BACKGROUND: Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection. METHODS: Male mice were subjected to glucoprivation thro...BACKGROUND: Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection. METHODS: Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH. RESULTS: Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK-regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection. CONCLUSION: Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.
4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a...4'-Phosphopantetheinyl (4'PP) groups are essential co-factors added to target proteins by phosphopantetheinyl transferase (PPTase) enzymes. Although mitochondrial 4'PP-modified proteins have been described for decades, a mitochondrially-localized PPTase has never been found in mammals. We discovered that the cytoplasmic PPTase aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT) is required for mitochondrial respiration and oxidative metabolism. Loss of AASDHPPT results in failed 4'PP modification of the mitochondrial acyl carrier protein and blunted activity of the mitochondrial fatty acid synthesis (mtFAS) pathway. We found that in addition to its cytoplasmic localization, AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 20 amino acids of the protein. Our data show that this novel mitochondrial localization of AASDHPPT is required to support mtFAS activity and oxidative metabolism. We further identify five variants of uncertain significance in AASDHPPT that are likely pathogenic in humans due to loss of mtFAS activity.
OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poo...OBJECTIVE: Coffee is one of the most widely consumed beverages globally and has been linked to favorable health outcomes. However, its system-wide relationships with human biology and the underlying mechanisms remain poorly characterized. This study aimed to investigate the relationship between coffee consumption and continuous glucose monitoring (CGM) metrics and other biological systems in healthy adults. RESEARCH DESIGN AND METHODS: In the Human Phenotype Project, 8666 generally healthy Israeli adults provided two weeks of real-time dietary logs, from which coffee intake was estimated. Participants wore CGM devices throughout this period, and multimodal data spanning 11 additional systems (e.g., gut microbiome, serum lipidomics, and body composition) were collected. We employed machine learning approaches to quantify the extent to which each system reflected coffee intake. We performed linear regression to identify individual traits associated with coffee intake, with false discovery rates < 0.05 considered significant. RESULTS: This cross-sectional study identified continuously-monitored glucose regulation and gut microbial composition as the most reflective systems of coffee intake, with further analyses revealing favorable glycemic profiles spanning diverse aspects of glucose regulation with increasing coffee intake, and Clostridium phoceensis (i.e., Lawsonibacter asaccharolyticus) as the most significant species positively associated with coffee intake. Additionally, coffee intake was favorably associated with traits across body composition, serum lipidomics, and hepatic, hematopoietic, and renal systems. CONCLUSIONS: This study found that habitual coffee intake was linked to multifaceted favorable glucose control captured by CGM and favorable profiles across multiple biological systems, providing mechanistic insights that may guide precision nutrition strategies for diabetes prevention.
Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dy...Contemporary lifestyle modifications such as changes in nutritional and sleep/wake rhythms increase the risk of metabolic and inflammatory complications linked to obesity, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). BMAL2 (Brain and Muscle ARNT Like Protein 2) is a transcription factor belonging to the circadian clock transcriptional feedback loop which synchronizes internal biological rhythms to environment. In humans, reduced expression in white adipose tissue (WAT) and specific polymorphisms of BMAL2 are associated with obesity and T2D. In this study we report that Bmal2 deletion in mice leads to increased body weight gain during diet-induced obesity. Loss of BMAL2 triggers the inflammatory response by increasing Tnfα expression and modifying adipocyte progenitor fate. This results in reduced lipid storage capacity within the WAT and increased ectopic storage in the liver. These functional and structural alterations culminate in the onset of hepatic steatosis and insulin resistance in liver and WAT. Overall, our investigations underscore the role of BMAL2 in the development and function of adipocytes, as well as in their inflammatory potential within the WAT. Our findings contribute to the understanding of the role of circadian clock genes in obesity and interconnected metabolic complications.
