Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallma...Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.
BACKGROUND: Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with card...BACKGROUND: Higher meat intake has been associated with adverse health outcomes, including cardiovascular disease (CVD). This study investigated plasma metabolites associated with meat intake and their relation with cardiometabolic biomarkers, subclinical CVD markers, and incident CVD. METHODS: Associations between self-reported meat intake and 1272 plasma metabolites were investigated in the SCAPIS cohort (n = 8,819; ages 50-64). Meat-associated metabolites were further examined for relation with subclinical CVD markers in the POEM cohort (n = 502; age 50) and incident CVD in the EpiHealth cohort (n = 2,278; ages 45-75; 107 incident cases over 9.6 years follow-up). Meat intake was categorized into white, unprocessed red, and processed red meat. Linear regression analyzed associations between meat intake, metabolites and cardiometabolic biomarkers, and subclinical CVD markers, while Cox models evaluated association between meat-associated metabolites and incident CVD. RESULTS: After correction for multiple testing, 458, 368, and 403 metabolites were associated with white, unprocessed red, and processed red meat, respectively. Processed red meat-associated metabolites were associated with higher levels of fasting insulin, hemoglobin A1c, and lipoprotein(a), and were inversely associated with maximal oxygen consumption. Two metabolites, 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (hazard ratios (HR: 1.32; 95 % CI: 1.08, 1.62)) and glutamine degradant (HR: 1.35; 95 % CI: 1.07, 1.72), that were inversely associated with intake of all meat types, were also associated with a higher risk of incident CVD. CONCLUSIONS: This study provides comprehensive analysis of self-reported meat intake and plasma metabolites. The findings may enhance our understanding of the relationship between meat intake and CVD, and provide insights into underlying mechanisms.
Hindsø M, Lundsgaard A, Marinkovic B
… +15 more, Jensen MH, Hedbäck N, Svane MS, Dirksen C, Jørgensen NB, London A, Jeppesen PB, Hvistendahl MK, Christoffersen C, Siebner HR, Kiens B, Holst JJ, Madsbad S, van Hall G, Bojsen-Møller KN
BACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12...BACKGROUND: Triacylglycerol (TAG) plasma excursions after a high-fat meal are blunted after Roux-en-Y gastric bypass (RYGB), but underlying mechanisms are poorly understood. We studied TAG absorption and metabolism in 12 RYGB-operated individuals and 12 unoperated controls (CON) matched on sex, age, and BMI. METHODS: Participants followed a 7-day controlled diet and on day 4 underwent H-MR Spectroscopy of liver TAG and a high-fat liquid meal with oral and intravenous labeled stable isotope metabolites, subcutaneous abdominal fat biopsies, and indirect calorimetry. Subsequently, participants collected stool for 96 h. RESULTS: Overall fat absorption from the controlled diet was moderately lower in RYGB than CON (88 % versus 93 %, P < 0.01), without indication of greater specific malabsorption of fat from the high-fat test meal (recovery of TAG and labeled TAG in 96-h stool samples). After an overnight fast, plasma TAG concentrations and incorporation of plasma fatty acids (IV tracer) into TAG did not differ between groups. The postprandial 6-h iAUC of plasma TAG plasma concentrations was markedly lower in RYGB than CON (15 versus 70 mmol/L × min, P = 0.03). The postprandial chylomicron (CM) particle response (plasma ApoB48) was initially higher in RYGB, but with lower CM-TAG plasma concentrations and appearance of labeled palmitate from the oral tripalmitin tracer over the 6 h. CONCLUSION: Fat absorption is only moderately lower after RYGB compared with unoperated matched controls. Nevertheless, postprandial TAG and CM plasma kinetics after a high-fat meal are markedly altered after RYGB with substantially lower TAG and CM-TAG concentrations despite a faster CM particle release.
Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypoth...Female reproduction is highly sensitive to body energy stores; persistent energy deficit, as seen in anorexia or strenuous exercise, is known to suppress ovulation via ill-defined mechanisms. We report herein that hypothalamic SIRT1, a key component of the epigenetic machinery that links nutritional status and puberty onset via modulation of Kiss1, plays a critical role in the control of the preovulatory surge of gonadotropins, i.e., the hormonal trigger of ovulation, and its repression by conditions of energy deficit. Kiss1 neurons in the preoptic area, with proven roles in the control of ovulation, express Sirt1 mRNA. Reciprocal changes in hypothalamic SIRT1 content and Kiss1 expression were observed during the pre-ovulatory phase in adult female rats. Central activation of SIRT1 reduced Kiss1 expression in the rostral hypothalamus, and attenuated the preovulatory surge, while blockade of central SIRT1 augmented it. Conditions of energy deficit enhanced hypothalamic SIRT1 activity and caused suppression of the pre-ovulatory surge and ovulation, which could be rescued by central SIRT1 inhibition. In turn, virogenetic induction of SIRT1 in rostral hypothalamic Kiss1 neurons in adult female mice disrupted ovarian cyclicity and suppressed reproductive indices, despite preserved body weight. Our data document the prominent function of hypothalamic SIRT1 as a key modulator of Kiss1 neurons and the hormonal surge driving ovulation in adulthood, with a major role in its inhibition during conditions of energy insufficiency.
