Metabolic Disorders Research Articles

Metabolic dysfunction-associated steatotic liver disease: The question of long-term high-normal alanine aminotransferase as a screening test

The growing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is being driven by the obesity epidemic. The quest for solutions continues particularly with regard to early detection. This editorial comments on the utility of long-term high-normal alanine aminotransferase (ALT) in screening for MASLD. Chen et al found that new onset MASLD can be detected by repetitively high normal ALT. Implicit in this concept is the question of what should be the accepted upper limit of normal (ULN) for ALT. It was previously set at 40 IU/L based on studies that included people with subclinical liver disease but the new consensus is 30/19 U/L in healthy males/females. Thus, when Chen et al defines the ULN as 40 U/L, others may view it as excessively high. It is important to recognize the variables affecting ULN e.g. instrumentation, diurnal variations, exercise and ageing. These variables matter when the distinctions are subtle e.g. normal vs high-normal. In this regard, the utility of long-term high normal ALT as a disease marker could be enhanced by combining it with other biomarkers, imaging and MASLD genetics to create machine learning classifiers. All in all, Chen et al ’s work on long-term high normal ALT as a marker of new-onset MASLD deserves merit.

Unlocking the potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in revolutionizing type 2 diabetes management: A comprehensive review

Diabetes mellitus (DM) is a long-term metabolic disorder caused by inadequate production and resistance to insulin. The prevalence of DM is rapidly increasing, with type 2 diabetes (T2D) accounting for more than 90% of cases. Despite new treatments, many patients with T2D do not meet their glycemic targets due to clinical inertia. This review provides an overview of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the management of T2D. The review synthesizes data from clinical trials and meta-analyses on the efficacy, safety, and cost-effectiveness of GLP-1 RAs. It also discusses the mechanisms of action, classification, and barriers to adherence and persistence in therapy. GLP-1 RAs improve glycemic control by lowering A1C levels and promoting weight loss. They have cardioprotective effects and may reduce endothelial inflammation, oxidative stress, and blood pressure. Adherence to GLP-1 RAs is better with once-weekly injections, though gastrointestinal side effects and cost can affect persistence. Semaglutide and liraglutide have shown significant weight reduction, with semaglutide being particularly effective. GLP-1 RAs are cost-effective due to reduced healthcare costs associated with fewer hospitalizations and lower mortality rates. Safety concerns include gastrointestinal issues, pancreatitis, and rare cases of diabetic retinopathy and thyroid C-cell tumors. For clinical practice, GLP-1 RAs represent a valuable option not only for glycemic control but also for weight management and cardiovascular protection. Incorporating GLP-1 RAs into treatment plans can improve patient outcomes, and optimizing dosing regimens and addressing barriers such as cost and side effects are crucial to enhancing patient adherence and long-term treatment success.

Establishing a new-onset diabetes-related metabolism signature for predicting the prognosis and immune landscape in pancreatic cancer

Abstract New-onset diabetes (NOD) is a common condition among patients with pancreatic adenocarcinoma (PAAD) and is related to poor clinical outcomes. The potential impact of NOD on PAAD progression and the tumor microenvironment remains unclear. Here, we revealed that NOD in PAAD was associated with metabolic disorders. Utilizing three machine learning algorithms, a new-onset diabetes-related metabolism signature (NRMS) was established. Validated in three independent cohorts, patients with a high NRMS score exhibited worse prognosis. Moreover, an elevated NRMS score was associated with an immunosuppressive microenvironment and diminished response to immunotherapy. Further experiments demonstrated that ALDH3A1, a key feature in NRMS, was significantly up-regulated in tissues from PAAD patients with NOD and played a crucial role in tumor progression and immune suppression. Our findings highlight the potential of NRMS as a prognostic biomarker and an indicator of immunotherapy response for patients with PAAD.

