Exercise-induced inflammation is regarded as a response to muscle damage from mechanical stress, but controlled immune signaling can be beneficial by promoting metabolic adaptation which, for example, decreases obesity and lowers the risk of diabetes. In addition to oxidative metabolism, mitochondria play a central role in initiating innate immune signaling. We review recent work that has identified

The mitochondrial unfolded protein response (UPRmt) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive maturity leads to suppression of the UPRmt, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the

Despite the crucial role of the placenta in supporting pregnancy and fetal development, research into its susceptibility to environmental exposures has been limited by methodological challenges. We review diverse approaches to studying placental biology and responses to chemical exposures, and provide a comprehensive assessment of traditional and emerging methodologies. Beginning with an overview of

Metabolic resilience is essential for organismal homeostasis under diverse external pressures, because responding and adapting to stressors requires energy and drives changes at every omic level. The goal of this paper is to synthesize recent advances in understanding the intricate interplay, especially between metabolic and transcriptomic responses, involved in addressing external perturbations. We

Insulin resistance is a central feature of metabolic disorders such as type 2 diabetes (T2D). While studies on this disorder have largely been linked to glucose metabolism and intracellular signaling, recent advances reveal that insulin resistance extends beyond traditional glucose regulatory pathways, impacting multiple organs including the brain, contributing to cognitive dysfunction and neurodegenerative

The rising prevalence of depressive disorder worldwide requires better interventional avenues. B vitamins are gaining increasing interest as potential therapeutic approaches in this context given current evidence for a bidirectional association between B vitamin deficiency and depressive disorder. We discuss how B vitamins and B vitamin-associated probiotic supplementation may represent an effective

Breast cancer (BC) remains the most prevalent malignancy among women worldwide. While genetic predisposition and reproductive history are key contributors to its development, modifiable risk factors are also important, particularly those linked to lifestyle behaviors, often influencing the endogenous metabolome. Over the past decade, mass spectrometry-based metabolomics has enabled agnostic investigations

Disorders of lipid metabolism, including hyperlipidemia, atherosclerosis, and metabolic dysfunction-associated steatotic liver disease, are increasing across the globe. Bempedoic acid (BPA) is a first-in-class drug for the treatment of hypercholesterolemia and cardiac risk reduction, which may particularly benefit those who do not tolerate statins. Inhibition of hepatic ATP-citrate lyase (ACLY) is

Non-communicable diseases (NCDs) pose a serious challenge to global public health, compounded by unhealthy nutrition and obesogenic environments. This science and society article emphasizes several evidence-based behavior-change strategies, policy interventions, and meaningful youth engagement to promote healthy nutrition choices among children and adolescents.

Transcription factor hepatocyte nuclear factor 4 alpha (HNF4α) is considered the master regulator of hepatocyte differentiation. During homeostasis, HNF4α maintains liver identity by supporting metabolism while inhibiting proliferation. It is downregulated in response to both acute and chronic insults; however, although this supports hepatic regeneration in mild acute settings, severe or chronic downregulation

Extending healthspan – the years lived in optimal health – holds transformative potential to reduce chronic diseases and healthcare costs. Dietary restriction (DR), particularly when combined with nutrient-rich diets and exercise, is among the most effective, evidence-based strategies for enhancing metabolic health and longevity. By targeting fundamental pathways, it mitigates the onset and progression

Establishment of the early-life gut microbiome, coinciding with the host development, predisposes to long-term disease risk if disrupted. Recently, Hill et al. precisely delineated a critical early-life window in humans and mice during which specific fungi and bacteria play indispensable roles in β-cell development, thereby regulating lifelong metabolic homeostasis.

Neurodegenerative diseases (NDDs) pose a significant and rapidly growing global health challenge, but there are no effective therapies to delay or halt progression. In recent years augmentation of nicotinamide adenine dinucleotide (NAD) has emerged as a promising disease-modifying strategy that targets multiple key disease pathways across multiple NDDs, such as mitochondrial dysfunction, energy deficits

Gestational diabetes mellitus (GDM) is a common pregnancy complication and a risk factor for the subsequent development of type 2 diabetes (T2D) in mothers and of several metabolic diseases in offspring. However, the molecular underpinnings of these risks are not well understood. Genome-wide association studies (GWAS) and epigenetic studies may provide complementary insights into the causal relationships

Endometriosis, characterized by uterine-like tissue growth outside the uterus, is a complex disorder with significant clinical implications. This review explores how body composition - both low body mass index (BMI) and obesity - modulates endometriosis progression through metabolic, hormonal, and immune-inflammatory pathways. Obesity-driven leptin signaling emerges as a pivotal link, promoting systemic

Investigating the association between glucagon-like peptide 1 receptor agonists (GLP1-RAs) and incident disease across 175 health outcomes in US Veterans with diabetes, Xie et al. recently reported lower risk for cardiokidney disease and substance use disorders, but higher risk for pancreatitis, gastrointestinal disorders, and arthritis. However, many apparent novel findings need testing or validation

Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the

The increasing global prevalence of obesity presents a substantial challenge to public health. Current nutrient-stimulated hormone (NuSH)-based therapeutics are hindered by receptor desensitization, muscle loss, and weight regain. The adipose tissue, the primary organ responsible for energy storage and metabolic management, is a promising target for obesity treatment. Nanomedicine holds promise to

Pyruvate kinase is a key regulator in hepatic glucose metabolism, encoded by the gene pyruvate kinase liver/red blood cells (PKLR). Systems biology-based approaches, including metabolic and gene co-expression networks analyses, as well as genome-wide association studies (GWAS), have led to the identification of PKLR as a pivotal gene influencing liver metabolism in patients with metabolic dysfunction-associated

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a pressing global health concern. The complexity of MASLD and the lack of universally effective treatments expose the limitations of current interventions, which focus mainly on lifestyle modifications. Here, we explore the multilayered nature of MASLD, emphasizing

Circadian rhythms are cell-intrinsic time-keeping mechanisms that allow organisms to adapt to 24-h environmental changes, ensuring coordinated physiological functions by aligning internal metabolic oscillations with external timing cues. Disruption of daily metabolic rhythms is associated with pathological events such as cancer development, yet the mechanisms by which perturbed metabolic rhythms contribute

The neuropeptide kisspeptin activates the hypothalamic-pituitary-gonadal (HPG) axis and influences neural circuits controlling sexual behavior. Animal studies have determined its sex-specific roles in reproductive behaviors, whereas human research has linked kisspeptin to increased brain activity in regions associated with sexual and emotional processing, making it a potential treatment for disorders

Youth-onset type 2 diabetes (YO-T2D) is an urgent public health challenge that demands immediate and innovative action. The devastating trajectory of this disease - from rapid β-cell decline to early complications and poor responses to medications - compels us to rethink our approach. Here, we argue that by investing in targeted research to unravel the unique mechanisms of this condition, ensuring

Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with a fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, ALS remains a rapidly disabling and life-shortening condition. The non-motor neuron features of ALS, including nutritional status, energy expenditure, and

Hormonal fluctuations across the female reproductive lifespan lead to physiological adjustments that impact insulin sensitivity and glucose metabolism, generating unique challenges in diabetes management. Although current guidelines focus primarily on diabetes care during pregnancy, they lack tailored recommendations for addressing glycaemic variability associated with menstrual cycles, contraceptive

Fasting is a recurrent daily energy stress that benefits healthspan and lifespan. While ketones fuel fasting in vertebrates, the underlying transcriptional mechanism remains incompletely understood. Recently, Korenfeld et al. revealed peroxisome proliferator-activated receptor alpha (PPARα)-dependent enhancer priming as a keystone for ketone production, increasing our understanding of mechanisms underlying

Dysregulation of immune homeostasis can precipitate chronic inflammation, thus significantly contributing to the onset and progression of metabolic and cardiovascular diseases. Myeloid-derived suppressor cells (MDSCs) constitute a heterogeneous population of immature myeloid cells that are mobilized in response to biological stressors such as tissue damage and inflammation. Although MDSCs have been

Ovarian aging is considered to be the pacemaker of female aging, and is linked to various comorbidities such as osteoporosis, cardiovascular diseases, and cognitive decline. Many efforts have been made to determine the mechanisms underlying ovarian aging, but their potential to act as hallmarks to predict and intervene in this process currently remains unclear. In this review we propose nine hallmarks

Plant-based diets emphasize higher intake of plant foods and are low in animal products. Individuals following plant-based diets have a lower risk of chronic conditions; however, the mechanisms underlying these associations are not completely understood. Omics data have opened opportunities to investigate the mechanistic effect of dietary intake on health outcomes. Here, we review omics analyses of

Prediabetes is a highly prevalent and increasingly common condition affecting a significant proportion of the global population. The heterogeneous nature of prediabetes presents a challenge in identifying individuals who particularly benefit from lifestyle or other therapeutic interventions aiming at preventing type 2 diabetes (T2D) and associated comorbidities. The phenotypic characteristics of individuals

Cardiovascular disease (CVD) remains a significant global health concern, with obesity recognized as a prominent risk factor. The ‘obesity paradox’ (OP) suggests that obesity does not always lead to adverse outcomes, particularly in heart failure (HF). In this forum, we discuss the relevance of the OP in the current therapeutic landscape for cardiometabolic diseases.

Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times. GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection. Furthermore, there is a growing platform of evidence that GLP-1RA has extended

Mitochondria perform essential metabolic processes that sustain cellular bioenergetics and biosynthesis. In a recent article, Ryu et al. explored how mitochondria coordinate biochemical reactions with opposing redox demands within the same cell. They demonstrate that subcellular mitochondrial heterogeneity enables metabolic compartmentalization to permit concurrent oxidative ATP production and reductive

Recent advances in lineage-tracing technologies have significantly improved our understanding of pancreatic cell biology, particularly in elucidating the ontogeny and regenerative capacity of pancreatic cells. A deeper appreciation of the mechanisms underlying pancreatic cell identity and plasticity holds the potential to inform the development of new therapeutic modalities for conditions such as diabetes

Liver fibrosis and biological sex variably modulate the risks of hepatocellular carcinoma (HCC) and extrahepatic cancers (EHCs) arising in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we highlight how these variables may have implications in the setting of chemoprevention and precision medicine approaches in MASLD and guide additional research.

Respiratory infections and diseases pose significant challenges to society and healthcare systems, underscoring the need for preventative and therapeutic strategies. Recent research in rodent models indicates that short-chain fatty acids (SCFAs), metabolites produced by gut bacteria, may offer medicinal benefits for respiratory conditions. In this opinion, we summarize the current literature that highlights

Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of

With the rising prevalence of type 2 diabetes mellitus (T2DM) and obesity, several previously under-recognised complications associated with T2DM are becoming more evident. The most common of these emerging complications are metabolic dysfunction-associated steatotic liver disease (MASLD), cancer, dementia, sarcopenia, and frailty, as well as other conditions involving the lung, heart, and intestinal

Prostate cancer (PC) is a notoriously immune-cold tumor in that it often lacks substantial infiltration by antitumor immune cells, and in advanced diseases such as neuroendocrine PC, it could be devoid of immune cells. A majority of PC patients thus have, unfortunately, been unable to benefit from recent advances in immunotherapies. What causes this immunosuppressive microenvironment around PC? In

Premenopausal women and endurance-trained individuals of either sex have reduced cardiovascular disease (CVD) risk. Endurance training shifts fuel selection towards fats to spare carbohydrates; interestingly, women prioritize fats as an energy resource more than men do during exercise. Relying on fats during exercise drives whole-body lipolysis and promotes lipid uptake and oxidation capacity in skeletal

Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder, affecting approximately 11–13% of women of reproductive age. Women with PCOS experience a higher prevalence of infertility, pregnancy complications, and cardiometabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus. Furthermore, psychiatric comorbidities, including depression and anxiety

Ferroptosis has been implicated in several reproductive disorders, but the underlying mechanisms remain unknown; thus, interventions targeting this pathway are lacking. Here we summarize the emerging findings on ferroptosis in reproductive biology and corresponding disorders, and highlight perspectives and challenges on future ferroptosis research with potential clinical applications.

Circadian rhythms are highly conserved biorhythms of ~24 h that govern many fundamental biological processes, including cardiovascular (CV) homeostasis. Disrupting the timing of cellular oscillators promotes cellular stress, and induction of pathogenic pathways underpins the pathogenesis of many CV diseases (CVDs). Thus, shift work, late eating, sleep disturbances, and other disruptors can result in

Perceived stress levels, prevalence of pregnancies complicated by metabolic disorders, and childhood obesity have been increasing steadily. We here propose a pathway integrating stress-responsive biological systems into the established effects of maternal diabetes and obesity during pregnancy, overall exerting a combined contribution to offspring adiposity risk.

Orosomucoids (ORMs) have historically been considered as carriers involved in drug and lipid delivery. However, recent studies indicate ORM2 as a hepatokine involved in metabolic regulation. Here, we highlight the functions of ORM2 in controlling metabolic health and disease, focusing on its newly discovered regulatory mechanisms.

Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and

When acute SARS-CoV-2 infections cause symptoms that persist longer than 3 months, this condition is termed long COVID. Symptoms experienced by patients often include myalgia, fatigue, brain fog, cognitive impairments, and post-exertional malaise (PEM), which is the worsening of symptoms following mental or physical exertion. There is little consensus on the pathophysiology of exercise-induced PEM

Inter-organ communication (IOC) is a complex mechanism involved in maintaining metabolic homeostasis and healthy aging. Dysregulation of distinct forms of IOC is linked to metabolic derangements and age-related pathologies, implicating these processes as a potential target for therapeutic intervention to promote healthy aging. In this review, we delve into IOC mediated by hormonal signaling, circulating

Endothelial cells (ECs) form the inner lining of blood vessels that is crucial for vascular function and homeostasis. They regulate vascular tone, oxidative stress, and permeability. Dysfunction leads to increased permeability, leukocyte adhesion, and thrombosis. ECs undergo metabolic changes in conditions such as wound healing, cancer, atherosclerosis, and diabetes, and can influence disease progression

It has long been thought that the functional identity of mammalian brain neurons is programmed during development and remains stable throughout adult life; however, certain populations of neurons continue to express active regulators of neuronal identity into adulthood. Prolonged exposure to diet-induced metabolic stress induces features of neuronal identity modification in adult mice, and maladaptive