The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress ene...The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHA neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHA neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHA neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHA neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHA neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHA neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHA neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHA neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHA neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state. SIGNIFICANCE STATEMENT: Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHA neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/DHA Lepr neurons as a distinct subgroup of glutamatergic and GABAergic neurons that are under indirect and direct influence of the interoceptive hormone leptin and if stimulated are uniquely capable to mediate beneficial metabolic effects. Our work significantly expands our knowledge of thermoregulatory circuits and puts a spotlight onto DMH-Lepr neurons for the integration into whole body energy and body weight homeostasis.
Conde KM, Wong H, Fang S
… +23 more, Li Y, Yu M, Deng Y, Liu Q, Fang X, Wang M, Shi Y, Ginnard OZ, Yang Y, Tu L, Liu H, Liu H, Yin N, Bean JC, Han J, Burt ME, Jossy SV, Yang Y, Tong Q, Arenkiel BR, Wang C, He Y, Xu Y
Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in un...Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HT➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HT neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HT neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.
BACKGROUND: The association between Life's Essential 8 (LE8) score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. METHODS: This population-based...BACKGROUND: The association between Life's Essential 8 (LE8) score and all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unknown. METHODS: This population-based prospective cohort study analyzed data of participants aged 20-79 years in the National Health and Nutrition Examination Survey from 2005 to 2018, with linked mortality information until 2019. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between different cardiovascular health (CVH) scores and all-cause mortality in participants with MASLD. RESULTS: Among 11,988 participants, 4109 (34.3 %) were diagnosed with MASLD. During the median 7.8 years of follow-up, 912 deaths were recorded. Unexpectedly, the total LE8 CVH score was not associated with all-cause mortality in patients with MASLD (all P > .05). However, individuals with MASLD with moderate and poor LE8 health behaviors scores exhibited an increased risk of all-cause mortality (moderate: HR, 1.51; 95 % CI, 1.05-2.17; poor: HR, 2.32; 95 % CI, 1.64-3.30), particularly among patients with advanced fibrosis (moderate: HR, 1.77; 95 % CI, 1.07-2.92; poor: HR, 2.43; 95 % CI, 1.23-4.78). Population-attributable fraction estimates suggest that 35.0 % of all-cause mortality attributed to poor or moderate health behaviors scores could be avoided if ideal CVH metrics were achieved in all patients with MASLD. CONCLUSION: These findings demonstrate a significant association between the LE8 health behaviors score and all-cause mortality in patients with MASLD, highlighting the usefulness of this score in optimizing risk management strategies for MASLD in future clinical practice.
The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction...The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.
Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrup...Endoplasmic reticulum (ER) is an essential organelle involved in vesicular transport, calcium handling, protein synthesis and folding, and lipid biosynthesis and metabolism. ER stress occurs when ER homeostasis is disrupted by the accumulation of unfolded and/or misfolded proteins in the ER lumen. Adaptive pathways of the unfolded protein response (UPR) are activated to maintain ER homeostasis. In obesity and type 2 diabetes mellitus (T2DM), accumulating data indicate that persistent ER stress due to maladaptive UPR interacts with insulin/leptin signaling, which may be the potential and central mechanistic link between obesity-/T2DM-induced metabolic dysregulation (chronic hyperglycemia, dyslipidemia and lipotoxicity in cardiomyocytes), insulin/leptin resistance and the development of diabetic cardiomyopathy (DiabCM). Meanwhile, these pathological conditions further exacerbate ER stress. However, their interrelationships and the underlying molecular mechanisms are not fully understood. A deeper understanding of ER stress-mediated pathways in DiabCM is needed to develop novel therapeutic strategies. The aim of this review is to discuss the crosstalk between ER stress and leptin/insulin signaling and their involvement in the development of DiabCM focusing on mitochondria-associated ER membranes and chronic inflammation. We also present the current direction of drug development and important considerations for translational research into targeting ER stress for the treatment of DiabCM.
