Obesity-associated adipose tissue dysfunction represents a key driver of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver disease. Emerging evidence highlights the vitamin D/vitamin D receptor (VD/VDR) axis as an important regulator of adipose tissue homeostasis. Beyond its classical role in mineral metabolism, vitamin D influences adipogenesis, inflammation, and insulin sensitivity, thereby modulating systemic metabolic health. In this review, we summarize the current understanding of the VD/VDR axis in adipose tissue biology, from molecular pathways controlling lipid turnover and immune responses to experimental and clinical evidence linking vitamin D status with obesity-related complications. We also discuss the role of genetic variability and tissue-specific VDR signaling in shaping metabolic outcomes. While results from supplementation trials remain inconsistent, maintaining adequate vitamin D levels appears crucial for the prevention of adipose tissue dysfunction and its cardiometabolic consequences. Future studies are warranted to define optimal strategies for harnessing the VD/VDR axis in therapeutic approaches to obesity and metabolic disease.

Metabolic-associated steatotic liver disease (MASLD) represents the most common chronic hepatopathy worldwide and an independent risk factor for cardiovascular disease and mortality, particularly when liver fibrosis occurs. Epigenetic alterations, such as DNA methylation, may influence MASLD susceptibility and progression; yet mechanisms underlying this process are limited. This study aimed to investigate whether active DNA demethylation in peripheral blood mononuclear cells (PBMCs) from individuals with MASLD, alongside the methylation and mRNA levels of inflammation- and fibrosis-related candidate genes, is associated with liver fibrosis. For this study, global demethylation intermediates (5-hydroxymethylcytosine [5hmC], 5-formylcytosine [5fC]) were quantified in PBMCs from 89 individuals with/without MASLD using ELISA. Site-specific DNA methylation of SOCS3, SREBF1, and TXNIP was analyzed by mass spectrometry-based bisulfite sequencing; mRNA expression was assessed via RT-PCR. Individuals with MASLD and moderate-to-high fibrosis risk (estimated by the fibrosis non-alcoholic steatohepatitis (NASH) index, FNI) progressively exhibited greater global 5hmC and 5fC levels. Higher FNI was associated with reduced methylation of the SOCS3 gene and increased mRNA expression of the SOCS3, TXNIP, IL-6, and MCP-1 genes. In conclusion, elevated fibrosis risk in MASLD is associated with active global DNA demethylation, as well as differential methylation and expression patterns of genes, which are key regulators of inflammation and fibrosis. These epigenetic alterations in PBMCs may mirror DNA methylation changes in the liver, which may potentially contribute to liver fibrogenesis and represent novel biomarkers for MASLD progression toward fibrosis.

Obesity-associated adipose tissue dysfunction represents a key driver of metabolic disorders, including type 2 diabetes, cardiovascular diseases, and fatty liver disease. Emerging evidence highlights the vitamin D/vitamin D receptor (VD/VDR) axis as an important regulator of adipose tissue homeostasis. Beyond its classical role in mineral metabolism, vitamin D influences adipogenesis, inflammation, and insulin sensitivity, thereby modulating systemic metabolic health. In this review, we summarize the current understanding of the VD/VDR axis in adipose tissue biology, from molecular pathways controlling lipid turnover and immune responses to experimental and clinical evidence linking vitamin D status with obesity-related complications. We also discuss the role of genetic variability and tissue-specific VDR signaling in shaping metabolic outcomes. While results from supplementation trials remain inconsistent, maintaining adequate vitamin D levels appears crucial for the prevention of adipose tissue dysfunction and its cardiometabolic consequences. Future studies are warranted to define optimal strategies for harnessing the VD/VDR axis in therapeutic approaches to obesity and metabolic disease.

Increased intestinal permeability has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its relationship with liver fibrosis independent of metabolic risk factors remains unclear. The aim of this study was to investigate the relationship between markers of gut-derived immune activation and liver fibrosis in individuals with metabolic disease. We enrolled 139 adults (48.8 ± 11 years; BMI 33.7 ± 9.5 kg/m²; 50% type 2 diabetes); liver steatosis and fibrosis were estimated using the Hepatic Steatosis Index (HSI) and Fibrotic NASH Index (FNI); liver biopsies were available in a bariatric subgroup. Plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) levels were measured by ELISA kits, and the LBP/sCD14 ratio was calculated. MASLD was present in 78% of participants; in these individuals, sCD14 levels correlated with HSI and FNI (both p < 0.01). In multivariable analysis adjusting for age, sex, BMI, waist circumference, and type 2 diabetes, sCD14 was independently associated with advanced fibrosis (OR: 3.16, 95% CI 1.32–7.55; p = 0.010). This association was confirmed by histology (p = 0.02). Overall, these findings point to a link between gut-derived immune activation and fibrotic burden in MASLD and provide insight into the pathophysiological relevance of the gut–liver axis in metabolic disease.

Background: Metabolic-associated steatotic liver disease (MASLD) represents the most common chronic hepatopathy worldwide and an independent risk factor for cardiovascular disease and mortality, particularly when liver fibrosis occurs. Epigenetic alterations, as DNA methylation, may influence MASLD susceptibility and progression; yet mechanisms underlying this process are limited. This study aimed to investigate active DNA demethylation in MASLD, alongside the methylation and mRNA levels of inflammation- and fibrosis-related candidate genes. Methods: Global demethylation intermediates (5-hydroxymethylcytosine[5hmC], 5-formylcytosine[5fC]) were quantified in peripheral blood mononuclear cells (PBMCs) from 89 individuals with/without MASLD using ELISA. Site-specific DNA methylation of SOCS3, SREBF1 and TXNIP was analyzed by mass spectrometry-based bisulfite sequencing; mRNA expression was assessed via rt-PCR. Results: Individuals with MASLD and moderate-to-high fibrosis risk (estimated by Fibrosis NASH Index, FNI) progressively exhibited greater global 5hmC and 5fC levels. FNI inversely correlated with methylation levels of SOCS3 gene promoter, and linearly with SOCS3, TXNIP, IL-6 and MCP-1 mRNA expression. Conclusions: Elevated fibrosis risk in MASLD is associated with active global DNA demethylation, as well as differential methylation and expression patterns of genes which are key regulators of inflammation and fibrosis. These epigenetic alterations may potentially contribute to fibrogenesis and represent novel biomarkers for MASLD progression toward fibrosis.