Some adipose-related parameters exhibit distinct prognostic value in patients with cirrhosis. However, the magnitude and direction of the association between individual adipose parameter and mortality in patients with cirrhosis are unclear.

This study aimed to evaluate the association between individual adipose parameter and mortality in patients with cirrhosis using the meta-analysis method.

The PubMed, Embase, Web of Science, China Biological Medicine, WanFang, and China National Knowledge Infrastructure databases were searched from inception through December 15, 2023, to identify eligible studies. The impact of each adipose parameter on mortality was assessed by the pooled unadjusted or adjusted hazard ratio (HR) with 95% confidence intervals (CIs) using the random effects model.

A total of 33 studies involving 9626 patients were included in our analysis, with 11 adipose parameters evaluated. The pooled prevalence of sarcopenic obesity (SO) and myosteatosis in patients with cirrhosis was 15.5% and 34.4%, respectively. In adjusted analysis, each unit increase in subcutaneous adipose tissue index (SATI) (HR: 0.99, 95% CI: 0.98-1.00) or muscle attenuation (MA) (HR: 0.94, 95% CI: 0.90-0.98) and each unit decrease in visceral-to-subcutaneous adipose tissue ratio (VSR) (HR: 1.92, 95% CI: 1.45-2.54) showed an independent association with a decreased risk of mortality. However, concurrent myosteatosis (HR: 1.88, 95% CI: 1.48-2.40) or SO (HR: 2.77, 95% CI: 1.95-3.93) significantly increased the risk of mortality in patients with cirrhosis.

Decreased SATI or MA, increased VSR, and concurrent myosteatosis or SO were independently associated with a higher risk of mortality in patients with cirrhosis.

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.

Participants followed a 7-day controlled diet and on day 4 underwent 1H-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.

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.

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.

Most aspects of physiology and behaviour fluctuate every 24 h in mammals. These circadian rhythms are orchestrated by an autonomous central clock located in the suprachiasmatic nuclei that coordinates the timing of cellular clocks in tissues throughout the body. The critical role of this circadian system is emphasized by increasing evidence associating disruption of circadian rhythms with diverse pathologies. Accordingly, mounting evidence suggests a bidirectional relationship where disruption of rhythms by circadian misalignment may contribute to liver diseases while liver diseases alter the central clock and circadian rhythms in other tissues. Therefore, liver pathophysiology may broadly impact the circadian system and may provide a mechanistic framework for understanding and targeting metabolic diseases and adjust metabolic setpoints.

Background and Objectives: Type 2 diabetes (T2D) and prediabetes represent major global health concerns, with obesity being a key risk factor. However, recent evidence suggests that the adipose tissue composition and distribution play a more critical role in metabolic dysfunction than the total body weight or body mass index (BMI). This study evaluates the predictive capacity of the Córdoba Equation for Estimating Body Fat (ECORE-BF) for identifying individuals at high risk of developing T2D and prediabetes. Materials and Methods: A cross-sectional study was carried out involving 418,343 Spanish workers. Body fat percentage was estimated using the ECORE-BF equation, and diabetes risk was assessed using validated predictive models, including the Finnish Diabetes Risk Score (FINDRISC), QDiabetes score (QD-score), and others. The discriminatory power of ECORE-BF in predicting T2D and prediabetes was assessed using receiver operating characteristic (ROC) curve analysis. Results: ECORE-BF showed a strong correlation with high-risk classifications across all diabetes risk scales. The area under the ROC curve (AUC) exceeded 0.95 for both men and women, demonstrating high predictive accuracy. Conclusions: Adipose tissue distribution, particularly visceral adiposity, is a central factor in metabolic dysfunction. ECORE-BF provides a cost-effective alternative for large-scale T2D and prediabetes risk assessment. Future research should explore the impact of visceral adipose tissue reduction on diabetes prevention and the integration of estimation scales into clinical and public health strategies.

Given that cardiovascular events induced by metabolic disorders are the leading cause of death in nonalcoholic fatty liver disease (NAFLD), this study aimed to explore the heterogeneity of cardiometabolic and liver fibrosis risks among lean, overweight, and obese NAFLD individuals.

A multicenter cross-sectional study was conducted across three hospitals in Pudong from July 2022 to June 2023. Health checkup data were obtained and stratified by BMI categories. Multivariable logistic regression was performed to analyze the association between NAFLD and risk factors for cardiometabolic diseases and liver fibrosis across different BMI categories.

