Objective: This review examines the evolution of obesity evaluation methods, from traditional anthropometric indices to advanced imaging techniques, focusing on their clinical utility, limitations, and potential for personalized assessment of visceral adiposity and associated metabolic risks.

Methods: A comprehensive analysis of existing literature was conducted, encompassing anthropometric indices (BMI, WC, WHR, WHtR, NC), lipid-related metrics (LAP, VAI, CVAI, mBMI), and imaging technologies (3D scanning, BIA, ultrasound, DXA, CT, MRI). The study highlights the biological roles of white, brown, and beige adipocytes, emphasizing visceral adipose tissue (VAT) as a critical mediator of metabolic diseases.

Conclusion: Although BMI and other anthropometric measurements are still included in the guidelines, indicators that incorporate lipid metabolism information can more accurately reflect the relationship between metabolic diseases and visceral obesity. At the same time, the use of more modern medical equipment, such as ultrasound, X-rays, and CT scans, allows for a more intuitive assessment of the extent of visceral obesity.

White adipose tissue (WAT) and brown adipose tissue (BAT) have distinct structural and physiological characteristics and serve opposing functions in the body. WAT primarily stores energy, whereas BAT is metabolically active and positively influences metabolic health, contributing to energy expenditure, reduced fat accumulation and enhanced mitochondrial metabolism. Recently, both classical BAT and beige fat (or inducible/recruitable BAT) that arises from the browning of WAT have attracted clinical interest as potential targets for improving mitochondrial metabolism and managing obesity-related metabolic disorders. Currently, there is a lack of specific metabolic biomarkers for characterizing classical BAT and beige fat tissues, which are essential for evaluating mitochondrial oxidative metabolism and screening browning agents for therapeutic use. In this study, we investigated the potential metabolic biomarker fatty acylcarnitine in interscapular BAT (iBAT) from the interscapular region and beige adipose tissue from the inguinal region of the animal using ex vivo 13C high-resolution magic angle spinning (HRMAS) NMR spectroscopy. We examined how mitochondrial oxidative metabolism was altered in response to a high-fat diet (HFD) and how it was restored through iBAT activation using stimuli such as cold exposure and β3-adrenergic receptor (β3-AR) agonist, CL-316,243 treatment. We identified fatty acylcarnitine as a potential metabolic marker present in iBAT and beige tissues, whereas it was absent in iWAT. The concentration of fatty acylcarnitine significantly decreased in HFD-fed animals due to impaired lipolysis resulting in inefficient shuttling of fatty acids for mitochondrial β oxidation. However, its concentration increased or was restored in response to iBAT activation through either β3-AR agonist treatment or cold exposure, indicating a high-energy metabolic state with enhanced mitochondrial metabolism in iBAT. Fatty acylcarnitine shows promise as a biomarker for evaluating mitochondrial metabolism and for screening potential browning agents and nutraceuticals capable of inducing the browning of WAT.

Inducing adipose browning to increase energy expenditure has recently emerged as a promising approach for antiobesity treatment. However, its therapeutic efficacy is often limited by poor adipose-targeted drug delivery and suboptimal browning efficiency. To address these challenges, an adipose-targeting aptamer (Apt8) and browning agent resveratrol (Res) were used to construct an Apt-modified and Res-loaded degradable mesoporous silica-coated Au nanorods nanocarriers (NC), termed Res@NC@Apt8, achieving adipose-targeted hyperthermia-pharmacotherapy. Upon internalization by adipocytes, laser irradiation induces mild local hyperthermia (LHT) via Res@NC@Apt8, triggering calcium ion (Ca2+) influx. Simultaneously, the interaction of the nanohybrid with local glutathione (GSH) releases Res. The dual mechanisms activate the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway, reduce the lipid droplet content, enhance mitochondrial biogenesis, and accelerate metabolism, thereby synergistically promoting adipose browning. Intravenous Res@NC@Apt8 administration in obese mice significantly drives adipose reduction and further achieves excellent antiobesity therapeutic efficacy. This synergistic treatment achieves a superior weight reduction of 17.2% compared with 6.9% and 10.6% achieved using LHT and pharmacotherapy alone, respectively. This study introduces a novel strategy for achieving activatable LHT and drug release for synergetic obesity treatment.

The brown adipose tissue is a potential target for interventions aimed at treating obesity and other metabolic disorders. Both genetic and environmental factors are known to regulate brown adipose tissue function and exploring the interaction between these factors could unveil new mechanisms involved in the regulation of thermogenesis. In this study, we evaluated three genetically distinct mice strains submitted to two environmental factors known to modulate brown adipose tissue function, namely, cold exposure and the consumption of a high-fat diet. The comparison of Balb/c, C57BL/6, and Swiss mice revealed that Balb/c mice were the most glucose-tolerant and the most cold-tolerant. In addition, Balb/c presented the greatest brown adipose tissue oxygen consumption, which was independent of differences in uncoupling protein 1 expression and function. The search for uncoupling protein 1-independent mechanisms that could explain the greatest cold tolerance of Balb/c mice resulted in the identification of the N-acyl amino acid regulator, PM20D1, which had a greater gene expression in the brown adipose tissue of Balb/c mice as compared to the other two strains. The immunoneutralization of PM20D1 in Balb/c mice, resulted in increased blood glucose levels and worsening of cold tolerance. In addition, the in silico knockout of Pm20d1 impacted several metabolic processes, including thermogenesis, glucose tolerance, and insulin sensitivity. In conclusion, Balb/c mice are protected from glucose and acute cold intolerance, independently of the diet. We propose that PM20D1, in an uncoupling protein 1-independent fashion, can have an important role in this protection.