AIMS/HYPOTHESIS: Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. Thi...AIMS/HYPOTHESIS: Nutritional disorders directly affect the endocrine pancreas, increasing the susceptibility to type 2 diabetes mellitus. However, the molecular mechanisms underlying these alterations remain unknown. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contact sites, known as mitochondrial-associated membranes (MAMs), in insulin secretion dysfunctions associated with undernutrition, obesity, and the double burden of malnutrition (DBM). METHODS: Rat pancreatic INS-1E β-cells were cultured in a medium without amino acids supplemented with 1 × (control) or 0.25 × (amino acid restriction) of an amino acid solution for 48 h, and then cells were exposed to a fatty acid mix for 48 h. Male C57BL/6 mice were fed a normoprotein diet (14 % protein) or protein-restricted diet (6 % protein) for 6 weeks and subsequently a high-fat diet (35 % kcal) for 12 weeks. ER-mitochondria interactions were evaluated by in situ proximity ligation assay and transmission electronic microscopy. RESULTS: Our findings indicate that protein restriction reduces ER-mitochondria contacts in pancreatic beta-cells, leading to decreased mitochondrial metabolism and glucose-stimulated insulin secretion (GSIS). In contrast, obesity increases ER-mitochondria contact points, mitochondrial metabolism, and GSIS in pancreatic beta-cells, without alterations in viability. DBM results in a significant increase in ER-mitochondria contacts, elevated mitochondrial calcium levels, increased production of reactive oxygen species, and cell death, collectively contributing to impaired GSIS response in the context of obesity. CONCLUSIONS/INTERPRETATION: These data indicates that MAMs play a crucial role in GSIS during nutritional disorders such as undernutrition, obesity, and DBM. Importantly, changes in MAMs precede GSIS impairment, therefore targeting these interactions might prevent further disruption in beta-cell function.
Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a...Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.
Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals...Sarcopenia is a progressive musculoskeletal condition associated with aging, marked by a decline in muscle mass, strength, and performance. This condition not only compromises functional independence in older individuals but also contributes to escalating healthcare and economic burdens. Although the underlying mechanisms are complex and multifaceted, recent discoveries have emphasized the regulatory influence of multiple forms of programmed cell death-including apoptosis, ferroptosis, necroptosis, and pyroptosis-on skeletal muscle degeneration. These cell death pathways contribute to key pathological features such as muscle fiber loss, proteostasis imbalance, neuromuscular dysfunction, mitochondrial deficits, and persistent inflammation. This review synthesizes current understanding of the molecular underpinnings of regulated cell death (RCD) in sarcopenia and discusses emerging therapeutic interventions aimed at modulating these pathways. These include pharmacological agents (e.g., ferroptosis inhibitors, polyphenols), structured exercise programs (notably resistance), targeted nutritional support (e.g., amino acids, vitamin D), cell-based therapies, and gene-targeted strategies. Despite growing evidence supporting RCD as a viable therapeutic target, the interplay among different cell death modalities and the translation of mechanistic insights into clinical practice remain insufficiently understood. Advancing sarcopenia treatment will require integrated multi-omics analyses, identification of predictive biomarkers, and rigorously designed clinical studies to support personalized and effective therapeutic approaches.
Exercise protects against several diseases including cardiometabolic disorders. However, the molecular mechanisms driving these adaptations remain incompletely defined. Endothelial nitric oxide synthase (eNOS), a key sou...Exercise protects against several diseases including cardiometabolic disorders. However, the molecular mechanisms driving these adaptations remain incompletely defined. Endothelial nitric oxide synthase (eNOS), a key source of nitric oxide (NO), is implicated in regulating glucose uptake, fatty acid metabolism, and mitochondrial remodeling in response to exercise. eNOS is expressed in both endothelial and non-endothelial cells and its effects on metabolism are multifaceted. Notably, eNOS is highly expressed in endothelial cells which are ubiquitous throughout all organ systems allowing them to closely integrate with surrounding cell types. This unique feature of the endothelium enables eNOS to influence both local microenvironments and signaling across organ systems. This review summarizes current findings on the role of eNOS-derived NO in exercise metabolism. Evidence suggests eNOS contributes to improved metabolic flexibility, enhanced mitochondrial function, and tissue crosstalk. However, data across experimental models remain mixed, with both supportive and conflicting results. Collectively, the literature indicates that eNOS plays a central, though context-dependent, role in facilitating exercise-induced metabolic benefits. Identifying the specific mechanisms and tissue contributions of eNOS activity remains an important area for future investigation, with potential relevance to metabolic disease prevention and treatment.