The study included 37,122 patients, with 25.25% diagnosed with NAFLD. Over 97% of these patients met the criteria for metabolic dysfunction-associated fatty liver disease. NAFLD detection rates were 7.72% in lean, 33.99% in overweight, and 63.56% in obese individuals. Non-obese patients had significantly lower cardiometabolic disease prevalence than obese patients (P < 0.001). All NAFLD subtypes, except lean NAFLD (negatively associated with total cholesterol) and obese NAFLD (no significant association with total triglycerides), were linked to other cardiometabolic or liver fibrosis risk factors (P < 0.05). Additioinally, only obese NAFLD demonstrated a negative correlation with age.

Non-obese NAFLD, despite a relatively better metabolic profile than obese NAFLD, still poses significant cardiometabolic and fibrosis risks. Interventions targeting cardiovascular events and liver disease progression are essential for all NAFLD subtypes, customized to their metabolic characteristics. The detection rates in this study provide a valuable reference for estimating local NAFLD prevalence.

Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro. Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8HKO) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.

Studies have proposed that probiotic intake may ameliorate some of the clinical components of metabolic syndrome (MetS). This study aimed to determine the effects of a new developed synbiotic yogurt containing Lactobacillus plantarum, Lactobacillus pentosus, and Chloromyces marcosianos yeast on the components of MetS in adults with MetS.

In this randomized, placebo-controlled, clinical trial, 44 participants were divided into two groups to receive 300 grams of synbiotic yogurt or regular yogurt daily for 12 weeks. Anthropometric measurements, blood pressure, and biochemical parameters evaluated before and after the intervention.

Daily consumption of synbiotic yogurt containing L. plantarum, L. pentosus, and C. marcosianos yeast in adults with MetS caused a significant decrease in the levels of fasting blood glucose (FBG) (p = 0.005), fasting insulin (p = 0.001), homeostatic model assessment for insulin resistance (HOMA-IR) index (p < 0.001), waist to hip ratio (WHR) (p = 0.02) and systolic blood pressure (p = 0.008) in the intervention group compared to the control group.

According to the findings of this study, daily consumption of the synbiotic yogurt was associated with improvements in insulin resistance, systolic blood pressure and WHR, which could be beneficial in patients with MetS.

Obesity is a significant risk factor for the progression of non-alcoholic fatty liver disease (NAFLD). However, a convenient and efficacious non-invasive test for monitoring NAFLD progression in patients with obesity is currently lacking. This study aims to investigate the associations between CT-based body composition and the progression of biopsy-proven NAFLD in patients with obesity.

Liver biopsy was conducted in patients with obesity, and the progression of NAFLD was evaluated by the NAFLD activity score (NAS). Body composition was assessed through abdominal computed tomography (CT) scans.

A total of 602 patients with an average age of 31.65 (±9.33) years old were included, comprising 217 male patients and 385 female patients. The wall skeletal muscle index (SMI), total SMI, and visceral fat index (VFI) were positively correlated with NAS in both male and female patients. Multivariate regression analysis demonstrated significant associations between high liver steatosis and wall SMI (HR: 1.60, 95% CI: 1.12 to 2.30), total SMI (HR: 1.50, 95% CI: 1.02 to 2.08), VSI (HR: 2.16, 95% CI: 1.48 to 3.14), visceral fat to muscle ratio (HR: 1.51, 95% CI: 1.05 to 2.18), and visceral to subcutaneous fat ratio (HR: 1.51, 95% CI: 1.07 to 2.12). Non-alcoholic steatohepatitis (NASH) was significantly associated with wall SMI (HR: 1.52, 95% CI: 1.06 to 2.19) and VSI (HR: 1.50, 95% CI: 1.03 to 2.17). Liver fibrosis ≥ F2 was significantly associated with psoas muscle index (HR: 0.64, 95% CI: 0.44 to 0.93) and psoas skeletal muscle density (HR: 0.61, 95% CI: 0.41 to 0.89).

Our study suggested that certain CT-based body composition indicators, notably high VFI, were significantly associated with the progression of NAFLD in patients with obesity. Great attentions and timely managements should be given to these patients with body composition characteristics associated with the risk of NAFLD progression.

Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.

