementia (FTD) is a neurodegenerative disorder that affects the frontal and temporal lobes of the brain, primarily in individuals under 65 years of age, and is the second most common form of dementia worldwide. There is no cure for FTD and current treatments offer limited symptomatic relief. Regular physical activity exhibits cognitive and neuroprotective benefits in healthy individuals and in various neurodegenerative diseases, such as Alzheimer's disease, but few studies have examined its efficacy in FTD.

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity.

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism.

CaMKK2 as an emerging treatment target for bipolar disorder.

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets.

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the mouse fed a high-fat diet.

Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential.

Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed.

Diet-induced gut dysbiosis and inflammation: Key drivers of obesity-driven NASH.

Sucrose, the primary circulating sugar in plants, contains equal amounts of fructose and glucose. The latter is the predominant circulating sugar in animals and thus the primary fuel source for various tissue and cell types in the body. Chronic excessive energy intake has, however, emerged as a major driver of obesity and associated pathologies including nonalcoholic fatty liver diseases (NAFLD) and the more severe nonalcoholic steatohepatitis (NASH).

Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary.

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition.

Exerkines in health, resilience and disease.

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood.

Deletion of GPR21 improves glucose homeostasis and inhibits the CCL2-CCR2 axis by divergent mechanisms.

Introduction: A potential role for the orphan G protein-coupled receptor, GPR21, in linking immune cell infiltration into tissues and obesity-induced insulin resistance has been proposed, although limited studies in mice are complicated by non-selective deletion of .

Research Design And Methods: We hypothesized that a -selective knockout mouse model, coupled with type 2 diabetes patient samples, would clarify these issues and enable clear assessment of GPR21 as a potential therapeutic target.

Results: High-fat feeding studies in mice revealed improved glucose tolerance and modest changes in inflammatory gene expression.

"Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis.

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous.

Immune-based therapies in cardiovascular and metabolic diseases: past, present and future.

Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins - a class of lipid-lowering drugs - have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders.

IL-6 family cytokines as potential therapeutic strategies to treat metabolic diseases.

Metabolic disease is highly prevalent. Here we discuss the therapeutic utility of using gp130 receptor ligands as a therapeutic strategy to treat metabolic disease.

Stable Isotopic Tracer Phospholipidomics Reveals Contributions of Key Phospholipid Biosynthetic Pathways to Low Hepatocyte Phosphatidylcholine to Phosphatidylethanolamine Ratio Induced by Free Fatty Acids.

There is a strong association between hepatocyte phospholipid homeostasis and non-alcoholic fatty liver disease (NAFLD). The phosphatidylcholine to phosphatidylethanolamine ratio (PC/PE) often draws special attention as genetic and dietary disruptions to this ratio can provoke steatohepatitis and other signs of NAFLD. Here we demonstrated that excessive free fatty acid (1:2 mixture of palmitic and oleic acid) alone was able to significantly lower the phosphatidylcholine to phosphatidylethanolamine ratio, along with substantial alterations to phospholipid composition in rat hepatocytes.

The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages.

Adipose tissue macrophages (ATMs) display tremendous heterogeneity depending on signals in their local microenvironment and contribute to the pathogenesis of obesity. The phosphoinositide 3-kinase (PI3K) signalling pathway, antagonized by the phosphatase and tensin homologue (PTEN), is important for metabolic responses to obesity. We hypothesized that fluctuations in macrophage-intrinsic PI3K activity via PTEN could alter the trajectory of metabolic disease by driving distinct ATM populations.