Pregnancy requires the coordination of metabolically active organs to support maternal nutrition and fetal growth. However, the metabolic cross-talk between adipose tissue and liver in females during pregnancy is still less clear. In this study, we evaluated the metabolic adaptations and phenotypes of liver in response to pregnancy-associated metabolic stress, particularly in the context of genetic ablation of Uncoupling protein 1 (Ucp1)-mediated catabolic circuit. Our results revealed that Ucp1 deficiency (UCP1 knockout, KO) mice during late pregnancy exhibited significantly deteriorated metabolic phenotypes, including hepatic steatosis and whole-body glucose and lipid homeostasis, as compared to Ucp1 deficiency or normal pregnancy mice. However, non-pregnant Ucp1 deficiency mice displayed nearly normal metabolic phenotypes and structure alterations similar to those of littermate controls. Moreover, transcriptomic analyses by RNA sequencing (RNA-seq) clearly revealed that Ucp1 deficiency led to a significant liver metabolic remodeling of differentially express genes (DEGs) before and especially during pregnancy. Consistently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses demonstrated the potential altered functions and signaling pathways, including metabolic dysfunctions in ribosome, oxidative phosphorylation, etc. Importantly, as derived from trend analyses of DEGs, our results further revealed the distinct expression pattern of each subcluster, which coincided with potential biological functions and relevant signaling pathways. The findings in the present study might provide valuable insights into the molecular mechanism of metabolic dysfunction-associated fatty liver disease (MAFLD) during pregnancy. Additionally, our data may provide a novel animal model of MAFLD, thus facilitating its potential therapies. NEW & NOTEWORTHY: Genetic ablation of Ucp1 during pregnancy increases hepatic steatosis and deteriorated whole-body glucose and lipid homeostasis. Moreover, changes in hepatic gene expression are closely associated with metabolic dysfunctions in ribosome and oxidative phosphorylation. This work highlights the therapeutic potential of targeting UCP1- mediated catabolic circuit between adipose and liver during pregnancy, and the utility of RNA-seq analysis to reveal valuable information for the distinct expression pattern of each subcluster that contribute to pregnancy-dependent MASLD progression.

Type 2 diabetes (T2D) is a persistent illness that has a high incidence rate. Still, there is no conclusive evidence on effectively improving blood sugar levels in patients through physical therapy. This study examined the regulatory effects of different intensities of low-intensity pulsed ultrasound (LIPUS) on T2D by stimulating brown adipose tissue (BAT). Eight-week-old C57BL/6J mice were divided into six groups (n = 10 per group): Control sham (C-Sham), Control-LIPUS (C-LIPUS), T2D-sham (T2D-Sham), T2D groups treated with LIPUS at spatial average-temporal-average intensity (Isata) of 60mW/cm² (T2D-L-60), 80mW/cm² (T2D-L-80), and 100mW/cm² (T2D-L-100). T2D models were induced by intraperitoneal injection of 40 mg/kg streptozotocin (STZ) three times after 12 wks of high-fat diet (HFD). The T2D-LIPUS group received LIPUS stimulation for 20 minutes per day for 6 weeks. The LIPUS stimulation had a duty cycle of 20%, a frequency of 1 MHz, and Isata of 60mW/cm², 80mW/cm², 100mW/cm². Subsequently, glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed, and body fat content in mice was analyzed using nuclear magnetic resonance (NMR). Metabolic changes were monitored using metabolic cages. The results indicated that 80mW/cm² intensity level significantly improved glucose tolerance, insulin sensitivity, and metabolic function after LIPUS exposure. Significant reductions in body fat content and enhanced thermogenesis were observed, highlighting the potential of LIPUS in T2D management. This provides the basis for the dose study of LIPUS in the treatment of T2D.

Brown adipose tissue (BAT) is a site of non-shivering thermogenesis (NST) in mammals. Since the rediscovery of BAT in adult humans, there has been a remarkable advance in human BAT researches, revealing the significant roles of this thermogenic tissue in cold-induced NST and cold adaptation. Cold stress influences BAT in various time spans: acute cold exposure promptly activates BAT to induce NST, which contributes to immediate maintenance of body temperature. Prolonged cold exposure recruits BAT, resulting in increased capacity of NST and improved cold tolerance. Such BAT adaptation not only occurs in the exposed individual but also is passed on to the next generation, probably via the paternal lineage. As such, BAT plays a role in acute, chronic, and transgenerational adaptation to cold environment in humans.

Studies indicate that the induction and activation of brown and beige adipocytes, which can enhance energy expenditure, may be beneficial for managing obesity and its associated diseases. This study investigated whether a novel lignan (-)-secoisolariciresinol 4-O-methyl ether (S4M) obtained from arctigenin inhibited diet-induced obesity by the browning of white adipose tissue (WAT). S4M treatment inhibited adipogenesis and lipid accumulation in white-induced 3T3-L1 adipocytes and in zebrafish embryonic development. Moreover, S4M treatment promoted browning in white adipocytes by increasing TOM20, UCP1, and PGC1α protein levels and consequently upregulating the mitochondrial content. S4M treatment significantly promoted mitochondrial fission by increasing the expression of DRP1. Furthermore, it enhanced peroxisomal biogenesis and function by inducing PEX13, ACOX1, and catalase. Mdivi-1, a mitochondrial dynamics inhibitor, diminished the browning effect of white adipocytes by the S4M treatment. This study found that S4M treatment inhibited weight gain in high-fat diet-induced obese mice, decreased the weight of WAT, and increased the abundance and function of mitochondria and peroxisomes in inguinal WAT, suggesting that S4M treatment could increase energy expenditure. The results suggest that S4M has potential as a therapeutic agent for combating obesity and its associated metabolic disorders.