The metabolic syndrome (MetS) is a multiplex modifiable risk factor for cardiovascular disease, type 2 diabetes mellitus and other health outcomes, and is a major challenge to clinical practice and public health. The rising global prevalence of MetS, driven by urbanization, sedentary lifestyles and dietary changes, underlines the urgency of addressing this syndrome. We explore the complex underlying mechanisms, including genetic predisposition, insulin resistance, accumulation of dysfunctional adipose tissue and ectopic lipids in abdominal obesity, systemic inflammation and dyslipidaemia, and how they contribute to the clinical manifestations of MetS. Diagnostic approaches vary but commonly focus on abdominal obesity (assessed using waist circumference), hyperglycaemia, dyslipidaemia and hypertension, highlighting the need for population-specific and phenotype-specific diagnostic strategies. Management of MetS prioritizes lifestyle modifications, such as healthy dietary patterns, physical activity and management of excess visceral and ectopic adiposity, as foundational interventions. We also discuss emerging therapies, including new pharmacological treatments and surgical options, providing a forward-looking perspective on MetS research and care. This Primer aims to inform clinicians, researchers and policymakers about MetS complexities, advocating for a cohesive, patient-centred management and prevention strategy. Emphasizing the multifactorial nature of MetS, this Primer calls for integrated public health efforts, personalized care and innovative research to address this escalating health issue.

Non-alcoholic fatty liver disease (NAFLD) is present in lean people. However, the magnitude of the prognostic hepatic and cardiovascular risk in these patients compared to non-lean counterparts remains unclear. We aimed to investigate this topic, and to explore whether these risks change based on factors related to NAFLD severity.

PubMed and Embase databases were searched for cohort studies (published through April 2024) that evaluated liver and cardiovascular (CV) outcomes in lean and non-lean individuals with NAFLD and reported unadjusted or adjusted data. We pooled risk ratios (RRs) or hazard ratios (HRs) using a random-effects modeling and performed subgroup and meta-regressions analyses.

We identified 22 studies with over 1 million NAFLD patients (13.0% were lean). Lean NAFLD showed a similar risk of liver-related events in unadjusted analysis (RR 1.08, 95% CI 0.79-1.49, I2 = 31%), but a higher risk in adjusted analysis (HR 1.66, 95% CI 1.17-2.36, I2 = 83%) compared to non-lean NAFLD. Lean NAFLD had a higher risk of liver-related mortality (RR 2.22, 95% CI 1.57-3.15, I2 = 0%; HR 2.26, 95% CI 1.14-4.51, I2 = 0%). For CV outcomes, lean NAFLD had a lower risk of any cardiovascular disease in unadjusted analysis (RR = 0.82, 95% CI 0.70-0.95, I2 = 88%), but similar risk in adjusted analysis (HR 0.89, 95% CI 0.77-1.02, I2 = 78%), and similar risk of cardiovascular mortality (RR 1.09, 95% CI 0.71-1.66, I2 = 85%; HR 1.26, 95% CI 0.89-1.78, I2 = 46%) compared to non-lean NAFLD.

Lean NAFLD patients have worse liver outcomes, but similar CV outcomes compared to non-lean NAFLD patients, highlighting the importance of monitoring both groups closely.

The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults.

Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated.

A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05).

There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention.

Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic β-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.

Epidemiologic findings suggest that measures of body fat distribution predict health outcomes independent of the overall body fat assessed by body mass index (BMI). This study aimed to evaluate the associations of overall and regional body fat with the severity of hepatic steatosis and fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease.

Bioelectric impedance analysis and two newly developed anthropometric indices, namely, A Body Shape Index (ABSI) and Body Roundness Index (BRI), were used to estimate the body fat. Based on fibroscan parameters, significant hepatic fibrosis and severe steatosis were defined as ≥F2 and >66%, respectively.

Higher total body fat (odds ratio [OR] 1.107, 95% confidence intervals (CI) 1.038-1.182, p = 0.002), trunk fat (OR 1.136, 95% CI 1.034-1.248, p = 0.008) and leg fat (OR 1.381, 95% CI 1.139-1.674, p = 0.001) were associated with liver fibrosis. However, in contrast to the total body fat (OR 1.088, 95% CI 1.017-1.164, p = 0.014) and leg fat (OR 1.317, 95% CI 1.066-1.628, p = 0.011), the trunk fat was not associated with severe hepatic steatosis. BRI performed better than trunk, leg and total body fat in predicting hepatic steatosis (OR 2.186, 95% CI 1.370-3.487, p = 0.001) and fibrosis (OR 2.132, 95% CI 1.419-3.204, p < 0.001). Moreover, the trunk to leg fat ratio and ABSI were not independent predictors of either steatosis or fibrosis (p > 0.05).

