Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT–liver crosstalk and the complications of MASLD in humans.

The expansion of adipose tissue is regulated by insulin and leptin through sterol regulatory element-binding protein-1c (SREBP-1c), up-regulating lipogenesis in tissues by Stearoylcoenzyme A desaturase 1 (SCD1) enzyme, while adipose triglyceride lipase (ATGL) enzyme is key in lipolysis. The research objective was to evaluate the expression of Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1), SCD1, Patatin Like Phospholipase Domain Containing 2 (PNPLA2), and leptin (LEP) genes in hepatic-adipose tissue, and related them with the increment and distribution of fat depots of individuals without insulin resistance. Thirty-eight subjects undergoing elective cholecystectomy with liver and adipose tissue biopsies (subcutaneous-omental) are included. Tissue gene expression was assessed by qPCR and biochemical parameters determined. Individuals are classified according to the body mass index, classified as lean (control group, n=12), overweight (n=11) and obesity (n=15). Abdominal adiposity was determined by anthropometric and histopathological study of the liver. Increased SCD1 expression in omental adipose tissue (p=0.005) and PNPLA2 in liver (p=0.01) were found in the obesity group. PNPLA2 decreased expression in subcutaneous adipose tissue was significant in individuals with abdominal adiposity (p=0.017). Anthropometric parameters positively correlated with liver PNPLA2 and the expression of liver PNPLA2 with serum leptin. SCD1 increased levels may represent lipid storage activity in omental adipose tissue. Liver PNPLA2 increased expression could function as a primary compensatory event of visceral fat deposits associated to the leptin hormone related to the increase of adipose tissue.

Genetic predisposition to cardiovascular risk may vary between different ethnic groups. We studied the effect of the FABP2 A54T polymorphism on biochemical and anthropometric cardiovascular risk factors in 114 obese Mexican subjects. The mean age of the patients studied was 36.8±13.3 years. Insulin resistance was present in 47%, hypercholesterolaemia in 49% and hyper-triglyceridaemia in 45%. Frequency of the FABP2 genotype was 39% AA, 54.8% AT and 6.2% TT. The AT/TT group showed an increase in body mass index (34±7.1 vs. 31±4.8 kg/m²), waist circumference (101±15.7 vs. 96.5±15.8 cm), triglycerides (145±60.8 vs. 127±79.4 mg/dL; 1.64±0.67 vs. 1.43±0.89 mmol/L), total cholesterol (176±39.4 vs. 164±38.2 mg/dL; 4.55±1.02 vs. 4.24±0.99 mmol/L), LDL (121±24.2 vs. 111±25.9 mg/dL; 3.13±0.62 vs. 2.88±0.67 mmol/L) and VLDL (28.8±12.1 vs. 25.1±16.1 mg/dL; 0.74±0.31 vs. 0.64±0.41 mmol/L) compared to the AA group (p<0.05). The AT/TT group had greatly increased cardiovascular risk, with an OR of 7.56 (95% CI, 1.82-36.24; p<0.001) compared to the AA group. Our results suggest that A54T polymorphism of the FABP2 gene is associated with cardiovascular disease risk in obese subjects.

Metabolically Dysfunctional-Associated Steatotic Liver Disease (MASLD) affects both metabolically healthy obese (MHO) individuals and metabolically unhealthy lean (MUL) individuals. Key genes linked to liver dysfunction, such as MLXIPL, PPARA, and FGF21, are under-researched in humans. We aimed to evaluate the ChREBP–PPARα–FGF21 axis in relation to metabolic liver dysfunction in MHO and MUL individuals. Liver histopathology, biochemical data, anthropometric measurements, mRNA expression as analyzed by qPCR, and heatmap visualization were utilized to identify relationships among variables and discern gene expression patterns. ChREBP–PPARA–FGF21 genes were analyzed in liver, subcutaneous (SAT), and omental adipose tissue (OAT) biopsies from 55 subjects, including metabolically unhealthy obese (MUO), MHO, MUL, and metabolically healthy lean (MHL) subjects as controls. The MHL, MUL, MHO, and MUO groups showed a gradual increase in liver PPARα, with a downward trend in ChREBPβ levels in SAT (p < 0.05). Liver ChREBPβ positively correlated with insulin resistance and FGF21. Levels of OAT ChREBPβ showed a negative correlation with anthropometric measurements and serum insulin levels. These findings suggest coordinated regulation under metabolic stress. Increased FGF21 expression in the MUL and MUO groups may aid as a metabolic biomarker of impaired energy homeostasis and compensatory hepatic response.