Metabolic Dysfunction-Associated Steatotic Liver Disease in Severe Obesity and Concordance between Invasive (Biopsy) and Noninvasive (OWLiver®) Diagnoses.

INTRODUCTION: 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. 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. RESULTS: 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. CONCLUSION: 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.

Photoperiod-Dependent Effects on Blood Biochemical Markers of Phenolic-Enriched Fruit Extracts.

Fruits are rich in bioactive compounds, such as (poly)phenols, and their intake is associated with health benefits, although recent animal studies have suggested that the photoperiod of consumption influences their properties. Fruit loss and waste are critical issues that can be reduced by obtaining functional fruit extracts. Therefore, the aim of this study was to obtain phenolic-enriched extracts from eight seasonal fruits that can modulate blood biochemical parameters and to investigate whether their effects depend on the photoperiod of consumption. Eight ethanol-based extracts were obtained and characterized, and their effects were studied in F344 rats exposed to short (6 h light, L6) and long (18 h light) photoperiods. Cherry and apricot extracts decreased blood triacylglyceride levels only when consumed under the L6 photoperiod. Pomegranate, grape, and orange extracts reduced cholesterol and fasting glucose levels during the L6 photoperiod; however, plum extract reduced fasting glucose levels only during the L18 photoperiod. The results showed the importance of photoperiod consumption in the effectiveness of phenolic-enriched fruit extracts and promising evidence regarding the use of some of the developed fruit extracts as potential functional ingredients for the management of several blood biomarkers.

Mid-term Effects of Bariatric Surgery on Metabolic Dysfunction-Associated Fatty Liver Disease Remission and Predictive Factors: A Prospective Study with a Focus on Non-invasive Diagnosis.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated fatty liver disease (MAFLD), is a growing health concern associated with obesity and type 2 diabetes. Bariatric surgery offers potential benefits, but its impact on MAFLD remains incompletely understood, with scarce long-term follow-up prospective studies. Moreover, being liver biopsy the gold standard for liver condition measurement, the need for non-invasive techniques that allow the assessment of MAFLD development after bariatric surgery is imperative. OWLiver® Care and OWLiver® represent two serum lipidomic tests, featuring panels comprising 11 and 20 triglycerides, respectively. MATERIALS AND METHODS: We conducted a prospective study involving 80 Caucasians to assess the effects of bariatric surgery on MAFLD using non-invasive diagnostics and to identify baseline predictors of MAFLD remission. Serum samples were collected before surgery and at a 3-year follow-up. RESULTS: After 3 years, the proportion of patients exhibiting a healthy liver escalated from 5.0% at baseline to 26.3%. Conversely, the percentage of steatohepatitis declined from 35.1% to a mere 7.6%. Younger age, female gender, and the absence of type 2 diabetes were associated with MAFLD remission. However, age stood as the only independent variable associated with this favorable liver evolution (R2 = 0.112). CONCLUSION: Bariatric surgery demonstrates mid-term benefits in improving MAFLD, with younger age as a baseline predictor of remission. Non-invasive diagnostic methods, like OWLiver®, are valuable tools for monitoring MAFLD evolution. Further research with larger populations and longer follow-up periods is warranted to refine personalized treatment approaches.

Vitis vinifera L. Bioactive Components Modulate Adipose Tissue Metabolic Markers of Healthy Rats in a Photoperiod-Dependent Manner.

SCOPE: The beneficial health effects of (poly)phenol-rich foods such as red grapes mainly depend on both the type and concentration of (poly)phenols. Since fruit (poly)phenol content is influenced by growing conditions, the study examines the seasonal effects of red grapes (Vitis vinifera L.), grown under various cultivation conditions, on metabolic markers of adipose tissue in healthy rats. METHODS AND RESULTS: For this purpose, Fischer 344 rats are exposed into three different light-dark cycles and daily supplemented with 100 mg kg-1 of either conventionally or organically grown red grapes for 10 weeks (n = 6). Seasonal consumption of organic grapes (OGs), which are richer in anthocyanins, increases energy expenditure (EE) of animals exposed to long photoperiod and enhances uncoupling protein 1 (UCP1) protein expression in brown adipose tissue of animals under standard photoperiod. Additionally, red grape consumption affects the gene expression profile of white adipose tissue (WAT), upregulating browning markers of subcutaneous WAT in 12 h light (L12) and 18 h light (L18) photoperiods, and downregulating adipogenic and lipolytic markers of visceral WAT in 6 h light (L6) and L12 photoperiods. CONCLUSIONS: These results clearly show that bioactive compounds of grapes can modulate the metabolic markers of white and brown adipose tissues in a photoperiod and depot-dependent manner, partly affecting EE when consumed out of season.