BRI revealed a superior predictive ability for identifying the degree of hepatic steatosis and stiffness than other obesity indices. Additionally, higher levels of adiposity in the trunk, legs, and overall body were linked to an increased risk of developing liver fibrosis. Although trunk fat did not show an association with severe hepatic steatosis, an increase in leg and total fat was related to liver steatosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) closely associates with obesity and type 2 diabetes. Lifestyle intervention and bariatric surgery aiming at substantial weight loss are cornerstones of MASLD treatment by improving histological outcomes and reducing risks of comorbidities. Originally developed as antihyperglycemic drugs, incretin (co-)agonists and SGLT2 inhibitors also reduce steatosis and cardiorenovascular events. Certain incretin agonists effectively improve histological features of MASLD, but not fibrosis. Of note, beneficial effects on MASLD may not necessarily require weight loss. Despite moderate weight gain, one PPARγ agonist improved adipose tissue and MASLD with certain benefit on fibrosis in post-hoc analyses. Likewise, the first THRβ-agonist was recently provisionally approved because of significant improvements of MASLD and fibrosis. We here discuss liver-related and metabolic effects induced by different MASLD treatments and their association with weight loss. Therefore, we compare results from clinical trials on drugs acting via weight loss (incretin (co)agonists, SGLT2 inhibitors) with those exerting no weight loss (pioglitazone; resmetirom). Furthermore, other drugs in development directly targeting hepatic lipid metabolism (lipogenesis inhibitors, FGF21 analogs) are addressed. Although THRβ-agonism may effectively improve hepatic outcomes, MASLD treatment concepts should consider all cardiometabolic risk factors for effective reduction of morbidity and mortality in the affected people.

With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) as a significant etiology for hepatocellular carcinoma (HCC), lean NAFLD-HCC has emerged as a specific distinct subtype. This study sought to investigate long-term outcomes following curative-intent hepatectomy for early-stage NAFLD-HCC among lean patients compared with overweight and obese individuals.

A multicenter retrospective analysis was used to assess early-stage NAFLD-HCC patients undergoing curative-intent hepatectomy between 2009 and 2022. Patients were stratified by preoperative body mass index (BMI) into the lean (<23.0 kg/m2), overweight (23.0-27.4 kg/m2) and obese (≥27.5 kg/m2) groups. Study endpoints were overall survival (OS) and recurrence-free survival (RFS), which were compared among groups.

Among 309 patients with NAFLD-HCC, 66 (21.3 %), 176 (57.0 %), and 67 (21.7 %) were lean, overweight, and obese, respectively. The three groups were similar relative to most liver, tumor, and surgery-related variables. Compared with overweight patients (71.3 % and 55.6 %), the lean individuals had a worse 5-year OS and RFS (55.4 % and 35.1 %, P = 0.017 and 0.002, respectively), which were comparable to obese patients (48.5 % and 38.2 %, P = 0.939 and 0.442, respectively). After adjustment for confounding factors, multivariable Cox-regression analysis identified that lean bodyweight was independently associated with decreased OS (hazard ratio: 1.69; 95 % confidence interval: 1.06-2.71; P = 0.029) and RFS (hazard ratio: 1.72; 95 % confidence interval: 1.17-2.52; P = 0.006) following curative-intent hepatectomy for early-stage NAFLD-HCC.

Compared with overweight patients, individuals with lean NAFLD-HCC had inferior long-term oncological survival after hepatectomy for early-stage NAFLD-HCC. These data highlight the need for examination of the distinct carcinogenic pathways of lean NAFLD-HCC and its potential consequences in HCC recurrence.

This study investigated the link between triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and nonalcoholic fatty liver disease (NAFLD) and liver fibrosis in American adults.

Information for 6495 participants from the National Health and Nutrition Examination Survey (NHANES) 2017-2020.03 was used for this cross-sectional study. The link between TG/HDL-C ratios and NAFLD and liver fibrosis was assessed by multiple linear regression before evaluating nonlinear correlations based on smoothed curve fitting models. Stratification analysis was then applied to confirm whether the dependent and independent variables displayed a stable association across populations.

TG/HDL-C ratios were positively correlated with NAFLD, with higher ratios being linked to increased prevalence of NAFLD. After adjusting for potential confounders, the odds ratios (OR) for NAFLD patients in the fourth TG/HDL-C quartile were 3.61 (95% confidence interval [CI], 2.94-4.38) (P for trend < 0.001) in comparison with those in the first quartile after adjusting for clinical variables. However, no statistical significance was noted for the ratio for liver fibrosis after adjusting for potential confounders (P for trend = 0.07). A nonlinear correlation between TG/HDL-C ratios and NAFLD was observed based on smoothed curve fitting models. However, a nonlinear relationship between the ratios and liver fibrosis was not established. In subgroup analyses, there was an interaction between smoking status and TG/HDL-C ratio in relation to the prevalence of liver fibrosis (P for interaction < 0.001).