The activation of brown adipose tissue (BAT) promotes energy expenditure is recognized as a promising therapeutic strategy for combating obesity. The deubiquitinating enzyme family members are widely involved in the process of energy metabolism. However, the specific deubiquitinating enzyme member that affects the BAT thermogenesis remains largely unexplored.

Adeno-associated virus, lentivirus and small molecule inhibitor were applied to generate USP2 gain- or loss-of-function both in vivo and in vitro. OxyMax comprehensive laboratory animal monitoring system, seahorse and transmission electron microscopy were used to determine the energy metabolism. Quantitative proteomics, immunofluorescence staining and co-immunoprecipitation were performed to reveal the potential substrates of USP2.

USP2 is upregulated upon thermogenic activation in adipose, and has a close correlation with UCP1 mRNA levels in human adipose tissue. BAT-specific Usp2 knockdown or systemic USP2 inhibition resulted in impaired thermogenic programs both in vivo and in vitro. Conversely, overexpression of Usp2 in BAT conferred protection against high-fat diet-induced obesity and associated metabolic disorders. Proteome-wide analysis identified EBF2 as the substrate of USP2 that mediates the thermogenic function of USP2 in BAT.

Our data demonstrated the vital role of USP2 in regulating BAT activation and systemic energy homeostasis. Activation of USP2-EBF2 interaction could be a potential therapeutic strategy against obesity.

Systemic administration of β-aminopropionitrile to inhibit lysyl oxidase (Lox) activity improves metabolism, but it exhibits a broad spectrum of effects. Clarification of the role of Lox in adipose tissue metabolism under high-fat diet (HFD) conditions is needed.

Mice with adipose tissue knockout of Lox (LoxAKO) and wild-type mice were subjected to a 16-week HFD regimen. A detailed evaluation encompassing adipose tissue, hepatic function, and systemic metabolism was conducted. RNA sequencing analysis was used to unravel the intricate mechanisms behind the metabolic enhancements in LoxAKO mice.

Compared with the control, although there was no difference in body weight, LoxAKO mice exhibited an improved metabolic phenotype, including enhanced insulin sensitivity, improved glucose tolerance, and reduced liver steatosis, along with reduced adipose tissue inflammation and fibrosis. LoxAKO mice showed increased thermogenic activity in brown adipose tissue with increased uncoupling protein 1 (UCP1) expression and oxygen consumption rate. Additionally, RNA sequencing analysis revealed that adipose deletion of Lox might facilitate the metabolic processing of glucose, branched-chain amino acids, and fatty acids in brown adipose tissue.

These findings indicate that adipocyte Lox deletion improves metabolic adaptability under an HFD, highlighting Lox as a promising therapeutic target for obesity-associated metabolic disorders.

Urolithiasis is associated with metabolic syndrome, and reactivation of brown adipose tissue (BAT) may improve metabolic syndrome. In this study, we aimed to evaluate the association of BAT, as detected using positron emission tomography-computed tomography (PET-CT), with urolithiasis in humans. This single center retrospective cohort study involved patients who underwent PET-CT for cancer screening as part of a medical checkup between January 2006 and December 2020. We obtained data on participant demographics, presence of urolithiasis, and metabolic factors (such as obesity, hypertension, diabetes, and hyperlipidemia) from 182 medical records. BAT data and calcification of the abdominal aorta (CAA) rate, determined using abdominal CT, were also recorded. Any association between urolithiasis and other factors was evaluated using logistic regression analysis. Body mass index was higher in participants with BAT than in those without BAT (26.92 vs. 22.86 kg/m2, p = 0.001). Participants with BAT had less urolithiasis and a lower CAA rate than those without BAT (10% vs. 37%, p = 0.031 and 50% vs. 79.6%, p = 0.008, respectively). Metabolic factors between the groups were similar (45.0% vs. 48.8%, p = 0.936). Furthermore, BAT and age were associated with a decreased odds ratio (OR) for urolithiasis (OR = 0.186, p = 0.037 and OR = 0.959, p = 0.02, respectively). We demonstrated that high BAT content is associated with a low risk of urolithiasis and CAA. Our findings may contribute to the development of novel preventive methods for urolithiasis.

Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.

Research on the effects of exogenous glucocorticoids on brown adipose tissue (BAT) is crucial for understanding how these hormones can induce metabolic disorders such as obesity. In this study, we explored the effects of glucocorticoids, specifically dexamethasone (Dex), on the metabolic transformation of BAT to white adipose tissue (WAT).

Our results indicate a significant whitening shift in BAT upon Dex treatment, characterized by increased lipid deposition, decreased mitochondrial density, a significant decline in cellular ATP content, and reduced expression of mitochondrial markers. We demonstrate the crucial role of leptin resistance in mediating mitochondrial function through the overexpression and inhibition of LEPR.

Our results suggest the role of leptin resistance in regulating of mitochondrial biogenesis and energy metabolism in glucocorticoid-induced brown adipose whiteness.

The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.

Obesity, marked by excessive fat accumulation, especially abdominal, is a global health concern with significant public impact. While obesity-associated chronic unresolved inflammation contributes to metabolic dysfunctions, acute inflammation supports healthy adipose tissue remodeling and expansion. Platelet-activating factor (PAF), a "primitive" signaling molecule, is among the key mediators involved in the acute phase of inflammation and in various pathophysiological processes. This article explores the role of PAF in fat accumulation and obesity by reviewing experimental data from cell cultures, animals, and humans. It proposes an emerging biochemical mechanism in an attempt to explain its dual role in the healthy and obese adipose tissue, including also data on PAF's potential involvement in epigenetic mechanisms that may be linked to the "obesity memory". Finally, it highlights the potential of natural PAF modulators in promoting functional adipose tissue, thermogenesis, and obesity prevention through a healthy lifestyle, including a Mediterranean diet rich in PAF weak agonists/PAF receptor antagonists and regular exercise, which help maintain controlled PAF levels. Conversely, in cases of obesity-related systemic inflammation with excessive PAF levels, potent PAF inhibitors like ginkgolide B and rupatadine may help mitigate metabolic dysfunctions with PAFR antagonists potentially enhancing their effects synergistically.