BACKGROUND: Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood....BACKGROUND: Gut microbiota and their metabolites play an essential role in type 2 diabetes (T2D). However, contributions of individual bacterial strains and their metabolites to T2D pathogenesis remain poorly understood. We investigated T2D regulation by Lactobacillus in various animal models to understand its therapeutic effects. METHODS AND RESULTS: We performed a case-control study of Chinese adults using metabolome profiling and identified an inverse correlation between l-glutamine and T2D serum concentrations. The glnA and GLUL genes encoding glutamine synthetase (GS) in L. plantarum 84-3 were also identified. L. plantarum 84-3 treatment significantly decreased serum inflammation and improved metabolic phenotypes in streptozotocin- or tetraoxypyrimidine-induced T2D rats, including blood glucose, glucose tolerance, insulin resistance, and lipids. We confirmed elevated serum l-glutamine levels in the L. plantarum 84-3 group. RNA sequencing analysis demonstrated that L. plantarum 84-3-derived l-glutamine is a vital bioactive molecule, improving glucose homeostasis by activating the liver AMPK/PPAR signaling pathway and ameliorating T2D. We conducted co-culture fermentation experiments in vitro and in vivo, and metagenomic and metabolomic analyses revealed that resistance starch combined with L. plantarum 84-3 significantly enriched of Lactobacillus abundance and increased the l-glutamine level, affecting of alanine, aspartate, and glutamate metabolism pathways, which was confirmed in vivo in rats. The reduced L. plantarum and l-glutamine levels were validated in a human T2D cohort. CONCLUSIONS: These findings revealed a novel therapeutic effect of L. plantarum in alleviating T2D-related glucose homeostasis by increasing circulating l-glutamine, which suggests viable preventive and therapeutic strategies for metabolic disorders.
BACKGROUND: The "thrifty genotype hypothesis" states that gene variants promoting efficient fat deposition may have been advantaged by natural selection to allow human survival during famine. Nowadays, such genes are ren...BACKGROUND: The "thrifty genotype hypothesis" states that gene variants promoting efficient fat deposition may have been advantaged by natural selection to allow human survival during famine. Nowadays, such genes are rendered detrimental by progress as they promote fat deposition in preparation for a famine that never comes, resulting in widespread obesity. Obesity is genetically heterogeneous, with a continuum between very rare syndromic, rare monogenic, and common polygenic forms of obesity. The identification of natural selection signatures has been largely restricted to polygenic obesity-susceptibility variants, and this approach has failed to validate the thrifty genotype hypothesis. However, polygenic variants may not be as relevant as monogenic mutations, characterized by strong phenotypic effects on body mass index variation and obesity risk, in detecting significant signatures of natural selection. METHODS: We investigated the patterns of natural selection of 65 syndromic and 8 monogenic obesity genes in the gnomAD multiethnic population (N = 807,162). RESULTS: Our data suggest that most dominant syndromic obesity genes display negative signatures of natural selection (i.e., deleterious alleles are selectively purged from the population). In contrast, monogenic obesity genes exhibit neither negative nor positive patterns of natural selection. Our findings do not support the thrifty genotype hypothesis for syndromic and monogenic hyperphagic obesity in 7 ethnic groups. CONCLUSION: Our work highlights the evolutionary mechanisms that have shaped the modern ethnic distribution of monogenic and syndromic obesity mutations, why some individuals are susceptible to obesity and have a profound impact on therapeutic strategies for managing chronic diseases.