Among American adults, the TG/HDL-C ratio was noted to be nonlinearly positively associated with the prevalence of NAFLD; however, this relationship was not present in liver fibrosis.

The worldwide prevalence of individuals with an elevated body weight has increased steadily over the past five decades. Billions of research dollars have been invested to improve our understanding of the causes and consequences of having an elevated body weight. All this knowledge has, however, failed to influence populational body weight trajectories of most countries around the world. Research on the definition of "obesity" has also evolved. Body mass index (BMI), the most commonly used tool to make its diagnosis, has major limitations. In this review article, we will highlight evidence from observational studies, genetic association studies and randomized clinical trials that have shown the remarkable inter-individual differences in the way humans store energy as body fat. Increasing evidence also suggests that, as opposed to weight inclusive, lifestyle-based approaches, weight-centric approaches advising people to simply eat less and move more are not sustainable for most people for long-term weight loss and maintenance. It is time to recognize that this outdated approach may have produced more harm than good. On the basis of pathophysiological, genetic and clinical evidence presented in this review, we propose that it may be time to shift away from the traditional clinical approach, which is BMI-centric. Rather, emphasis should be placed on actionable lifestyle-related risk factors aiming at improving overall diet quality and increasing physical activity level in the general population.

Nonalcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is an escalating health concern linked to obesity and type 2 diabetes. Despite liver biopsy being the gold standard, its invasiveness underscores the need for noninvasive diagnostic methods.

A cross-sectional study was performed to assess MASLD using the noninvasive OWLiver® serum lipidomics test in a cohort of 117 patients with severe obesity undergoing bariatric surgery, comparing outcomes with liver biopsy. Exclusions (n = 24) included insufficient data, liver disease etiology other than MASLD, corticosteroid treatment, excessive alcohol consumption, low glomerular filtration rate, and declination to participate. Comprehensive laboratory tests, demographic assessments, and liver biopsies were performed. Serum metabolites were analyzed using OWLiver®, a serum lipidomic test that discriminates between healthy liver, steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and MASH with fibrosis ≥2 by means of three algorithms run sequentially.

Liver biopsy revealed a MASLD prevalence of 95.7%, with MASH present in 28.2% of cases. OWLiver® demonstrated a tendency to diagnose more severe cases. Body mass index (BMI), rather than the presence of type 2 diabetes, emerged as the sole independent factor linked to the probability of concordance. Therefore, the all-population concordance of 63.2% between OWLiver® and liver biopsy notably raised to 77.1% in patients with a BMI <40 kg/m2. These findings suggest a potential correlation between lower BMI and enhanced concordance between OWLiver® and biopsy.

This study yields valuable insights into the concordance between liver biopsy and the noninvasive serum lipidomic test, OWLiver®, in severe obesity. OWLiver® demonstrated a tendency to amplify MASLD severity, with BMI values influencing concordance. Patients with BMI <40 kg/m2 may derive optimal benefits from this noninvasive diagnostic approach.

Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17β-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated.

To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes.

Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively.

Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level.

In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Metabolic associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, currently lacking universally recognized therapeutic drugs, thereby increasing the risk of cirrhosis and hepatocellular carcinoma. Research has reported an association between white adipose tissue and MAFLD.

White adipose tissue (WAT) is involved in lipid metabolism and can contribute to the progression of MAFLD by mediating insulin resistance, inflammation, exosomes, autophagy, and other processes. This review aims to elucidate the mechanisms through which WAT plays a role in the development of MAFLD.

WAT participates in the occurrence and progression of MAFLD by mediating insulin resistance, inflammation, autophagy, and exosome secretion. Fibrosis and restricted expansion of adipose tissue can lead to the release of more free fatty acids (FFA), exacerbating the progression of MAFLD. WAT-secreted TNF-α and IL-1β, through the promotion of JNK/JKK/p38MAPK expression, interfere with insulin receptor serine and tyrosine phosphorylation, worsening insulin resistance. Adiponectin, by inhibiting the TLR-4-NF-κB pathway and suppressing M2 to M1 transformation, further inhibits the secretion of IL-6, IL-1β, and TNF-α, improving insulin resistance in MAFLD patients. Various gene expressions within WAT, such as MBPAT7, Nrf2, and Ube4A, can ameliorate insulin resistance in MAFLD patients. Autophagy-related gene Atg7 promotes the expression of fibrosis-related genes, worsening MAFLD. Non-pharmacological treatments, including diabetes-related medications and exercise, can improve MAFLD.