Secreted endoplasmic reticulum membrane complex subunit 10 (scEMC10) has been implicated in obesity in mice and humans. In this study, the associations of serum scEMC10 levels with thermoneutrality-modulated brown adipose tissue (BAT) activity and thyroid hormone (TH)-dependent thermogenesis were investigated in humans.

Serum scEMC10 levels were measured in participants from multiple cohorts using enzyme-linked immunosorbent assay, including participants with or without active BAT determined by PET-CT scanning, participants with positive BAT before and after thermoneutrality, and patients with hyperthyroidism before and after anti-thyroid drug (ATD) treatment. The difference in serum scEMC10 between participants with positive or negative BAT, and the changes of serum scEMC10 in participants with positive BAT before and after thermoneutrality and in patients with Grave's disease-caused hyperthyroidism before and after ATD treatment were determined.

PET-CT scan with 18F-FDG indicated participants with positive BAT were significantly younger and leaner than ones with negative BAT. There was, however, no significant difference in serum scEMC10 between the two groups. Serum scEMC10 levels in participants with positive BAT were significantly elevated by 2-h thermoneutrality (p = 0.0017), concomitant with disappearance of active BAT. No significant association of serum scEMC10 with serum levels of either TSH, FT3, or FT4 was observed in participants from both Chinese and White cohorts. ATD treatment normalized thyroid function and reduced the uptake of 18F-FDG into skeletal muscle of patients with hyperthyroidism. Serum scEMC10 concentration, however, remained unchanged in these patients before and after ATD treatment.

Serum scEMC10 levels are inversely associated with BAT activity in humans.

Cardiovascular disease is the leading cause of death throughout most of the industrialized world. Metabolic syndrome (MetS) and its associated pathologies are underlying factors in the etiology of cardiovascular disease, as well as a plethora of other maladies which cause excess morbidity and mortality. Adipose tissue (AT) has come to be regarded as a bona fide endocrine organ which secretes specific molecular entities constituting part of a complex web of inter-organ crosstalk that functions as a key determinant of whole-body metabolic phenotype. Brown adipose tissue (BAT) has classically been regarded as a thermogenic tissue exerting its metabolic effects primarily through its capacity to oxidize substrates decoupled from ATP resynthesis, thereby resulting in increased energy expenditure (EE) and heat production. However, in recent years, BAT has begun to receive attention as a secretory organ in its own right. The molecules secreted specifically by BAT have been termed "batokines", and currently available evidence supports the notion that batokines exert favorable metabolic effects on multiple organ systems. While maintenance of healthy body composition by conferring resistance to excessive adiposity is a rather obvious mechanism by which BAT operates via increased EE, effects on critical organs such as the heart remain unclear. This narrative review focuses on four types of batokines (FGF21, neuregulin 4, 12,13-diHOME, and BAT-derived microRNAs) for which evidence of modulation of cardiovascular function exists in the context of pathological states such as hypertension, atherosclerosis, and ischemia/reperfusion injury. Given the overwhelming burden of cardiometabolic disease, further study of the functions of BAT and its secretome is warranted and will intensify in the future.

Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Through a retrospective analysis of existing FDG PET-MRI images, we recently demonstrated that metformin increases the accumulation of FDG in the intestinal lumen, suggesting that metformin stimulates glucose excretion into the intestine. However, the details of this phenomenon remain unclear. We here investigate the detailed dynamics of intestinal glucose excretion, including the rate of excretion and the metabolism of excreted glucose, in both the presence and absence of metformin.

We quantified intestinal glucose excretion using newly developed FDG PET-MRI-based bioimaging in individuals with type 2 diabetes, both treated and untreated with metformin. The metabolism of excreted glucose was analyzed through mass spectrometry of fecal samples from mice intravenously injected with 13C-labeled glucose.

Continuous FDG PET/MRI image taking reveals that FDG is initially observed in the jejunum, suggesting its involvement in FDG excretion. Metformin-treated individuals excrete a significant amount of glucose (~1.65 g h-1 per body) into the intestinal lumen. In individuals not receiving metformin, a certain amount of glucose (~0.41 g h-1per body) is also excreted into the intestinal lumen, indicating its physiological importance. Intravenous injection of 13C-labeled glucose in mice increases the content of 13C in short-chain fatty acids (SCFAs) extracted from feces, and metformin increased the incorporation of 13C into SCFAs.

A previously unrecognized, substantial flux of glucose from the circulation to the intestinal lumen exists, which likely contributes to the symbiosis between gut microbiota and the host. This flux represents a potential target of metformin's action in humans.

Thyroid hormones (THs) are important modulators of many metabolic processes, being strictly associated with the control of energy balance, mainly through activities on the brain, white and brown adipose tissue, skeletal muscle, liver, and pancreas. In this review, the principal mechanisms of TH regulation on metabolic processes will be discussed and THs' relevance in metabolic disease progression will be evaluated, especially in the cardiovascular context and correlated diseases. Moreover, we will discuss THs' regulatory role on metabolic events in white and brown adipose tissue, with a special focus on the process of "browning", which consists of the gradual acquisition by white adipocytes of the physical and functional characteristics of brown adipocytes. The advancements in research on molecular mechanisms and proposed physiopathological relevance of this process will be discussed.