BACKGROUND: Hypoparathyroidism (HypoPT) is characterized by low serum calcium due to insufficient parathyroid hormone (PTH). This manuscript builds upon the 2022 international HypoPT guidelines and three systematic revie...BACKGROUND: Hypoparathyroidism (HypoPT) is characterized by low serum calcium due to insufficient parathyroid hormone (PTH). This manuscript builds upon the 2022 international HypoPT guidelines and three systematic reviews, which have been further informed by updated narrative reviews and expert consensus. This paper presents current best practice consensus recommendations for the diagnosis and management of HypoPT. METHODS: An International Panel of Experts updated the previous systematic reviews (SR's), conducted narrative reviews, developed, and subsequently approved these best practice recommendations at the Parathyroid Summit, held as a pre-Endocrine Society meeting in May 2024 (Boston, USA). RESULTS: Diagnostic criteria for chronic HypoPT require hypocalcemia with inappropriately normal or low PTH levels. Conventional therapy is recommended as first line therapy and includes calcium supplementation, active vitamin D, correction of vitamin D inadequacy and correction of abnormalities in serum magnesium. Monitoring is required to achieve optimal serum calcium while avoiding hyperphosphatemia, hypercalciuria and declines in renal function. Assessment of HypoPT complications is required including skeletal health assessment in postmenopausal women and men over the age of 50 years. Specific strategies are provided for managing HypoPT during pregnancy and lactation as well as in children. PTH replacement with palopegteriparatide has been approved and is an important therapeutic option, especially when conventional therapy is inadequate or not tolerated. CONCLUSION: These best practice recommendations provide a framework for HypoPT diagnosis and management, emphasizing individualized care, role of DNA analysis in the diagnosis of nonsurgical HypoPT, and role of PTH or PTH analogue therapy as appropriate. They complement the 2022 international guidelines and incorporate updated therapeutic recommendations from the past 3 years including the positioning of the newly approved molecule palopegteriparatide based on recent clinical trial data and expert consensus.
During the last decades, sedentary behaviour has been recognised as an interdependent risk factor for cardiometabolic health and premature mortality. Prolonged sedentary behaviour is associated with increased risks for c...During the last decades, sedentary behaviour has been recognised as an interdependent risk factor for cardiometabolic health and premature mortality. Prolonged sedentary behaviour is associated with increased risks for chronic non-communicable diseases (NCDs) such as obesity, chronic respiratory diseases, type 2 diabetes mellitus, cardiovascular diseases and cancer due to disturbances in cardiometabolic health. However, despite the increased evidence supporting these associations, the underlying molecular mechanisms to the development of these NCDs remain largely unknown. In this review, we therefore discuss the existing evidence with regard to the potential underlying molecular mechanisms of sedentary behaviour-induced perturbations in cardiometabolic health. Here, various potential mechanisms related to carbohydrate metabolism, lipid metabolism, oxidative stress, inflammation and micro- and macro vascular function will be outlined. In addition, we summarise the current evidence on various strategies to interrupt sedentary behaviour and their effects on cardiometabolic health outcomes, including insulin sensitivity, blood lipid profiles, and cardiovascular health. Finally, we highlight key research gaps in the field of sedentary behaviour in relation to the underlying molecular mechanisms.
BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood...BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood. In this study, we aimed to investigate the role of CCL20 in MASH progression. METHODS: Using RNA sequencing data and murine models of MASH, we analyzed the expression levels of CCL20 in liver tissues, as well as the correlation of CCL20 levels with liver function parameters. Hepatic CCL20-knockdown and hepatic progenitor cell (HPC)/cholangiocyte-specific CCL20-knockout mice were used to assess the role of CCL20 in hepatic steatosis and inflammation. The mechanisms by which CCL20 influences MASH were explored via in vitro and in vivo gain- and loss-of-function approaches. RESULTS: We observed that CCL20 is significantly upregulated in MASH livers from mice and humans and that hepatic CCL20 expression is positively correlated with MASH severity. CCL20, which is mainly produced by HPCs/cholangiocytes, is transcriptionally activated by RELB and SOX9. In mice, CCL20 knockout in HPCs/cholangiocytes attenuated pathological changes in the liver. Mechanistically, by binding to CCR6, CCL20 activates the JNK signaling pathway, which increases OLR1 expression, thereby promoting oxLDL uptake and cholesterol deposition in hepatocytes. CONCLUSION: These findings implicate the CCL20-CCR6-JNK-OLR1 axis as a crucial determinant of MASH progression and highlight CCL20 inhibition as an attractive therapeutic strategy for MASH.