The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.

A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). They are now defined as metabolic dysfunction-associated steatotic liver disease (MASLD), which includes cardiometabolic criteria in adults. This condition, extensively studied in obese or overweight patients, constitutes around 30% of the population, with a steady increase worldwide. Lean patients account for approximately 10%-15% of the MASLD population. However, the pathogenesis is complex and is not well understood.

To systematically review the literature on the diagnosis, pathogenesis, characteristics, and prognosis in lean MASLD patients and provide an interpretation of these new criteria.

We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023, specifically focusing on lean NAFLD, MAFLD, or MASLD patients. We include original articles with patients aged 18 years or older, with a lean body mass index categorized according to the World Health Organization criteria, using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population.

We include 85 studies in our analysis. Our findings revealed that, for lean NAFLD patients, the prevalence rate varied widely, ranging from 3.8% to 34.1%. The precise pathogenesis mechanism remained elusive, with associations found in genetic variants, epigenetic modifications, and adaptative metabolic response. Common risk factors included metabolic syndrome, hypertension, and type 2 diabetes mellitus, but their prevalence varied based on the comparison group involving lean patients. Regarding non-invasive tools, Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients. Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles, with some medications showing efficacy to a lesser extent. However, lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart.

MASLD is a complex disease comprising epigenetic, genetic, and metabolic factors in its pathogenesis. Results vary across populations, gender, and age. Limited data exists on clinical practice guidelines for lean patients. Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD). In humans, mRNA expression of P2Y13-R in WAT was negatively correlated to adipocyte lipolysis. In mice, adipocytes lacking P2Y13-R displayed higher intracellular cAMP levels, indicating impaired Gi signaling. Consistently, the absence of P2Y13-R was linked to increased lipolysis in adipocytes and WAT explants via hormone-sensitive lipase activation. Metabolic studies indicated that mice lacking P2Y13-R showed a greater susceptibility to diet-induced IR, systemic inflammation, and MASLD compared with their wild-type counterparts. Assays conducted on precision-cut liver slices exposed to WAT conditioned medium and on liver-specific P2Y13-R-knockdown mice suggested that P2Y13-R activity in WAT protects from hepatic steatosis, independently of liver P2Y13-R expression. In conclusion, our findings support the idea that targeting adipose P2Y13-R activity may represent a pharmacological strategy to prevent obesity-associated disorders, including type 2 diabetes and MASLD.

The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the other is improved. This is partly explained by their belonging to a multisystemic disease that includes components of the metabolic syndrome and shared pathogenetic mechanisms. Throughout the progression of NAFLD to more advanced stages, complex systemic and local metabolic derangements are involved. During fibrogenesis, a significant metabolic reprogramming occurs in the hepatic stellate cells, hepatocytes, and immune cells, engaging carbohydrate and lipid pathways to support the high-energy-requiring processes. The natural history of NAFLD evolves in a variable and dynamic manner, probably due to the interaction of a variable number of modifiable (diet, physical exercise, microbiota composition, etc.) and non-modifiable (genetics, age, ethnicity, etc.) risk factors that may intervene concomitantly, or subsequently/intermittently in time. This may influence the risk (and rate) of fibrosis progression/regression. The recognition and control of the factors that determine a rapid progression of fibrosis (or its regression) are critical, as the fibrosis stages are associated with the risk of liver-related and all-cause mortality.

Obesity, which is the accumulation of fat in adipose tissue, has adverse impacts on human health. Obesity-related metabolic dysregulation has similarities to the metabolic alterations observed in aging. It has been shown that the adipocytes of obese individuals undergo cellular aging, known as senescence. Senescence can be transmitted to other normal cells through a series of chemical factors referred to as the senescence-associated secretory phenotype (SASP). Most of these factors are pro-inflammatory compounds. The immune system removes these senescent T-cells, but immunosenescence, which is the senescence of immune cells, disrupts the clearance of senescent T-cells. Immunosenescence occurs as a result of aging or indirectly through transmission from senescent tissues. The significant occurrence of senescence in obesity is expected to cause immunosenescence and impairs the immune response to resolve inflammation. The sustained and chronic inflammation disrupts insulin's metabolic actions in metabolic tissues. Therefore, this review focuses on the role of senescent adipocyte cells in obesity-associated immunosenescence and subsequent metabolic dysregulation. Moreover, the article suggests novel therapeutic approaches to improve metabolic syndrome by targeting senescent T-cells or using senotherapeutics.