Brown adipose tissue (BAT), located in the supraclavicular region, has been associated with a better cardiometabolic profile and reduced risk of developing non-communicable chronic diseases (NCD), in addition to being associated with a healthier phenotype in obesity. However, it is unknown whether greater supraclavicular adipose tissue activity could be associated with a healthier metabolic profile in people already diagnosed with type 2 diabetes (T2DM). Thus, the present work evaluated if supraclavicular adipose tissue activity is associated with metabolic and molecular markers in individuals with T2DM.

Based on a cluster study, individuals with T2DM were divided into groups according to high or low-standard uptake value (SUV) evaluated in the supraclavicular adipose tissue area by [18F]-fluorodeoxyglucose and positron emission tomography-computed tomography (18F-FDG-PET/CT) after mild cold exposure). Functional, biochemical, inflammatory, and molecular markers were measured.

When we evaluated the whole sample, women showed higher SUV, which favored a difference between groups in sex-related markers. On the other hand, volunteers in the high-SUV group showed lower BMI, monocytes count, triglycerides/glucose index (TYG-index) and z score of metabolic syndrome (MS) values, as well as lower triglycerides, and VLDL concentrations. Moreover, they also had enhanced expression of thermogenic genes in subcutaneous fat. When analyzing only women, the differences in markers associated with sex disappear, and a lower count of leukocytes, platelets, along with lower TYG-index, z score of MS values, and triglycerides, VLDL, LDL, and TNFα concentrations were observed in women with the high SUV. In addition, higher expression of thermogenic genes and BECN1 were detected.

Higher supraclavicular adipose tissue SUV in individuals with T2DM is associated with a better cardiometabolic/inflammatory profile and expression of thermogenic genes.

UTN: U1111-1202-1476 - 08/20/2020.

The thermogenesis of brown adipose tissue (BAT) is interesting because the contribution to human adaptation to cold and obesity resistance has been suggested. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a common method for measuring BAT activity; however, it has been studied in few large cohorts due to concerns about safety and cost. Studies using alternative methods make it challenging to directly compare BAT activity among studies and interpret those results because the procedure is various. We measured the supraclavicular BAT thermogenesis of 122 healthy Japanese and Chinese adults under mild cold stress using standardized infrared thermography (IRT) and examined the effects of various factors on BAT variation. BAT thermogenesis was significantly higher in females than in males (p < 0.001) and significantly higher in Chinese than in Japanese individuals (p < 0.05). Among the 27 participants enrolled in both summer and winter experiments, BAT thermogenesis increased during winter (p < 0.05) only in Japanese participants. Additionally, individuals born at higher latitudes exhibited greater BAT thermogenesis (p < 0.05), suggesting the involvement of genetic background or cold exposure in early life stages. We obtained interesting anthropological and physiological findings with the use of non-invasive IRT.

The ongoing increase in the prevalence of obesity and its comorbidities such as cardiovascular disease, type 2 diabetes (T2D) and dyslipidemia warrants discovery of novel therapeutic options for these metabolic diseases. Obesity is characterized by white adipose tissue expansion due to chronic positive energy balance as a result of excessive energy intake and/or reduced energy expenditure. Despite various efforts to prevent or reduce obesity including lifestyle and behavioral interventions, surgical weight reduction approaches and pharmacological methods, there has been limited success in significantly reducing obesity prevalence. Recent research has shown that thermogenic adipocyte (brown and beige) activation or formation, respectively, could potentially act as a therapeutic strategy to ameliorate obesity and its related disorders. This can be achieved through the ability of these thermogenic cells to enhance energy expenditure and regulate circulating levels of glucose and lipids. Thus, unraveling the molecular mechanisms behind the formation and activation of brown and beige adipocytes holds the potential for probable therapeutic paths to combat obesity. In this review, we provide a comprehensive update on the development and regulation of different adipose tissue types. We also emphasize recent interventions in harnessing therapeutic potential of thermogenic adipocytes by bioactive compounds and new pharmacological anti-obesity agents.

Triglyceride-rich lipoproteins carry lipids in the bloodstream, where the fatty acid moieties are liberated by lipoprotein lipase (LPL) and taken up by peripheral tissues such as brown adipose tissue (BAT) and white adipose tissue (WAT), whereas the remaining cholesterol-rich remnant particles are cleared mainly by the liver. Elevated triglyceride (TG) levels and prolonged circulation of cholesterol-rich remnants are risk factors for cardiovascular diseases. Acute cold exposure decreases postprandial TG levels and is a potential therapeutic approach to treat hypertriglyceridemia. However, how acute cold exposure regulates TG metabolism remains incompletely understood. In the current study, we found that acute cold exposure simultaneously increases postprandial very-low-density lipoprotein production and TG clearance, with the latter playing a dominant role and resulting in decreased TG levels. Acute cold exposure increases LPL activity and TG uptake in BAT, while suppressing LPL activity and TG uptake in WAT. Mechanistically, acute cold exposure increases BAT LPL activity through transcriptional upregulation of Lpl and posttranscriptional regulation via inhibiting the hepatic insulin-ANGPTL8-ANGPTL3 axis, while suppressing WAT LPL activity through upregulation of ANGPTL4. Angptl8 knockout mice have dramatically decreased levels of circulating TG. In the absence of ANGPTL8, acute cold exposure increases rather than decreases circulating TG levels. Thus, our study reveals multilayered regulation of acute cold response and postprandial TG metabolism, highlighting the key functions of ANGPTL3, 4, and 8 in response to acute cold exposure.

Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors (Sox4-MKO) or brown adipocytes (Sox4-BKO) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.

Given the potential role of brown adipose tissue (BAT) in stimulating energy expenditure, activating BAT can be an effective anti-obesity treatment. Here, we aimed to use adenoviruses to establish the effect of the inducible degrader of the low density lipoprotein receptor (IDOL) in the formation of BAT.

