Obesity is a multifactorial disease influenced by several factors including poor diet, physical inactivity, and genetic predisposition. In recent years, the social and environmental context, along with race/ethnicity and gender, have been recognized as factors influencing obesity risk beyond traditional risk factors. This review aims to increase knowledge of these causal determinants and their implications for the treatment and management of obesity, addressing not only the individual but also the societal sphere. A growing body of evidence emphasizes the interaction between the physical and social environments in shaping personal behaviors related to obesity. Social disparities, such as socioeconomic status (income, education, employment), racial/ethnic differences, and gender, contribute significantly to weight gain from childhood to adulthood. These factors increase the risk of obesity and related cardiovascular risk factors, independent of clinical and demographic variables, and may lead to stigma and discrimination against those affected. Obesity prevention solutions, from community programs to national policies, may be more effective if they address social, gender, and ethnic barriers. Understanding obesity requires a comprehensive approach that includes social, environmental, and psychological factors, as well as biological causes, to help obesity experts develop more effective interventions tailored to obesity and related diseases.

Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1α, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The complex interplay between estrogen deficiency, visceral fat accumulation, metabolic syndrome (MetS), and inflammation accelerates disease progression, increases cardiovascular (CV) risk, and triggers a cycle of worsening adiposity, metabolic dysfunction, and psychological problems, including eating disorders. Weight loss in postmenopausal women can significantly improve both metabolic and psychological outcomes, helping to prevent MASLD and related conditions. This review examines the prevalence of MASLD, its comorbidities (type 2 diabetes T2D, CV, mental disorders), pathogenetic mechanisms, and pharmacological treatment with GLP-1 receptor agonists (GLP1-RAs), with a focus on postmenopausal women. Given the use of GLP1-RAs in the treatment of obesity and T2D in MASLD patients, and the increase in MetS and MASLD after menopause, this review analyzes the potential of a stable GLP-1–estrogen conjugate as a therapeutic approach in this subgroup. By combining the synergistic effects of both hormones, this dual agonist has been shown to increase food intake and food reward suppression, resulting in greater weight loss and improved insulin sensitivity, glucose, and lipid metabolism. Therefore, we hypothesize that this pharmacotherapy may provide more targeted therapeutic benefits than either hormone alone by protecting the liver, β-cells, and overall metabolic health. As these effects are only supported by preclinical data, this review highlights the critical need for future research to evaluate and confirm the mechanisms and efficacy in clinical settings, particularly in postmenopausal women.

The introduction of the term “Metabolic Steatotic Liver Disease” (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver’s increased production of proteins known as “hepatokines” has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.

Biliverdin reductase A (BVR-A) is an enzyme involved in the regulation of insulin signalling. Knockout (KO) mice for hepatic BVR-A, on a high-fat diet, develop more severe glucose impairment and hepato-steatosis than the wild type, whereas loss of adipocyte BVR-A is associated with increased visceral adipose tissue (VAT) inflammation and adipocyte size. However, BVR-A expression in human VAT has not been investigated. We evaluated BVR-A mRNA expression levels by real-time PCR in the intra-operative omental biopsy of 38 obese subjects and investigated the association with metabolic impairment, VAT dysfunction, and biopsy-proven non-alcoholic fatty liver disease (NAFLD). Individuals with lower VAT BVR-A mRNA levels had significantly greater VAT IL-8 and Caspase 3 expression than those with higher BVR-A. Lower VAT BVR-A mRNA levels were associated with an increased adipocytes’ size. An association between lower VAT BVR-A expression and higher plasma gamma-glutamyl transpeptidase was also observed. Reduced VAT BVR-A was associated with NAFLD with an odds ratio of 1.38 (95% confidence interval: 1.02–1.9; χ² test) and with AUROC = 0.89 (p = 0.002, 95% CI = 0.76–1.0). In conclusion, reduced BVR-A expression in omental adipose tissue is associated with VAT dysfunction and NAFLD, suggesting a possible involvement of BVR-A in the regulation of VAT homeostasis in presence of obesity.

Background: Age over 50, menopause, obesity and type 2 diabetes (T2D) are key risk factors for Metabolic dysfunction-associated steatotic liver disease (MASLD). This observational study aimed to assess sex differences in anthropometric and clinical profile, including non-invasive liver steatosis indices, in subjects with MASLD, obesity and/or T2D, aged ≥ 50 years. Methods: Anthropometric and clinical parameters, non-invasive indices for steatosis and fibrosis and FibroScan^® data were collected. Results: Among 213 patients (65.7% women, median age 63.0 years and mean Body Mass Index (BMI 34.9 kg/m²), men had higher body weight and waist circumference (WC), whereas women showed higher BMI and waist-to-height ratio (WHtR), and were more likely to exceed WC sex-specific and WHtR risk cut-offs. While transaminases values were higher in men, sex-specific cut-offs revealed that women more frequently exceeded these thresholds. No sex-differences were found for Fatty Liver Index (FLI), Fibrosis-4 (FIB-4) or FibroScan^®, although higher rate of mild fibrosis in women. The diagnostic accuracy of FLI for detecting steatosis was significantly higher in men and unsatisfactory in women (Area Under the ROC Curve, AUC 0.863 vs. 0.655). Conclusions: While MASLD is more common in men, these results suggest that postmenopausal women with visceral obesity showed similar or worse liver and cardiometabolic profiles than men, despite appearing healthier based on standard clinical parameters. Notably, common markers like transaminases and the FLI were less accurate in detecting steatosis in women, underscoring the need for sex-specific diagnostic criteria and greater clinical attention to older women, particularly those with central obesity, to ensure early identification and management of MASLD.