Metabolic-associated fatty liver disease (MAFLD) is a major cause of chronic liver disease worldwide and is generally thought to be closely related to obesity and diabetes. However, it also affects non-obese individuals, particularly in Asian cultures.

Healthy physical examination subjects and MAFLD patients were included in the endocrinology department of Jiangsu Provincial Hospital of Traditional Chinese Medicine. MAFLD was defined as fatty liver in imaging without virus infection, drug, alcohol, or other known causes of chronic liver disease. Non-obese MAFLD was defined as MAFLD in non-obese subjects (BMI<25 kg/m2).

The final analysis comprised 1047 participants in total. Of 946 MAFLD patients, 162 (17.12%) were diagnosed with non-obese MAFLD. Non-obese MAFLD patients were older, had lower alanine aminotransferase (ALT), triglyceride, and waist circumference, but had higher high density lipoprotein cholesterol (HDL-c) than obese MAFLD patients. Compared with non-obese healthy controls, non-obese MAFLD patients had higher BMI, ALT, gamma-glutamyl transferase (GGT), uric acid (UA), triglycerides (TG), and low density lipoprotein cholesterol (LDL-c). In terms of body composition, body fat mass (BFM), waist-hip ratio (WHR), percent body fat (PBF), visceral fat area (VFA), and fat mass index (FMI) were lower in non-obese healthy controls than non-obese MAFLD patients. A binary logistic regression analysis revealed that non-obese MAFLD was linked with lower GGT and higher HDL-c.

In this study cohort, non-obese MAFLD was present at a prevalence of 13.90%. In contrast to non-obese healthy controls, non-obese MAFLD patients exhibited different metabolic profiles, but they also had different body compositions.

Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome.

Sixty-two patients with NAFLD (60 % men) were studied before and after 12 months of treatment with synbiotic or placebo and provided SAT samples. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. RNA-sequencing and histological analysis of SAT were performed to determine differential gene expression, CCGE and the presence of collagen fibres. Regression modelling and receiver operator characteristic curve analysis were used to test associations with, and risk prediction for, ≥F2 liver fibrosis.

Patients with ≥F2 liver fibrosis (n = 24) had altered markers of AT dysfunction and a SAT gene expression signature characterised by enrichment of inflammatory and extracellular matrix-associated genes, compared to those with

CONCLUSION

A differential gene expression signature in SAT associates with ≥F2 liver fibrosis is explained by a measure of systemic insulin resistance and is not changed by synbiotic treatment. SAT CCGE values are a good predictor of ≥F2 liver fibrosis in NAFLD.

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We examined the roles of type 2 diabetes (T2D) and obesity in disease activity and fibrosis progression/regression in patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH).

This multi-center, retrospective study included patients with suspected or histologically proven NAFLD/NASH from the NASH Clinical Research Network. Outcomes included disease activity and rate of fibrosis, assessed using liver-biopsy driven measures (NAFLD activity score [NAS] and fibrosis score [FS]). Logistic regression and doubly robu estimation of causal effects tested relationships among T2D, obesity, and NAFLD/NASH.

The analytical sample included 870 adult patients with baseline biopsy data and 157 patients with multiple biopsy data. Patients with NAFLD/NASH and T2D had significantly higher baseline average NAS (4.52 vs. 4.13; p = 0.009) and FS (2.17 vs. 1.56; p < 0.0001); those with T2D had a significantly greater reduction in average NAS over time (-0.77/year vs. -0.17/year; p = 0.0008). Change in FS over time did not differ significantly by T2D status (-0.23/year vs. -0.04/year; p = 0.34). Baseline NAS, baseline FS, and change in average NAS over time did not differ significantly by obesity status (4.17 vs. 4.47; p = 0.16; 1.73 vs.1.92; p = 0.31; -0.40/year vs. -0.59/year; p = 0.62, respectively). Patients with obesity had a slight increase in FS but those without obesity had a reduction in average FS over time (0.07/year vs. -0.27/year; p = 0.008).

Patients with NAFLD/NASH and T2D had greater baseline disease activity versus those without T2D, but there was greater regression of disease activity over time among those with T2D. Patients with NAFLD/NASH and obesity had worsening of fibrosis versus those without obesity. NCT00063622.