Delayed immune-related adverse events profile associated with immune checkpoint inhibitors: a real-world analysis

BackgroundImmune-related adverse events (irAEs) typically occur within 3 months of initiating immune-checkpoint inhibitors (ICIs), which has been extensively documented. But the clinical profiles of late-onset irAEs remain inadequately characterized. Therefore, this study aims to quantify the correlation between delayed irAEs and ICIs, and to delineate the profiles of delayed toxicities associated with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).MethodsData from the January 2011 to December 2023 in FAERS database were extracted. Four signal detection indices, reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS), were employed to evaluate the associations between ICIs and delayed irAEs.ResultsA total of 147,854 cases were included in this study, of which 3,738 cases related to delayed irAEs were identified. Generally, 8 signals at System Organ Class (SOC) level were found to be associated with ICIs. Males had a slightly higher reporting frequencies for respiratory disorders (ROR975 = 0.95) and blood and lymphatic system disorders (ROR025 = 1.22), but lower reporting frequencies for immune system disorders (ROR025 = 1.16). Three monotherapy (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing gastrointestinal disorders (ROR025 = 1.66, 1.16, 1.99) and metabolism disorders (ROR025 = 2.26, 1.74, 3.13). Anti-PD-1 therapy exhibited higher rates of respiratory toxicities (ROR025 = 1.46 versus 0.82) and skin toxicities (ROR025 = 1.27 versus 0.94) compared with anti-CTLA-4 therapy. At PT levels, pneumonitis (ROR025: from 11.85 to 29.27) and colitis (ROR025: from 2.11 to 24.84) were the most notable PT signals associated with all three ICI regimens. For outcomes of delayed irAEs, gastrointestinal disorders showed the highest proportion (51.06%) of death.ConclusionOur pharmacovigilance analysis indicates that a small percentage of patients receiving ICIs therapy experience delayed irAEs, which are challenging to manage and may result in severe consequences. Prompt identification and intervention of these delayed irAEs are crucial in clinical practice.

Noninvasive Monitoring of Steatotic Liver Disease in Western Diet‐Fed Obese Mice Using Automated Ultrasound and Shear Wave Elastography

ABSTRACTBackground and AimsUltrasound imaging and shear wave elastography (SWE) can be used to noninvasively stage hepatopathologies and are widespread in clinical practice. These techniques have recently been adapted for small animal use in a novel 3D in vivo imaging system capable of high‐throughput automated scanning. Our goal was to evaluate the feasibility of using this imaging tool in the murine Western diet (WD) model, a highly translatable preclinical model of obesity, metabolic disease and liver fibrosis.MethodsFemale C57BL/6 mice (N = 48) were placed on WD or chow diet and imaged longitudinally for a period of 48 weeks. Imaging consisted of 3D B‐mode and targeted SWE captures. Liver volume, liver echogenicity and liver stiffness were quantified from in vivo imaging data. A subset of mice was sacrificed at various timepoints (0, 12, 24 and 48 weeks) for histological workup. Correlation analysis was performed between in vivo imaging and histological measurements to determine level of agreement.ResultsNoninvasive imaging showed statistically significant increases in liver volume and echogenicity, but non‐significant increase in liver stiffness in the WD‐fed cohort, suggesting development of hepatomegaly and steatosis, but negligible fibrosis. Ex vivo analysis confirmed significant increases in liver weight, liver triglycerides and ALT, but limited increases in fibrosis corroborating noninvasive imaging results. Correlation analysis between imaging and histology demonstrated good agreement between liver volume/liver weight (R2 = 0.85) and echogenicity/triglycerides (R2 = 0.76).ConclusionsThis study demonstrated that noninvasive ultrasound liver assessments are feasible in the WD mouse model and closely reflect the underlying pathological state of the animal. Automated ultrasound can serve as a high‐throughput noninvasive screening method for preclinical liver disease research and drug development.

