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 cardiok...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 in randomized trials.
Rahman MS, Park Y, Hosseinirad H
… +2 more, Shin JH, Jeong JW
Trends Endocrinol Metab
· 2025 Dec · PMID 40280861
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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...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 inflammation, angiogenesis, and lesion persistence via Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Shared molecular mechanisms between endometriosis and obesity highlight opportunities for precision medicine and targeted therapies. By addressing leptin-driven pathways and metabolic dysfunction, we introduce innovative strategies, offering novel insights into the improved management of this multifaceted condition.
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 o...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 role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.
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 weig...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 precisely deliver medication to the adipose tissue to maximize therapeutic efficacy and minimize off-target effects; indeed, various adipose tissue-targeting nanomedicines have shown impressive anti-obesity effects by optimizing drug pharmacokinetic profiles and reducing nonspecific distribution in preclinical studies. Here we examine the current state of the art of adipose tissue-targeting nanomedicines, offering insights into recent advances, future possibilities, and the remaining challenges associated with their application in obesity treatment.
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 universal...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 its pathophysiology in shaping future medical and lifestyle interventions from a personalized medicine perspective, based on individual molecular profiles. Additionally, we address the limitations of current animal models in reflecting human metabolic syndrome and sex-specific differences. We argue that a holistic approach, integrating social determinants of health, patient preferences, and adherence patterns, is essential for advancing MASLD management effectively.
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 an...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 steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we review the critical role of PKLR in MASLD and HCC progression and examine the effects of PKLR modulation both in vitro and in vivo. We also discuss the development of therapeutic strategies for patients with MASLD and HCC by modulating PKLR, highlighting its promising future in a broader range of liver diseases.
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 exte...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 to tumorigenesis remain unclear. Herein we review how circadian clocks drive balanced rhythmic metabolism which in turn governs physiological functions of locomotor, immune, and neuroendocrine systems. Misaligned metabolic rhythms cause pathological states which further drive cancer initiation, progression, and metastasis. Restoring the balance of metabolic rhythms with chemical, hormonal, and behavioral interventions serves as a promising strategy for cancer therapy.
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 behavi...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 of sexual desire. Here I discuss the current evidence on the promise of kisspeptin as a therapy for sexual dysfunction, highlight the challenges currently hindering its application, and advocate future studies focusing on sex-specific effects and interactions within the neuroendocrine system. Understanding its broader physiological roles and improving delivery methods will be key to unlocking kisspeptin's therapeutic potential.
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 po...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 equitable access to cutting-edge clinical trials, and building clinical care models tailored specifically for youth, we can rewrite the narrative for these at-risk youth.
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 contribut...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 metabolic imbalance, are increasingly gaining attention. Indeed, the bioenergetic failure and mitochondrial dysfunction of patients with ALS impact not only the high energy-demanding motor neurons but also organs and brain areas long considered irrelevant to the disease. As such, here we discuss how considering energy balance in ALS is reshaping research on this disease, opening the path to novel targetable opportunities for its treatment.
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 curren...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 needs, and menopause. Low rates of prepregnancy counselling, limited contraceptive guidance, and underuse of hormone replacement therapy further complicate care for women with diabetes. Here we examine these care gaps, identify unmet needs across reproductive stages, and suggest research directions to develop comprehensive, stage-specific management strategies that better support women's health and improve diabetes outcomes throughout the reproductive years.
Trends Endocrinol Metab
· 2025 Apr · PMID 40057442
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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 e...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 metabolic benefits of alternate-day fasting (ADF).
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) co...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 extensively characterized in the contexts of cancer and infectious diseases, emerging evidence highlights their pivotal roles in the pathophysiology of metabolic and cardiovascular disorders. We discuss growing evidence for the involvement of MDSCs in the progression of metabolic and cardiovascular diseases, with the aim of deepening our understanding of MDSCs in cardiometabolic physiology and identifying the necessary steps for the development of innovative MDSC-targeted therapeutic strategies.
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 m...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 as common features of ovarian aging: genomic instability, telomere attrition, epigenetic alterations, impaired autophagy, cellular senescence, deregulated nutrient-sensing, mitochondrial dysfunction, oxidative stress, and chronic inflammation. Understanding the interaction between these hallmarks poses a significant challenge but may also pave the way to the identification of pharmaceutical targets that can attenuate ovarian aging.
Trends Endocrinol Metab
· 2025 Jun · PMID 39984401
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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 associati...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 plant-based diets in feeding and observational studies, showing that although metabolomics and proteomics identified candidate biomarkers and distinct pathways modifiable by plant-based diets, current evidence from transcriptomics and methylomics is limited. We also argue that future studies should examine how unhealthful plant-based diets are associated with a higher risk of health outcomes and integrate multiple omics data from feeding studies to provide further mechanistic insights.