Pancreatic adenocarcinoma (PaC) is one of the deadliest cancers, primarily due to late-stage diagnosis and limited treatment options. A bidirectional relationship exists between PaC and diabetes mellitus (DM), where gluc...Pancreatic adenocarcinoma (PaC) is one of the deadliest cancers, primarily due to late-stage diagnosis and limited treatment options. A bidirectional relationship exists between PaC and diabetes mellitus (DM), where glucose abnormalities both cause and result from PaC. In this review, we examine the complex pathophysiology of PaC-induced hyperglycemia, focusing on impaired insulin sensitivity, β cell dysfunction, chronic inflammation, and alterations in the gut microbiome and circadian rhythm. We discuss how PaC induces insulin resistance through disrupted signaling and proinflammatory factors, as well as β cell dysfunction through oxidative stress and adrenomedullin-mediated insulin secretion inhibition. In addition, emerging research highlights the role of the gut microbiome in PaC and hyperglycemia. Comprehensive understanding of these mechanisms is critical for early detection and improved treatment strategies for PaC.
Current research on inflammatory disorders tends to focus on the advanced stages of disease; however, acting against chronic low-grade inflammation (a stage before overt disease) through early nutritional interventions m...Current research on inflammatory disorders tends to focus on the advanced stages of disease; however, acting against chronic low-grade inflammation (a stage before overt disease) through early nutritional interventions may be an alternative, beneficial approach. We systematically evaluate how diet modulates chronic low-grade inflammation through several physiological processes. Furthermore, we suggest three intervention strategies tailored to specific stages of disease: (i) promoting anti-inflammatory dietary patterns in the general population, (ii) implementing precision nutrition targeting inflammatory biomarkers in individuals at risk, and (iii) utilizing adjuvant dietary therapies for existing inflammation. Overall, we argue that early nutritional interventions could address the unmet clinical need to alter inflammatory trajectories before clinical manifestation.
Heme has remarkable functions in mitochondrial energetics. Recently, Duerre et al. found that branched-chain amino acids (BCAA) are preferentially utilized for heme biosynthesis to facilitate mitochondrial thermogenesis...Heme has remarkable functions in mitochondrial energetics. Recently, Duerre et al. found that branched-chain amino acids (BCAA) are preferentially utilized for heme biosynthesis to facilitate mitochondrial thermogenesis in brown fat. Disrupting heme biosynthesis shifts the metabolic fate of BCAAs toward histone propionylation, inhibiting the transcription of thermogenic genes.
Trends Endocrinol Metab
· 2026 Feb · PMID 40555575
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Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are essential regulators of MAPK signaling pathways. MKPs perform critical roles in various cellular responses by dephosphorylating the regulatory residues and...Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) are essential regulators of MAPK signaling pathways. MKPs perform critical roles in various cellular responses by dephosphorylating the regulatory residues and thereby inactivating MAPKs. Many studies have highlighted the role of MKPs in metabolic diseases, including obesity, diabetes, and cardiovascular disorders. These metabolic diseases disrupt key pathways such as insulin signaling, glucose homeostasis, lipid metabolism, and other inflammatory processes. Here, we provide a comprehensive overview of the current understanding of the role played by MKPs in metabolism and highlight their roles in metabolic diseases and potential as therapeutic targets.
Trends Endocrinol Metab
· 2026 Feb · PMID 40514287
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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 a...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 cGAS-STING-NF-κB signaling pathway, activated by the downregulation of mitochondrial proteins CHCHD4 and TRIAP1, as mediating skeletal muscle adaptation to exercise training as well as potentially promoting cellular resilience to environmental stresses. Notably, CHCHD4 haploinsufficiency prevents obesity in aging mice; therefore, this innate immune signaling pathway could be targeted to achieve some of the health benefits of exercise.
The mitochondrial unfolded protein response (UPR) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive...The mitochondrial unfolded protein response (UPR) 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 UPR, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the reproduction-associated suppression of UPR is a representative example of the physiological costs of reproduction. We focus on the germline-to-soma intertissue signaling mechanisms recently identified in C. elegans, which modulate systemic physiological responses during reproduction. These findings not only illuminate the trade-offs between stress resistance and reproductive capacity but also underscore the broader implications of intertissue communication in coordinating resource allocation.
Veiga-Lopez A, Elkin ER, Harris SM
… +4 more, Blake BE, Paquette AG, Aleksunes LM, Stapleton PA
Trends Endocrinol Metab
· 2026 Jan · PMID 40473500
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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 approac...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 placental biology and species differences, we evaluate in vivo and in vitro models, and discuss their strengths and limitations. We examine advances, including placental transfer models, toxicokinetic frameworks, and 3D microphysiological systems, for their potential to address current gaps. Last, we consider molecular epidemiology and high-throughput analyses as complementary strategies. Together, these tools support better experimental design and enhance our understanding of placental vulnerability to chemical exposures.