IDOL or green fluorescent protein was overexpressed by adenovirus and injected into the scapula of C57BL/6J mice and fed with high-fat diet for 12 weeks. We measured the body weight, morphology of lipid droplets, lipid profiles and adipogenesis protein expression levels. BAT was isolated, and RNA sequencing was performed to identify the differentially expressed genes and related signaling pathways. Finally, we conducted western blot to verify the authenticity and reliability of the RNA sequencing results.

Compared with the control group, IDOL overexpression led to a significant reduction in body weight, consistent with the weight of adipose tissues and organs. Further studies show IDOL promotion increased ATGL, perilipin 1 and UCP-1 expression in BAT. However, perilipin 1 protein expression was significantly reduced in the Ad-IDOL group in epididymal white adipose tissue, while there was no significant difference in adiponectin, ATGL and perilipin 1 protein expression in inguinal white adipose tissue. Notably, serum FGF21 and leptin protein expression were negatively related to the adipose tissue decrease after Ad-IDOL administration. RNA sequencing analysis identified 1256 differentially expressed genes that were prominently enriched across nine signalling pathways. Additionally, the protein expression of PGAM2, G6PC1 and phosphorylation-AMPK was significantly increased after overexpression IDOL in BAT, which was consistent with the results of the RNA sequencing analysis.

Our research demonstrated that IDOL overexpression alleviates the body weight by promoting the phosphorylation of AMPK to upregulate the UCP-1 and ATGL exacerbating lipolysis in BAT.

Polystyrene nanoplastics (PSNPs) have been recognized as emerging environmental pollutants with potential health impacts, particularly on metabolic disorders. However, the mechanism by which gestational exposure to PSNPs induces obesity in offspring remains unclear. This study, focused on the whitening of brown adipose tissue (BAT), aims to elucidate the fundamental mechanisms by which prenatal exposure to PSNPs promotes obesity development in mouse offspring.

Pregnant dams were subjected to various doses of PSNPs (0 µg/µL, 0.5 µg/µL, and 1 µg/µL), and their offspring were analyzed for alterations in body weight, adipose tissue morphology, thermogenesis, adipogenesis, and lipophagy. The findings revealed a notable reduction in birth weight and an increase in white adipocyte size in adult offspring mice. Notably, adult male mice exhibited BAT whitening, correlated with a negative dose-dependent downregulation of UCP1 expression, indicating thermogenesis dysfunction. Further investigation revealed augmented lipogenesis evidenced by the upregulation of FASN, SREBP-1c, CD36, and DGAT2 expression, coupled with the inhibition of lipophagy, indicated by elevated levels of mTOR, AKT, and p62 proteins and reduced levels of LC3II/LCI and Lamp2 proteins in male offspring.

These findings indicate that gestational PSNP exposure plays a role in the development of obesity in offspring through the whitening of brown adipose tissue, which is triggered by lipogenesis and lipophagy inhibition, providing a novel insight into the metabolic risks associated with gestational PSNPs exposure.

Total metabolic tumor volume (TMTV) at baseline becomes a key biomarker in several lymphoma subtypes. Variability in segmentation methods such as 41%SUVmax and SUVmax > 4 has limited its clinical application. Additionally, immune-checkpoint-inhibitors introduced challenges in response assessment due to pseudoprogression, complicating the use of traditional metrics. This study investigates the prognostic impact of baseline- and residual-TMTV and introduces a novel personalized-liver-based-threshold (pTMTVliver) to enhance precision in patient stratification.

We analyzed 91 patients with relapsed/refractory diffuse-large-B-cell lymphoma and follicular lymphoma from the GATA trial, comparing patient's outcome according to three segmentation methods: TMTV41%, TMTV4, and pTMTVliver. pTMTVliver used a threshold of 200%SUVmeanliver aligning with 125%SUVmaxliver to enhance standardization and reduce variability.

Baseline-TMTV significantly influenced prognosis with higher TMTV correlating with shorter PFS and OS (p < 0.0001 for all methods). Residual-TMTV, particularly with pTMTVliver and TMTV4, stratified no-CMR patients with the lowest predictive errors and better predictive accuracy compared to TMTV41% Multivariate analyses confirmed residual-pTMTVliver as superior for prognostic performance for PFS (HR:5.10; C-index:0.724) and OS (HR:4.00; C-index:0.853) compared to TMTV4 and Deauville Score (DS). The DS alone did not fully capture the heterogeneity of outcomes of DS4-5 patients.

Baseline- and residual-TMTV strongly influence prognosis and response in lymphoma patients. The novel personalized pTMTVliver method offers improved accuracy of patient stratification, particularly for those with DS4-5, providing more reliable risk assessment. Larger cohorts are needed to validate these findings and optimize residual-TMTV-based clinical applications.

Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4's critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.

Brown adipose tissue (BAT) thermogenesis dissipates energy through heat production and thereby it opposes metabolic disease. It is mediated by mitochondrial membrane uncoupling, yet the mechanisms sustaining the mitochondrial membrane potential (ΔΨm) in brown adipocytes are poorly understood. Here we show that isocitrate dehydrogenase (IDH) activity and the expression of the soluble adenylate cyclase 10 (ADCY10), a CO2/bicarbonate sensor residing in mitochondria, are upregulated in BAT of cold-exposed mice. IDH inhibition or ADCY10 deficiency reduces cold resistance of mice. Mechanistically, IDH increases the ΔΨm in brown adipocytes via ADCY10. ADCY10 sustains complex I activity and the ΔΨm via exchange protein activated by cAMP1 (EPAC1). However, neither IDH nor ADCY10 inhibition affect uncoupling protein 1 (UCP1) expression. Hence, we suggest that ADCY10, acting as a CO2/bicarbonate sensor, mediates the effect of IDH on complex I activity through cAMP-EPAC1 signaling, thereby maintaining the ΔΨm and enabling thermogenesis in brown adipocytes.