Photoperiod-Dependent Effects of Grape-Seed Proanthocyanidins on Adipose Tissue Metabolic Markers in Healthy Rats.

SCOPE: Variations in photoperiod patterns drive metabolic adaptations in mammals, involving important changes in body weight and adiposity. Moreover, (poly)phenols can help heterotrophs adopt metabolic adaptations to face the upcoming environmental conditions. Particularly, proanthocyanidins from grape-seeds show photoperiod-dependent effects on different metabolic parameters. The present study aims to explore whether grape-seed proanthocyanidin extract (GSPE) consumption differently affects the expression of metabolic markers in WAT (subcutaneous and visceral depots) and BAT in a photoperiod-dependent manner. METHODS AND RESULTS: GSPE (25 mg kg-1  day-1 ) is orally administrated for 4 weeks to healthy rats exposed to three photoperiods (L6, L12, and L18). In WAT, GSPE consumption significantly upregulates the expression of lipolytic genes in all photoperiods, being accompanied by increased serum concentrations of glycerol and corticosterone only under the L6 photoperiod. Moreover, adiponectin mRNA levels are significantly upregulated in response to GSPE regardless of the photoperiod, whereas Tnfα and Il6 expression are only downregulated in L6 and L18 photoperiods but not in L12. In BAT, GSPE upregulates Pgc1α expression in all groups, whereas the expression of Pparα is only increased in L18. CONCLUSIONS: The results indicate that GSPE modulates the expression of important metabolic markers of WAT and BAT in a photoperiod-dependent manner.

Grape-Seed Proanthocyanidins Modulate Adipose Tissue Adaptations to Obesity in a Photoperiod-Dependent Manner in Fischer 344 Rats.

Seasonal rhythms drive metabolic adaptations that influence body weight and adiposity. Adipose tissue is a key regulator of energy homeostasis in the organism, and its healthiness is needed to prevent the major consequences of overweight and obesity. In this context, supplementation with proanthocyanidins has been postulated as a potential strategy to prevent the alterations caused by obesity. Moreover, the effects of these (poly)phenols on metabolism are photoperiod dependent. In order to describe the impact of grape-seed proanthocyanidins extract (GSPE) on important markers of adipose tissue functionality under an obesogenic environment, we exposed Fischer 344 rats to three different photoperiods and fed them a cafeteria diet for five weeks. Afterwards, we supplemented them with 25 mg GSPE/kg/day for four weeks. Our results revealed that GSPE supplementation prevented excessive body weight gain under a long photoperiod, which could be explained by increased lipolysis in the adipose tissue. Moreover, cholesterol and non-esterified fatty acids (NEFAs) serum concentrations were restored by GSPE under standard photoperiod. GSPE consumption slightly helped combat the obesity-induced hypertrophy in adipocytes, and adiponectin mRNA levels were upregulated under all photoperiods. Overall, the administration of GSPE helped reduce the impact of obesity in the adipose tissue, depending on the photoperiod at which GSPE was consumed and on the type of adipose depots.

Photoperiodic Remodeling of Adiposity and Energy Metabolism in Non-Human Mammals.

Energy homeostasis and metabolism in mammals are strongly influenced by seasonal changes. Variations in photoperiod patterns drive adaptations in body weight and adiposity, reflecting changes in the regulation of food intake and energy expenditure. Humans also show distinct patterns of energy balance depending on the season, being more susceptible to gaining weight during a specific time of the year. Changes in body weight are mainly reflected by the adipose tissue, which is a key metabolic tissue and is highly affected by circannual rhythms. Mostly, in summer-like (long-active) photoperiod, adipocytes adopt a rather anabolic profile, more predisposed to store energy, while food intake increases and energy expenditure is reduced. These metabolic adaptations involve molecular modifications, some of which have been studied during the last years and are summarized in this review. In addition, there is a bidirectional relation between obesity and the seasonal responses, with obesity disrupting some of the seasonal responses observed in healthy mammals, and altered seasonality being highly associated with increased risk of developing obesity. This suggests that changes in photoperiod produce important metabolic alterations in healthy organisms. Biological rhythms impact the regulation of metabolism to different extents, some of which are already known, but further research is needed to fully understand the relationship between energy balance and seasonality.

Proanthocyanidins Restore the Metabolic Diurnal Rhythm of Subcutaneous White Adipose Tissue According to Time-Of-Day Consumption.