Trends Endocrinol Metab
· 2025 Dec · PMID 40425398
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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 i...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 highlight the importance of timing and sequence in immediate and long-term adjustments; furthermore, we underscore the evolutionary significance of metabolic resilience and its potential for developing innovative therapeutic interventions, making it a timely contribution to contemporary biological, biomedical, and environmental research fields.
Trends Endocrinol Metab
· 2026 Jan · PMID 40393910
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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 rev...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 diseases such as Alzheimer's disease (AD). This opinion revisits insulin resistance through molecular, cellular, and systemic perspectives, emphasizing the intersection between peripheral and brain insulin resistance (BIR), the role of the blood-brain barrier (BBB), and emerging biomarkers. Furthermore, we integrate insights from multi-omics and neuroimaging studies to refine our understanding, advocating for a broader perspective that informs early detection and intervention in metabolic and neurodegenerative diseases.
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 b...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 adjunctive treatment for depression, and highlight the key metabolic mechanisms involved. We also provide a perspective on the future of this field and advocate for further high-quality clinical trials to assess the benefits of B vitamins in this context and optimize their clinical implementation.
Trends Endocrinol Metab
· 2026 Jan · PMID 40368708
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Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population and spans a spectrum of liver abnormalities, including simple steatosis, inflammation, fibrosis, cirrhosis, and h...Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population and spans a spectrum of liver abnormalities, including simple steatosis, inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent studies have identified triggering receptors expressed on myeloid cells 2 (TREM2)-expressing macrophages as key regulators of MASLD progression. TREM2 plays a pivotal role in regulating macrophage-mediated processes such as efferocytosis, inflammatory control, and fibrosis resolution. Additionally, soluble TREM2 (sTREM2) was proposed as a noninvasive biomarker for diagnosing and monitoring MASLD progression. However, the molecular mechanisms through which TREM2 influences MASLD pathogenesis remain incompletely understood. This review summarizes the current understanding of TREM2-expressing macrophages in MASLD, with the goal of illuminating future research and guiding the development of innovative therapeutic strategies targeting TREM2 signaling pathways.
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, p...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 into correlations between the metabolome and BC risk. Here we review recent results from prospective nested case-control studies, which have led to the identification of significantly different metabolites between women who subsequently developed BC and those who did not. As replication of these findings remains limited, we emphasize the need for robust quantitative validation studies, cancer subtype-specific analyses in diverse populations, and expanded chemical space coverage of analytical assays.
Trends Endocrinol Metab
· 2025 Oct · PMID 40345862
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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 t...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 widely accepted as the main mediator of its observed clinical effects. However, BPA treatment also has ACLY-independent effects on lipid metabolism, as the structural similarity of BPA to endogenous fatty acids allows it to trigger multiple lipid-signaling pathways. Here, we review the molecular targets of BPA and related 'decoy fatty acid' drugs and identify areas where further study is warranted as these molecules are evaluated for clinical indications.
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 behavio...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 inhibitin...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 may further compromise liver function and lead to a lethal outcome. Here, we provide an overview of liver diseases associated with downregulation, altered expression, or dysfunction of HNF4α and suggest the potential underlying mechanisms. We further propose that therapy with Hnf4a mRNA or HNF4α agonists to reactivate HNF4α may be beneficial in pathophysiological contexts characterized by loss of liver function.
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...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 of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), neurodegeneration, and cancer. This review synthesizes human data on the impact of DR and exercise on metabolic and age-related diseases, while emphasizing key biological mechanisms such as nutrient sensing, insulin sensitivity, inflammation, mitochondrial function, and gut microbiota. We also examine the emerging role of pharmacologically induced DR, focusing on glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) that partially mimic DR and present opportunities for chronic disease prevention.
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...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 di...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, proteostasis, and neuroinflammation. Several early clinical trials of NAD augmentation have been completed, and many more are currently underway, reflecting the growing optimism and urgency within the field. We discuss the rationale and evolving therapeutic landscape of NAD augmentation. We argue that, to fully realize its therapeutic potential, it is essential to determine the specific contexts in which NAD supplementation is most effective and to address crucial knowledge gaps.
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 mol...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 between GDM exposure and maternal/offspring metabolic outcomes. In this review we discuss the potential pathophysiological roles of specific genetic variants and commonly reported differentially methylated loci in GDM development, and their link to the progression to T2D in both the mother and the offspring in later life, pointing to the potential for tailored interventional strategies based on these genetic and epigenetic mechanisms.