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

Non-Alcoholic Fatty Liver Disease (NAFLD) refers to the accumulation of lipid laden vacuoles in hepatocytes, occurring in the context of visceral adiposity, insulin resistance and other features of the metabolic syndrome. Its more severe form (NASH, Non-Alcoholic Steatohepatitis) is becoming the leading aetiology of end-stage liver disease and hepatocellular carcinoma, and also contributes to cardiovascular disease, diabetes and extrahepatic malignancy. Management is currently limited to lifestyle modification and optimisation of the metabolic co-morbidities, with some of the drugs used for the latter also having shown some benefit for the liver. Licensed treatment modalities are currently lacking. A particular difficulty is the notorious heterogeneity of the patient population, which is poorly understood. A spectrum of disease severity associates in a non-linear way with a spectrum of severity of underlying metabolic factors. Heterogeneity of the liver in terms of mechanisms to cope with the metabolic and inflammatory stress and in terms of repair mechanisms, and a lack of knowledge hereof, further complicate the understanding of inter-individual variability. Genetic factors act as disease modifiers and potentially allow for some risk stratification, but also only explain a minor fraction of disease heterogeneity. Response to treatment shows a large variation in treatment response, again with little understanding of what is driving the absence of response in individual patients. Management can be tailored to patient's preferences in terms of diet modification, but tailoring treatment to knowledge on disease driving mechanisms in an individual patient is still in its infancy. Recent progress in analysing liver tissue as well as non-invasive tests hold, however, promise to rapidly improve our understanding of disease heterogeneity in NAFLD and provide individualised management.

A fatty liver index (FLI) greater than sixty (FLI ≥ 60) is an established score for metabolic dysfunction-associated steatotic liver disease (MASLD), which carries a high risk for diabetes and cardiovascular disease, while a FLI ≤ 20 rules out the presence of steatosis. Thus, we investigated whether FLI was associated with cardiometabolic risk factors, i.e., visceral (VAT), subcutaneous (SC), epicardial (EPI), extrapericardial (PERI), and total cardiac (CARD-AT) adipose tissue, hepatic fat ((by magnetic resonance imaging, MRI, and spectroscopy, MRS), and insulin resistance (IR, HOMA-IR and OGIS-index), and components of metabolic syndrome. All individuals with FLI ≥ 60 had MASLD, while none with FLI ≤ 20 had steatosis (by MRS). Subjects with FLI ≥ 60 had a higher BMI and visceral and cardiac fat (VAT > 1.7 kg, CARD-AT > 0.2 kg). FLI was positively associated with increased cardiac and visceral fat and components of metabolic syndrome. FLI, VAT, and CARD-AT were all associated with IR, increased blood pressure, cholesterol, and reduced HDL. For FLI ≥ 60, the cut-off values for fat depots and laboratory measures were estimated. In conclusion, FLI ≥ 60 identified not only subjects with steatosis but also those with IR, abdominal and cardiac fat accumulation, increased blood pressure, and hyperlipidemia, i.e., those at higher risk of cardiometabolic diseases. Targeted reduction of FLI components would help reduce cardiometabolic risk.

The ketogenic diet (KD) is, nowadays, considered an interesting nutritional approach for weight loss and improvement in insulin resistance. Nevertheless, most of the studies available in the literature do not allow a clear distinction between its effects on insulin sensitivity per se, and the effects of weight loss induced by KDs on insulin sensitivity. In this review, we discuss the scientific evidence on the direct and weight loss mediated effects of KDs on glycemic status in humans, describing the KD's biochemical background and the underlying mechanisms.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but is also common in individuals with a normal body mass index (BMI), who also experience the hepatic inflammation, fibrosis, and decompensated cirrhosis associated with NAFLD progression. The clinical evaluation and treatment of NAFLD in this patient population are challenging for the gastroenterologist. A better understanding of the epidemiology, natural history, and outcomes of NAFLD in individuals with normal BMI is emerging. This review examines the relationship between metabolic dysfunction and clinical characteristics associated with NAFLD in normal-weight individuals.

Despite a more favorable metabolic profile, normal-weight NAFLD patients exhibit metabolic dysfunction. Visceral adiposity may be a critical risk factor for NAFLD in normal-weight individuals, and waist circumference may be better than BMI for assessing metabolic risk in these patients. Although screening for NAFLD is not presently recommended, recent guidelines may assist clinicians in the diagnosis, staging, and management of NAFLD in individuals with a normal BMI.

Individuals with a normal BMI likely develop NAFLD as a result of different etiologies. Subclinical metabolic dysfunction may be a key component of NAFLD in these patients, and efforts to better understand this relationship in this patient population are needed.