Overweight patients with cardiovascular disease (CVD) tend to survive longer than normal-weight patients, a phenomenon known as the "obesity paradox". The phenotypic characteristics of adipose distribution in these patients (who survive longer) often reveal a larger proportion of subcutaneous white adipose tissue (scWAT), suggesting that the presence of scWAT is negatively associated with all-cause mortality and that scWAT appears to provide protective benefits in patients facing unhealthy states. Exercise-mediated browning is a crucial aspect of the benign remodeling process of adipose tissue (AT). Reduced accumulation, reduced inflammation, and associated adipokine secretion are directly related to the reduction in CVD mortality. This paper summarized the pathogenetic factors associated with AT accumulation in patients with CVD and analyzed the possible role and pathway of exercise-mediated adipose browning in reducing the risk of CVD and CVD-related mortality. It is suggested that exercise-mediated browning may provide a new perspective on the "obesity paradox"; that is, overweight CVD patients who have more scWAT may gain greater cardiovascular health benefits through exercise.

This review aims to update our understanding of human cold adaptation. First, an overview of the thermoregulatory response to cold is provided, with some recent updates in human brown adipose tissue (BAT). Variation in BAT activity and multiorgan contributions to cold-induced thermogenesis were introduced. We found that individuals with less BAT activity rely more on shivering to compensate for less non-shivering thermogenesis (NST). The mechanisms of cold-induced vasoconstriction are summarized, including the role of arteriovenous anastomoses, adrenergic neural function, and inhibition of the nitric oxide vasodilator pathway. In addition, cold-induced vasodilation (CIVD) during cold immersion of the distal extremities is summarized with some recent updates in physiological mechanism. Furthermore, the cold shock response at the onset of cold immersion is introduced. Next, categorization of cold acclimatization/acclimation into habituation of shivering and metabolic and insulative adaptation are provided, with some recent updates. Especially, the rediscovery of human BAT has clarified metabolic acclimation, where increased NST replace shivering. Then, a greater CIVD response in populations in cold regions has been reported, whereas recent laboratory studies suggest no increase in CIVD after repeated cold exposure. To prevent cold injuries, individuals should not rely on habituation through repeated cold exposure. In addition, habituation to the cold shock response after repeated cold water immersion could help reduce the number of drownings. Furthermore, cross-adaptation between cold and nonthermal factors in the thermoregulatory response is summarized. Recent studies explored the relationship between exercise training and BAT activity, although this remains unresolved, depending on the exercise intensity and environmental conditions. The effects of exercise with cold exposure on the thermoregulatory response to cold are summarized in studies including divers working in cold water. We investigated the effect of exercise training in cold water, which resulted in increased muscle deoxygenation during submaximal exercise and greater anerobic power. Moreover, the effects of a hypoxic environment on cold adaptation are summarized. Elevated basal metabolism and higher distal skin temperature in highlanders could improve their cold tolerance. Finally, factors affecting cold adaptation are discussed. The type of cold adaptation may depend on the specific thermoregulatory responses repeated during the adaptation process.

Sepsis is a leading cause of death, with the liver being particularly vulnerable to sepsis-related injuries. This damage significantly contributes to disease progression, underscoring the need for new treatments. Brown adipose tissue (BAT) secretes various cytokines, including neuregulin 4 (Nrg4), which plays a protective role in hepatic glucose and lipid metabolism. Ferroptosis, a key type of cell death in sepsis-induced liver injury, has recently gained attention. This study aimed to investigate how BAT-secreted cytokines alleviate liver ferroptosis in sepsis. Septic liver injury was induced in the control and BAT group using cecal ligation and puncture (CLP) and lipopolysaccharide injections. BAT removal worsened ferroptosis; in contrast, CL316243 activation reduced it. These findings suggest that Nrg4 secretion following BAT activation protects the liver during sepsis by inhibiting ferroptosis. Future therapies targeting BAT activation and Nrg4 could potentially mitigate sepsis-induced liver damage, offering new insights into treatment strategies.

Thermogenic adipocytes are able to dissipate energy as heat from lipids and carbohydrates through enhanced uncoupled respiration, due to UCP1 activity. PPAR family of transcription factors plays an important role in adipocyte biology. The purpose of this work was to characterize the role of PPARα and pemafibrate in the control of thermogenic adipocyte formation and function.

We used human multipotent adipose-derived stem cells and primary cultures of stroma-vascular fraction cells, transfected with siRNA against PPARα, differentiated into white or beige adipocytes, by the treatment of rosiglitazone or pemafibrate. The expression of key marker genes of adipogenesis and thermogenesis was determined using RT-qPCR and Western blotting. An RNAseq analysis was also performed.

We show that inhibition of PPARα mRNA increases UCP1 mRNA and protein expression in beige adipocytes induced by rosiglitazone. Knock-down of PPARα also increases stimulated glycerol release. Pemafibrate, described as a selective PPARα modulator, induces adipogenesis and the expression of UCP1 in the absence of PPARα expression. These effects are inhibited by a specific PPARγ antagonist highly suggesting that the pemafibrate effects in adipogenesis and beiging were mediated by PPARγ.

Conversion of white into thermogenic adipocytes is mainly due to the activation of PPARγ. Moreover, we show that PPARα seems to act as a hindrance for PPARγ-dependent beiging. Our data question the role of PPARα in human adipocyte browning and the specificity of pemafibrate in adipocytes.