Consumption of grape seed proanthocyanidin extract (GSPE) has beneficial effects on the functionality of white adipose tissue (WAT). However, although WAT metabolism shows a clear diurnal rhythm, whether GSPE consumption could affect WAT rhythmicity in a time-dependent manner has not been studied. Ninety-six male Fischer rats were fed standard (STD, two groups) or cafeteria (CAF, four groups) diet for 9 weeks (n = 16 each group). From week 6 on, CAF diet animals were supplemented with vehicle or 25 mg GSPE/kg of body weight either at the beginning of the light/rest phase (ZT0) or at the beginning of the dark/active phase (ZT12). The two STD groups were also supplemented with vehicle at ZT0 or ZT12. In week 9, animals were sacrificed at 6 h intervals (n = 4) to analyze the diurnal rhythms of subcutaneous WAT metabolites by nuclear magnetic resonance spectrometry. A total of 45 metabolites were detected, 19 of which presented diurnal rhythms in the STD groups. Although most metabolites became arrhythmic under CAF diet, GSPE consumption at ZT12, but not at ZT0, restored the rhythmicity of 12 metabolites including compounds involved in alanine, aspartate, and glutamate metabolism. These results demonstrate that timed GSPE supplementation may restore, at least partially, the functional dynamics of WAT when it is consumed at the beginning of the active phase. This study opens an innovative strategy for time-dependent polyphenol treatment in obesity and metabolic diseases.

Time-of-day dependent effect of proanthocyanidins on adipose tissue metabolism in rats with diet-induced obesity.

BACKGROUND: Grape-seed proanthocyanidin extract (GSPE) improve white adipose tissue (WAT) expansion during diet-induced obesity. However, because adipose metabolism is synchronized by circadian rhythms, it is plausible to speculate that the bioactivity of dietary proanthocyanidins could be influenced by the time-of-day in which they are consumed. Therefore, the aim of the present study was to determine the interaction between zeitgeber time (ZT) and GSPE consumption on the functionality of WAT in rats with diet-induced obesity. METHODS: Male Wistar rats were fed a cafeteria diet for 9 weeks. After 5 weeks, the animals were supplemented with 25 mg GSPE/kg for 4 weeks at the beginning of the light/rest phase (ZT0) or of the dark/active phase (ZT12). Body fat content was determined by nuclear magnetic resonance and histological analyses were performed in the epididymal (EWAT) and inguinal (IWAT) fat depots to determine adipocyte size and number. In addition, the expression of genes related to adipose metabolism and circadian clock function were analyzed by qPCR. RESULTS: GSPE consumption at ZT0 was associated with a potential antidiabetic effect without affecting adiposity and energy intake and downregulating the gene expression of inflammatory markers in EWAT. In contrast, GSPE consumption at ZT12 improved adipose tissue expansion decreasing adipocyte size in IWAT. In accordance with this adipogenic activity, the expression of genes involved in fatty acid metabolism were downregulated at ZT12 in IWAT. In turn, GSPE consumption at ZT12, but not at ZT0, repressed the expression of the clock gene Cry1 in IWAT. CONCLUSIONS: The interaction between ZT and GSPE consumption influenced the metabolic response of WAT in a tissue-specific manner. Understanding the impact of circadian clock on adipose metabolism and how this is regulated by polyphenols will provide new insights for the management of obesity.

Supplementation with a Specific Combination of Metabolic Cofactors Ameliorates Non-Alcoholic Fatty Liver Disease, Hepatic Fibrosis, and Insulin Resistance in Mice.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have emerged as the leading causes of chronic liver disease in the world. Obesity, insulin resistance, and dyslipidemia are multifactorial risk factors strongly associated with NAFLD/NASH. Here, a specific combination of metabolic cofactors (a multi-ingredient; MI) containing precursors of glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+) (betaine, N-acetyl-cysteine, L-carnitine and nicotinamide riboside) was evaluated as effective treatment for the NAFLD/NASH pathophysiology. Six-week-old male mice were randomly divided into control diet animals and animals exposed to a high fat and high fructose/sucrose diet to induce NAFLD. After 16 weeks, diet-induced NAFLD mice were distributed into two groups, treated with the vehicle (HFHFr group) or with a combination of metabolic cofactors (MI group) for 4 additional weeks, and blood and liver were obtained from all animals for biochemical, histological, and molecular analysis. The MI treatment reduced liver steatosis, decreasing liver weight and hepatic lipid content, and liver injury, as evidenced by a pronounced decrease in serum levels of liver transaminases. Moreover, animals supplemented with the MI cocktail showed a reduction in the gene expression of some proinflammatory cytokines when compared with their HFHFr counterparts. In addition, MI supplementation was effective in decreasing hepatic fibrosis and improving insulin sensitivity, as observed by histological analysis, as well as a reduction in fibrotic gene expression (Col1α1) and improved Akt activation, respectively. Taken together, supplementation with this specific combination of metabolic cofactors ameliorates several features of NAFLD, highlighting this treatment as a potential efficient therapy against this disease in humans.