Phosphate metabolism: its impact on disorders of mineral metabolism

Phosphate metabolism: its impact on disorders of mineral metabolism

Cerebrotendinous Xanthomatosis (CTX) Disease Prevalance in Patients with Autism Spectrum Disorder (ASD): A Prospective Observational Study

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system.It has been demonstrated that many congenital metabolic diseases like CTX are associated with Autism Spectrum Disorder (ASD). The aim of this study is to identify the prevalence of CTX disease in patients with ASD. Method: The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A socio-demographic form and Gilliam Autism Rating Scale-2 were applied to all participants. Results: In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, four patients with mutations in the CYP27A1 gene, two homozygous variants and two different heterozygous mutations were identified. Most common symptom was diarrhea. 67.3% of all patients and 3 in 4 cases with CYP27A1 gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations.Moreover, all mutant cases had comorbid Oppositional Defiant Disorder (ODD). 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder. Conclusion: psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration and permanent disability through early initiation of chenodeoxycholic acid treatment.

Elevated serum growth differentiation factor 15 and decorin predict the fibrotic progression of metabolic dysfunction-associated steatotic liver disease

Elevated serum growth differentiation factor 15 and decorin predict the fibrotic progression of metabolic dysfunction-associated steatotic liver disease

Letter to Editor: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study

Letter to Editor: Prevalence of subclinical hypothyroidism and longitudinal thyroid stimulating hormone changes in youth with metabolic dysfunction-associated steatotic liver disease: an observational study

Investigation of the Effects of Biotinidase Deficiency on Plasma Cholinesterase Activity

Purpose: Biotinidase deficiency (BD) is a rare autosomal recessive metabolic disorder that impairs the body's ability to recycle biotin, a crucial coenzyme for carboxylase enzymes involved in various metabolic processes. This study aims to evaluate the effects of biotinidase deficiency on cholinesterase activity in plasma, hypothesizing that the metabolic disruptions caused by inadequate biotin recycling may lead to alterations in cholinesterase function. Materials and methods: Plasma samples were collected from 73 individuals categorized into four genetic groups: wild type (n = 12), heterozygous (n = 30), homozygous (n = 19), and compound heterozygous (n = 12). Cholinesterase activity was measured using a colorimetric method. Results: The study discovered that the cholinesterase activity of the Heterozygous group was higher than the homozygous group (p = 0.0356). Additionally, cholinesterase activity was significantly lower in homozygous and compound heterozygous people than in wild and heterozygous groups (p = 0.0272). The statistically significant changes suggested a relationship between biotinidase deficiency and altered cholinergic activity. Conclusion: The findings indicate that biotinidase deficiency, particularly in its severe variants, may cause considerable reductions in cholinesterase activity, contributing to the neurological symptoms found in affected patients. More studies are needed to investigate the processes behind this association and develop strategies for reducing the effects of BD on cholinesterase activity and neurological health.

Association between proteinuria and mineral metabolism disorders in chronic kidney disease: the Japan chronic kidney disease database extension (J-CKD-DB-Ex)

Chronic kidney disease-mineral and bone disorder (CKD-MBD) are recognized as a systemic disease affecting the prognosis of patients with CKD. Proper management of CKD-MBD is important to improve the prognosis of patients with CKD. Although proteinuria is recognized as a poor prognostic factor in these patients, few reports have examined its association with CKD-MBD. We examined the association between proteinuria and CKD-MBD using data from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex). Among the patients registered in the J-CKD-DB-Ex, 30,977 with CKD stages G2–G5 who had serum creatinine, albumin, calcium, and phosphate concentrations measured at least once and urinalysis performed were included. The patients were divided into four groups (negative, 1+, 2+, and 3+) according to the degree of proteinuria. The association between proteinuria and CKD-MBD was examined by a logistic regression analysis. In a model adjusted for age, sex, diabetes, and the estimated glomerular filtration rate (eGFR), the odds ratio of the 3 + group compared with the negative group significantly increased to 2.67 (95% confidence interval, 2.29–3.13) for hyperphosphatemia, 2.68 (1.94–3.71) for hypocalcemia, and 1.56 (1.24–1.98) for hypomagnesemia. Proteinuria is associated with hyperphosphatemia, hypocalcemia, and hypomagnesemia in patients with CKD independently of eGFR.