There is general consensus that an improper diet negatively impacts health and that nutrition is a primary tool for the prevention of non-communicable diseases. Unfortunately, the importance of studying body composition,...There is general consensus that an improper diet negatively impacts health and that nutrition is a primary tool for the prevention of non-communicable diseases. Unfortunately, the importance of studying body composition, which can reveal early predictors of gender-related diseases, is still not well understood in this context. Currently, individuals are still classified as obese based solely on their body mass index, without considering the amount of fat, its distribution, and the quantity of muscle and bone mass. In this regard, the body composition phenotype defined as "osteosarcopenic obesity" affects approximately 6-41 % of postmenopausal women, with prevalence increasing with age due to the hormonal and metabolic changes that occur during this period. This particular phenotype arises from the strong relationship between visceral fat, muscle, bone, and gut microbiota and predispose postmenopausal women to frailty. Frailty is a complex clinical phenomenon with significant care and economic implications for our society. Recent studies suggest that women have a higher prevalence of frailty syndrome and its individual components, such as osteoporosis, fractures and sarcopenia, compared to men. Here, we provide a comprehensive overview of recent advances regarding the impact of gender on body composition and frailty. Furthermore, we reflect on the crucial importance of personalized nutritional interventions, with a focus on reducing visceral fat, increasing protein intake and optimizing vitamin D levels. A review of the scientific literature on this topic highlights the importance of studying body composition for a personalized and gender-specific approach to nutrition and dietetics, in order to identify frailty syndrome early and establish personalized treatments. This new method of researching disease predictors could likely help clarify the controversial results of studies on vitamin D, calcium and proteins, translate into practical wellness promotion across diverse elderly populations.
BACKGROUND AND AIMS: The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relati...BACKGROUND AND AIMS: The disrupted homeostasis of branched-chain amino acids (BCAAs, including leucine, isoleucine, and valine) has been strongly correlated with diabetes with a potential causal role. However, the relationship between BCAAs and diabetic kidney disease (DKD) remains to be established. Here, we show that the elevated BCAAs from BCAAs homeostatic disruption promote DKD progression unexpectedly as an independent risk factor. METHODS AND RESULTS: Similar to other tissues, the suppressed BCAAs catabolic gene expression and elevated BCAAs abundance were detected in the kidneys of type 2 diabetic mice and individuals with DKD. Genetic and nutritional studies demonstrated that the elevated BCAAs from systemic disruption of BCAAs homeostasis promoted the progression of DKD. Of note, the elevated BCAAs promoted DKD progression without exacerbating diabetes in the animal models of type 2 DKD. Mechanistic studies demonstrated that the elevated BCAAs promoted fibrosis-associated epithelial-mesenchymal transition (EMT) by enhancing the activation of proinflammatory macrophages through mTOR signaling. Furthermore, pharmacological enhancement of systemic BCAAs catabolism using small molecule inhibitor attenuated type 2 DKD. Finally, the elevated BCAAs also promoted DKD progression in type 1 diabetic mice without exacerbating diabetes. CONCLUSION: BCAA homeostatic disruption serves as an independent risk factor for DKD and restoring BCAA homeostasis pharmacologically or dietarily represents a promising therapeutic strategy to ameliorate the progression of DKD.
Sun N, Krauss T, Seeliger C
… +12 more, Kunzke T, Stöckl B, Feuchtinger A, Zhang C, Voss A, Heisz S, Prokopchuk O, Martignoni ME, Janssen KP, Claussnitzer M, Hauner H, Walch A
BACKGROUND: Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on...BACKGROUND: Cancer cachexia (CCx) presents a multifaceted challenge characterized by negative protein and energy balance and systemic inflammatory response activation. While previous CCx studies predominantly focused on mouse models or human body fluids, there's an unmet need to elucidate the molecular inter-organ cross-talk underlying the pathophysiology of human CCx. METHODS: Spatial metabolomics were conducted on liver, skeletal muscle, subcutaneous and visceral adipose tissue, and serum from cachectic and control cancer patients. Organ-wise comparisons were performed using component, pathway enrichment and correlation network analyses. Inter-organ correlations in CCx altered pathways were assessed using Circos. Machine learning on tissues and serum established classifiers as potential diagnostic biomarkers for CCx. RESULTS: Distinct metabolic pathway alteration was detected in CCx, with adipose tissues and liver displaying the most significant (P ≤ 0.05) metabolic disturbances. CCx patients exhibited increased metabolic activity in visceral and subcutaneous adipose tissues and liver, contrasting with decreased activity in muscle and serum compared to control patients. Carbohydrate, lipid, amino acid, and vitamin metabolism emerged as highly interacting pathways across different organ systems in CCx. Muscle tissue showed decreased (P ≤ 0.001) energy charge in CCx patients, while liver and adipose tissues displayed increased energy charge (P ≤ 0.001). We stratified CCx patients by severity and metabolic changes, finding that visceral adipose tissue is most affected, especially in cases of severe cachexia. Morphometric analysis showed smaller (P ≤ 0.05) adipocyte size in visceral adipose tissue, indicating catabolic processes. We developed tissue-based classifiers for cancer cachexia specific to individual organs, facilitating the transfer of patient serum as minimally invasive diagnostic markers of CCx in the constitution of the organs. CONCLUSIONS: These findings support the concept of CCx as a multi-organ syndrome with diverse metabolic alterations, providing insights into the pathophysiology and organ cross-talk of human CCx. This study pioneers spatial metabolomics for CCx, demonstrating the feasibility of distinguishing cachexia status at the organ level using serum.