BACKGROUND: In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse li...BACKGROUND: In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM). METHODS: SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (>36 vs.<30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD plus 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates versus reference (no SLD/MetS traits). RESULTS: Median follow-up was 148 to 149 months. Comparing MASLD with one versus five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03-5.00) and 9.19 (4.98-16.95); for MetALD, aHRs were 1.65 (0.53-5.11) and 8.54 (3.65-19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19-1.92) and 4.81 (4.06-5.69) respectively; with MetALD, aHRs were 1.46 (1.00-2.13) and 4.64 (3.51-6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87-1.23) and 1.46 (1.29-1.66) respectively; with MetALD, aHRs were 1.01 (0.79-1.29) and 1.51 (1.24-1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72-42.61); 43.36, 20.53-91.58 respectively). CONCLUSION: In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.
BACKGROUND: It has been suggested that dietary factors correlated with red meat may contribute to its adverse health effects, while consuming red meat within a healthy diet may not necessarily increase disease risk. METH...BACKGROUND: It has been suggested that dietary factors correlated with red meat may contribute to its adverse health effects, while consuming red meat within a healthy diet may not necessarily increase disease risk. METHODS: Among 204,740 participants from three prospective cohorts, we examined the association between red meat consumption and risk of type 2 diabetes (T2D) across different levels of diet quality, measured by Alternative Healthy Eating Index (AHEI)-2010 (excluding red and processed meat component), using multivariable-adjusted Cox proportional hazards models. Dietary intake was assessed using repeated food frequency questionnaires. RESULTS: During a median follow-up of 28 years, 18,868 cases were documented. Mean values were 47.3 (SD 8.5) for AHEI-2010 and 6.5 (SD 3.5), 1.8 (SD 1.5), and 4.8 (SD 2.5) servings/week for total, processed, and unprocessed red meat, respectively. Greater red meat consumption was consistently associated with a higher T2D risk across AHEI-2010 strata. Comparing the highest with the lowest quintile of red meat consumption in the highest diet quality quintile, the multivariable-adjusted HRs were 1.95 (1.72, 2.21) for total, 1.88 (1.67, 2.13) for processed, and 1.67 (1.47, 1.90) for unprocessed red meat. Substituting red meat with major food groups was associated with a lower T2D risk, particularly among those with high diet quality. The benefit of lowering red meat consumption was greater in participants with higher diet quality. CONCLUSIONS: The risk associated with high red meat consumption persisted even among participants with a relatively high diet quality, underscoring the importance of limiting red meat consumption to prevent T2D.
Fatty acids (FAs) have various functions on cell regulation considering their abundant types and metabolic pathways. In addition, the relation between FA and other nutritional metabolism makes their functions more comple...Fatty acids (FAs) have various functions on cell regulation considering their abundant types and metabolic pathways. In addition, the relation between FA and other nutritional metabolism makes their functions more complex. As the first place for diet-derived FA metabolism, intestine is significantly influenced despite lack of clear conclusions due to the inconsistent findings. In this review, we discuss the regulation of fatty acid metabolism on the fate of intestinal stem cells in homeostasis and disorders, and also focus on the intestinal tumor development and treatment from the aspect of gut microbiota-epithelium-immune interaction. We summarize that the balances between FA oxidation and glycolysis, between oxidative phosphorylation and ketogenesis, between catabolism and anabolism, and the specific roles of individual FA types determine the diverse effects of intestinal FA metabolism in different cases. We hope this will inspire further dissection and suggest precise dietary/metabolic intervention for different demands related to intestinal health.