Tissue adaptation to metabolic stress: insights from SUMOylation

Post-translational modification (PTM) plays a crucial role in adaptation of mammals to environmental changes, enabling them to survive in stressful situations. One such PTM is SUMO modification, which is evolutionarily conserved. It involves the covalent and reversible attachment of a small ubiquitin-like modifier (SUMO) to lysine (Lys) residues in the target protein. SUMOylation regulates various functions, including cell proliferation, differentiation, apoptosis, senescence, and maintenance of specific cellular activities. It achieves this by influencing protein-protein interactions, subcellular localization, protein stability, and DNA binding activity. Mounting evidence suggests that SUMOylation is implicated in the pathogenesis of metabolic disorders such as obesity, insulin resistance, and fatty liver. This review aims to provide an overview of the role of SUMOylation in regulating tissue adaptation to metabolic stress. Recent advancements in spectroscopic techniques have shed light on potential targets of SUMOylation and the underlying regulatory mechanisms have been elucidated, laying the theoretical foundation for the development of targeted SUMOylation interventions for metabolic syndrome while minimizing side effects.

STRUCTURE AND CHARACTERISTICS OF THE SECOND MODULE IN THE "INDIVIDUAL RESEARCH WORK" COURSE (“MEDICINE” PROGRAM)

Providing access to quality education is one of the Sustainable Development Goals (SDGs) set by the United Nations to be achieved by 2030 (Goal №4: Quality Education – “Ensure inclusive and equitable quality education and promote lifelong learning opportunities for all”). The unique aspect of higher medical education is that its quality also supports the fulfillment of another SDG (Goal №3: Good Health and Well-being). Higher medical education is dynamic, with a growing global trend toward increasing the emphasis on scientific knowledge within educational programs. In leading countries, courses are being developed that actively incorporate the study of research methods in medicine. The introduction of new educational components aimed at developing scientific competencies in medical students represents a promising approach to improving the quality of education. The aim of this study was to analyze and characterize the structure of the second module in the course “Individual Scientific Work” within the educational and professional program “Medicine”. In preparing the manuscript, the authors employed the following general scientific theoretical research methods: analysis, synthesis, concept comparison, abstraction, and generalization. The primary goal of studying Module №2, “Methods of Researching Pathological Changes in Organs and Systems”, as part of the “Individual Scientific Work” in the educational and professional program “Medicine”, is to develop students’ skills in the methodology of conducting medical research. The thematic plan for Module №2 includes the following topics: Methods of registering functional changes in organs and systems; Methods of researching metabolic disorders; Methods of studying the development of oxidative stress in various organs and systems; Study of changes in the production and signaling of gas transmitters, including nitric oxide, hydrogen sulfide, and carbon monoxide. In conclusion, it should be noted that the structure and content of the second module of the course “Individual Scientific Work” in the context of professional program “Medicine”, developed by the Department of Pathophysiology at Poltava State Medical University, align with the requirements of modern higher medical education.

Post-traumatic stress disorder and metabolic syndrome: the role of some antioxidants in treatment

The basis for the pathogenesis of cardiovascular, cancer, metabolic diseases, low-grade chronic inflammation (LGCI) and many other disorders is an imbalance between prooxidants and the antioxidant defense system. It is believed that the link between post-traumatic stress disorder (PTSD) and metabolic syndrome (MetS) is based on oxidative stress (OS), increased autonomic nervous system activity, glucocorticoid synthesis activation, or immunological dysregulation. Moreover, pathophysiological changes in the systemic LGCI pathways that result from modifications in glucocorticoid receptor reactivity (secondary to emotional and physiological arousal) may be the basis for inappropriate social behavior consistent with PTSD and MetS manifestations. Recently, evidence has emerged suggesting that a combination of high levels of systemic OS and activation of LGCI plays an important role in the pathogenesis of PTSD. On the other hand, PTSD is a type of recurrent and long-term trauma that exacerbates OS and accele­rates cellular aging. LGCI is accompanied by the release of reactive oxygen and nitrogen species, proinflammatory cytokines, and other biologically active substances that cause OS. The purpose of this review was to discuss the role of individual antioxidants, in particular polyphenols, flavonoids, carotenoids, N-acetylcysteine, melatonin, L-arginine, C and E vitamins, zinc, copper, and selenium, in the prevention/treatment of comorbid pathology of PTSD and MetS, as well as to analyze new trends and directions for future research. The search was conducted in Scopus, Science Direct (from Else­vier) and PubMed, including MEDLINE databases. The keywords used were “post-traumatic stress disorder,” “metabolic syndrome,” and “antioxidants.” To identify research results that could not be found during the online search, a manual search of the bibliography of publications was used.