Obesity leads to the development of several diseases and chronic death worldwide. Mitochondrial dysfunction is one of the vital causes to develop obesity. Targeting mitochondrial uncoupling protein 1 (UCP1) may well be a potential therapeutic approach against obesity or mitochondrial dysfunction-related illnesses. To assess the significance of mitochondrial adenosine triphosphate (ATP) synthesis, mitochondrial DNA quantity and in vitro pharmacodynamics and pharmacokinetics, we used CX-6258 HCl (pan-Pim kinase inhibitor) in this work. CX-6258 HCl significantly reduces ATP production both in white and brown adipocytes and, therefore, improves thermogenesis, which helps to reduce fat in adipocytes. On the HEK293T cell line, no appreciable cell growth was seen. The in silico analysis identifies a potential interaction between CX-6258 HCl and the UCP1 protein. To treat disorders linked to mitochondrial dysfunction or obesity, CX-6258 HCl may be a promising therapeutic option. The role of pan-Pim kinase inhibitor on obesity and mitochondrial dysfunction-related disorders remains unknown. Further investigation will be leading to the development of the mechanism of action and therapeutic potential of CX-6258 HCl (pan-Pim kinase inhibitor).

Emerging evidence has demonstrated the unfavourable cardiovascular risk of individuals with lean type 2 diabetes mellitus (T2DM). Our study aims to investigate the prognostic value of lean T2DM in patients with acute myocardial infarction (AMI), stratified by sex.

The study cohort examines the clinical characteristics and long-term outcomes of individuals with AMI, stratified by four phenotypes based on T2DM and lean body category-lean T2DM, non-lean T2DM, lean non-T2DM and non-lean non-T2DM. The primary outcome was long-term all-cause mortality. Cox regression model was constructed to investigate the associations of lean and non-lean T2DM phenotypes with mortality, adjusted for age, ethnicity, previous AMI, AMI type, chronic kidney disease, angiotensin converting enzyme inhibitor or angiotensin receptor blockers, beta-blockers, and smoking status.

A cohort of 9545 AMI patients was examined, with a mean follow-up duration of 3.4 ± 2.4 years. Majority had the non-lean T2DM phenotype (40.4%), followed by non-lean non-T2DM (29.8%), lean non-T2DM (15.9%), and lean T2DM (13.9%). In the T2DM group, one-quarter was lean (N = 1324), while the vast majority (74.5%) was non-lean. Individuals with lean T2DM tended to be female and older. Patients with lean T2DM had the highest rates of heart failure (23.3%, p < 0.001), cardiogenic shock (9.1%, p = 0.036), and long-term all-cause mortality (32.6%, p < 0.001). Cox regression demonstrated that lean T2DM was an independent predictor of mortality (adjusted hazard ratio [aHR] 1.171, 95% CI 1.040-1.319, p = 0.009) after adjustment. The presence of higher mortality risk following AMI was present in males (aHR 1.201, 95% CI 1.037-1.391, p = 0.015), but not in females (aHR 1.066, 95% CI 0.869-1.308, p = 0.538).

The lean T2DM phenotype was present in one-quarter of the AMI cohort with T2DM. The lean T2DM phenotype was an independent predictor of long-term mortality following AMI, although this association was stronger in males than in females.

Obesity has become a global pandemic. The approaches researched to prevent it include decreasing energy intake and/or enhancing energy expenditure. Therefore, research on brown adipose tissue is of great importance. Brown adipose tissue is characterized by its high mitochondrial content. Mitochondrial uncoupling protein 1 (UCP1) releases energy as heat instead of chemical energy. Thermogenesis increases energy expenditure. Berberine, a phytochemical widely used in Asian countries, has positive effects on body weight control. While the precise mechanisms behind this effect remain unclear, the adenosine monophosphate-activated protein kinase (AMPK) pathway is known to play a crucial role. Berberine activates AMPK through phosphorylation, significantly impacting brown adipose tissue by enhancing lipolytic activity and increasing the expression of UCP1, peroxisome proliferator-activated receptor γ-co-activator-1α (PGC1α), and PR domain containing 16 (PRDM16). While investigating the mechanism of action of berberine, both the AMPK pathway is being examined in more detail and alternative pathways are being explored. One such pathway is growth differentiation factor 15 (GDF15), known for its appetite-suppressing effect. Berberine's low stability and bioavailability, which are the main obstacles to its clinical use, have been improved through the development of nanotechnological methods. This review examines the potential mechanisms of berberine on browning and summarizes the methods developed to enhance its effect.

Obesity, a global epidemic, is a major risk factor for chronic diseases such as type 2 diabetes, cardiovascular disorders, and metabolic syndrome. Adipose tissue, once viewed as a passive fat storage site, is now recognized as an active endocrine organ involved in metabolic regulation and inflammation. In obesity, adipose tissue dysfunction disrupts metabolic balance, leading to insulin resistance and increased production of adipose-derived extracellular vesicles (AdEVs). These vesicles play a key role in intercellular communication and contribute to metabolic dysregulation, affecting organs such as the heart, liver, and brain. AdEVs carry bioactive molecules, including microRNAs, which influence inflammation, insulin sensitivity, and tissue remodeling. In the cardiovascular system, AdEVs can promote atherosclerosis and vascular dysfunction, while those derived from brown adipose tissue offer cardioprotective effects. In type 2 diabetes, AdEVs exacerbate insulin resistance and contribute to complications such as diabetic cardiomyopathy and cognitive decline. Additionally, AdEVs are implicated in metabolic liver diseases, including fatty liver disease, by transferring inflammatory molecules and lipotoxic microRNAs to hepatocytes. These findings highlight the role of AdEVs in obesity-related metabolic disorders and their promise as therapeutic targets for related diseases.