BACKGROUND & PURPOSE: Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype...BACKGROUND & PURPOSE: Cellular senescence spreads systemically through blood circulation, but its mechanisms remain unclear. High mobility group box 1 (HMGB1), a multifunctional senescence-associated secretory phenotype (SASP) factor, exists in various redox states. Here, we investigate the role of redox-sensitive HMGB1 (ReHMGB1) in driving paracrine and systemic senescence. METHODS: We applied the paracrine senescence cultured model to evaluate the effect of ReHMGB1 on cellular senescence. Each redox state of HMGB1 was treated extracellularly to assess systemic senescence both in vitro and in vivo. Senescence was determined by SA-β-gal & EdU staining, p16 and p21 expression, RT-qPCR, and Western blot methods. Bulk RNA sequencing was performed to investigate ReHMGB1-driven transcriptional changes and underlying pathways. Cytokine arrays characterized SASP profiles from ReHMGB1-treated cells. In vivo, young mice were administered ReHMGB1 systemically to induce senescence across multiple tissues. A muscle injury model in middle-aged mice was used to assess the therapeutic efficacy of HMGB1 blockade. RESULTS: Extracellular ReHMGB1, but not its oxidized form, robustly induced senescence-like phenotypes across multiple cell types and tissues. Transcriptomic analysis revealed activation of RAGE-mediated JAK/STAT and NF-κB pathways, driving SASP expression and cell cycle arrest. Cytokine profiling confirmed paracrine senescence features induced by ReHMGB1. ReHMGB1 administration elevated senescence markers in vivo, while HMGB1 inhibition reduced senescence, attenuated systemic inflammation, and enhanced muscle regeneration. CONCLUSION: ReHMGB1 is a redox-dependent pro-geronic factor driving systemic senescence. Targeting extracellular HMGB1 may offer therapeutic potential for preventing aging-related pathologies.
Ribas-Latre A, Hoffmann A, Gebhardt C
… +18 more, Weiner J, Arndt L, Raulien N, Gericke M, Ghosh A, Krause K, Klöting N, Pfluger PT, Sheikh BN, Ebert T, Tönjes A, Stumvoll M, Wolfrum C, Blüher M, Wagner U, Vendrell J, Fernández-Veledo S, Heiker JT
Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue t...Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.
Fernández-Duval G, Razquin C, Wang F
… +25 more, Yun H, Hu J, Guasch-Ferré M, Rexrode K, Balasubramanian R, García-Gavilán J, Ruiz-Canela M, Clish CB, Corella D, Gómez-Gracia E, Fiol M, Estruch R, Lapetra J, Fitó M, Serra-Majem L, Ros E, Liang L, Dennis C, Asensio EM, Castañer O, Planes FJ, Salas-Salvadó J, Hu FB, Toledo E, Martínez-González MA
Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseli...Metabolome-based biomarkers contribute to identify mechanisms of disease and to a better understanding of overall mortality. In a long-term follow-up subsample (n = 1878) of the PREDIMED trial, among 337 candidate baseline plasma metabolites repeatedly assessed at baseline and after 1 year, 38 plasma metabolites were identified as predictors of all-cause mortality. Gamma-amino-butyric acid (GABA), homoarginine, serine, creatine, 1-methylnicotinamide and a set of sphingomyelins, plasmalogens, phosphatidylethanolamines and cholesterol esters were inversely associated with all-cause mortality, whereas plasma dimethylguanidino valeric acid (DMGV), choline, short and long-chain acylcarnitines, 4-acetamidobutanoate, pseudouridine, 7-methylguanine, N6-acetyllysine, phenylacetylglutamine and creatinine were associated with higher mortality. The multi-metabolite signature created as a linear combination of these selected metabolites, also showed a strong association with all-cause mortality using plasma samples collected at 1-year follow-up in PREDIMED. This association was subsequently confirmed in 4 independent American cohorts, validating the signature as a consistent predictor of all-cause mortality across diverse populations.