The Possible Roles of Glucosamine-6-Phosphate Deaminases in Ammonium Metabolism in Cancer

Nearly 5% of the glucose-6-phosphate (Glc6P) in cells is diverted into the hexosamine biosynthetic pathway (HBP) to synthesize glucosamine-6-phosphate (GlcN6P) and uridine diphosphate N-acetyl-glucosamine-6-phosphate (UDP-GlcN6P). Fructose-6-phosphate (Fru6P) is a common intermediary between glycolysis and the HBP. Changes in HBP regulation cause abnormal protein N-glycosylation and O-linked-N-acetylglucosamine modification (O-GlcNAcylation), affecting protein function and modifying cellular responses to signals. The HBP enzymes glucosamine-6-phosphate deaminases 1 and 2 (GNPDA1 and 2) turn GlcN6P back into Fru6P and ammonium, and have been implicated in cancer and metabolic diseases. Despite the plentiful literature on this topic, the mechanisms involved are just beginning to be studied. In this review, we summarize, for the first time, the current knowledge regarding the possible roles of the isoenzymes of both GNPDAs in the pathogenesis and development of metabolic diseases and cancer from a molecular point of view, highlighting their importance not only in supplying carbon from glycolysis, but also in ammonia metabolism.

Loss of Runx2 in Gli1 + Osteogenic Progenitors Prevents Bone Loss Following Ovariectomy

Abstract Osteoporosis is a metabolic bone disorder characterized by low bone mass and bone mineral density. It is the most prevalent bone disease and a common cause of fracture in aging adults. Low bone mass, as seen in osteoporosis, results from an imbalance between osteoblast and osteoclast activity. Gli1+ cells are indispensable to the maintenance of bone tissue homeostasis. These cells give rise to osteoprogenitors and are present at the osteogenic fronts of long bones in adult mice. Runx2 is a key regulator of osteogenesis and plays a crucial role in osteoblastic differentiation and maturation during development. However, its function in maintaining adult bone tissue homeostasis remains unclear. In this study, we investigated the role of Runx2 in maintaining adult bone homeostasis in the context of ovariectomy-induced estrogen deficiency, a model for postmenopausal osteoporosis. Our results show that deletion of Runx2 in the Gli1+ osteogenic progenitor population prevents loss of both cortical and trabecular bone mass and mineralization after ovariectomy. At the cellular level, loss of Runx2 leads to a decrease in osteoclast activity. Our study indicates that Runx2 is essential for maintaining adult bone tissue homeostasis by regulating osteoclast differentiation.

Structural and Functional Biology of Mammalian ALOX Isoforms with Particular Emphasis on Enzyme Dimerization and Their Allosteric Properties

The human genome involves six functional arachidonic acid (AA) lipoxygenase (ALOX) genes, and the corresponding enzymes (ALOX15, ALOX15B, ALOX12, ALOX12B, ALOXE3, ALOX5) have been implicated in cell differentiations and in the pathogenesis of inflammatory, hyperproliferative, metabolic, and neurological disorders. Humans express two different AA 15-lipoxygenating ALOX isoforms, and these enzymes are called ALOX15 (15-LOX1) and ALOX15B (15-LOX2). Chromosomal localization, sequence alignments, and comparison of the enzyme properties suggest that pig and mouse ALOX15 orthologs (leukocyte-type 12-LOX) on the one hand and rabbit and human ALOX15 orthologs on the other (reticulocyte-type 15-LOX1) belong to the same enzyme family despite their different reaction specificities with AA as a substrate. In contrast, human ALOX12 (platelet-type 12-LOX), as well as pig and mouse ALOX15 (leukocyte-type 12-LOX), belong to different enzyme families, although they exhibit a similar reaction specificity with AA as a substrate. The complex multiplicity of mammalian ALOX isoforms and the controversial enzyme nomenclatures are highly confusing and prompted us to summarize the current knowledge on the biological functions, enzymatic properties, and allosteric regulation mechanisms of mammalian ALOX15, ALOX15B, and ALOX12 orthologs that belong to three different enzyme sub-families.