Sachan V, LeDévéhat M, Roubtsova A
… +22 more, Essalmani R, Laurendeau JF, Garçon D, Susan-Sesiga D, Duval S, Mikaeeli S, Hamelin J, Evagelidis A, Chong M, Paré G, Chernetsova E, Gao ZH, Robillard I, Ruiz M, Trinh VQ, Estall JL, Faraj M, Austin RC, Sauvageau M, Prat A, Kiss RS, Seidah NG
Zeng XF, Varady KA, Wang XD
… +52 more, Targher G, Byrne CD, Tayyem R, Latella G, Bergheim I, Valenzuela R, George J, Newberry C, Zheng JS, George ES, Spearman CW, Kontogianni MD, Ristic-Medic D, Peres WAF, Depboylu GY, Yang W, Chen X, Rosqvist F, Mantzoros CS, Valenti L, Yki-Järvinen H, Mosca A, Sookoian S, Misra A, Yilmaz Y, Kim W, Fouad Y, Sebastiani G, Wong VW, Åberg F, Wong YJ, Zhang P, Bermúdez-Silva FJ, Ni Y, Lupsor-Platon M, Chan WK, Méndez-Sánchez N, de Knegt RJ, Alam S, Treeprasertsuk S, Wang L, Du M, Zhang T, Yu ML, Zhang H, Qi X, Liu X, Pinyopornpanish K, Fan YC, Niu K, Jimenez-Chillaron JC, Zheng MH
Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervent...Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD.
BACKGROUND: Recently, the American Heart Association introduced Life's Essential 8 (LE8) as a new cardiovascular health (CVH) metric, and studies have reported associations between LE8 and CVH outcomes. However, there is...BACKGROUND: Recently, the American Heart Association introduced Life's Essential 8 (LE8) as a new cardiovascular health (CVH) metric, and studies have reported associations between LE8 and CVH outcomes. However, there is limited understanding of LE8's impact on the risk of transitions between different stages of CVH. The current study investigated whether adhering to LE8 during a healthy stage could mitigate the progression from hypertension (HT) to cardiovascular diseases (CVDs), and consequent death. METHODS: The study included 107,682 participants in the UK Biobank who were initially free of HT and CVDs. CVH were evaluated using LE8 metrics (diet, physical activity, nicotine exposure, sleep duration, body mass index, non-high-density lipoprotein cholesterol, blood glucose, and blood pressure). Multistate models were used to analyse the impacts of LE8 on the progression of CVDs. RESULTS: During a median follow-up of 12.2 years, 5727 participants developed HT, 7243 developed CVDs, and 1183 died afterwards. LE8 was negatively associated with the dynamic disease progression. A per-10 points increase of CVH scores was significantly associated with the reduced risk [Hazard ratios (95 % confidence intervals)] at 0.71 (0.69, 0.72), 0.83 (0.81, 0.85), 0.79 (0.77, 0.82), and 0.91 (0.86, 0.96) in the transition from healthy to HT, CVDs, death, and from CVDs to death, respectively. Mediation analyses indicated that HT significantly mediated LE8-reduced risks of CVDs and mortality. CONCLUSIONS: This study offered evidence that LE8 may influence the stages of CVD progression. The findings underscore the significance of adhering to LE8 in health management and CVDs management.
BACKGROUND: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global heal...BACKGROUND: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex. METHODS: Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI). RESULTS: In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17]). CONCLUSION: In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), encompasses a progressive spectrum of liver conditions, ranging from steatosis to metabolic d...Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), encompasses a progressive spectrum of liver conditions, ranging from steatosis to metabolic dysfunction-associated steatohepatitis, characterised by hepatocellular death and inflammation, potentially progressing to cirrhosis and/or liver cancer. In both experimental and human MASLD, necroptosis-a regulated immunogenic necrotic cell death pathway-is triggered, yet its exact role in disease pathogenesis remains unclear. Noteworthy, necroptosis-related signalling pathways are emerging as key players in metabolic reprogramming, including lipid and mitochondrial metabolism. Additionally, metabolic dysregulation is a well-established contributor to MASLD development and progression. This review explores the intricate interplay between cell metabolism and necroptosis regulation and its impact on MASLD pathogenesis. Understanding these cellular events may offer new insights into the complexity of MASLD pathophysiology, potentially uncovering therapeutic opportunities and unforeseen metabolic consequences of targeting necroptosis.