Role of metabolic dysfunction-associated steatotic liver disease and of its genetics on kidney function in childhood obesity

Role of metabolic dysfunction-associated steatotic liver disease and of its genetics on kidney function in childhood obesity

Dietary supplementation with citrus peel extract in transition period improves rumen microbial composition and ameliorates energy metabolism and lactation performance of dairy cows

BackgroundDuring the transition period, excessive negative energy balance (NEB) lead to metabolic disorders and reduced milk yield. Rumen microbes are responsible for resolving plant material and producing volatile fatty acids (VFA), which are the primary energy source for cows. In this study, we aimed to investigate the effect of citrus peel extract (CPE) supplementation on rumen microbiota composition, energy metabolism and milk performance of peripartum dairy cows.MethodsDairy cows were fed either a basal diet (CON group) or the same basal diet supplemented with CPE via intragastric administration (4 g/d, CPE group) for 6 weeks (3 weeks before and 3 weeks after calving; n = 15 per group). Samples of serum, milk, rumen fluid, adipose tissue, and liver were collected to assess the effects of CPE on rumen microbiota composition, rumen fermentation parameters, milk performance, and energy metabolic status of dairy cows.ResultsCPE supplementation led to an increase in milk yield, milk protein and lactose contents, and serum glucose levels, while reduced serum concentrations of non-esterified fatty acid, β-hydroxybutyric acid, insulin, aspartate aminotransferase, alanine aminotransferase, and haptoglobin during the first month of lactation. CPE supplementation also increased the content of ruminal VFA. Compared to the CON group, the abundance of Prevotellaceae, Methanobacteriaceae, Bacteroidales_RF16_group, and Selenomonadaceae was found increased, while the abundance of Oscillospiraceae, F082, Ruminococcaceae, Christensenellaceae, Muribaculaceae UCG-011, Saccharimonadaceae, Hungateiclostridiaceae, and Spirochaetaceae in the CPE group was found decreased. In adipose tissue, CPE supplementation decreased lipolysis, and inflammatory response, while increased insulin sensitivity. In the liver, CPE supplementation decreased lipid accumulation, increased insulin sensitivity, and upregulated expression of genes involved in gluconeogenesis.ConclusionsOur findings suggest that CPE supplementation during the peripartum period altered rumen microbiota composition and increased ruminal VFA contents, which further improved NEB and lactation performance, alleviated lipolysis and inflammatory response in adipose tissue, reduced lipid accumulation and promoted gluconeogenesis in liver. Thus, CPE might contribute to improve energy metabolism and consequently lactation performance of dairy cows during the transition period.

Lipid metabolism and food ingredients from the perspective of thermogenic adipocytes

Abstract The high heat-producing capacity of brown and beige adipocytes, collectively known as thermogenic adipocytes, contributes to whole-body energy expenditure and is an attractive target for the management of obesity. It has been revealed that the functions of thermogenic adipocytes are important for the regulation of whole-body carbohydrate and lipid metabolism, and the activation of thermogenic adipocytes seems to have beneficial effects for the management of obesity-related metabolic disorders, such as dyslipidemia. Recent studies have showed that specific food ingredients have the potential to activate thermogenic adipocytes via various mechanisms. Some of these are effective not only in rodents, but also in humans, and effective prevention of obesity using these food ingredients is expected. In this review, we introduce the recent findings on the regulatory mechanisms of lipid metabolism by thermogenic adipocytes and food ingredients, demonstrating the potential to activate thermogenic adipocytes and their underlying mechanisms.