Cyclodipeptides Reversed Liver Damage and Adipose Tissue Dysfunction in a Chronic Obesity MASLD Rat Model by Remodeling White Adipocytes Toward a Beige-like Adipocyte Phenotype.

Background: MASLD is a disorder linked to lipid metabolism and obesity, increasingly prevalent among sedentary people and leading to hepatic fibrosis. Cyclodipeptides (CDPs) have promising anti-obesogenic and liver-protective potential. Methods: CDP treatment was evaluated in a chronic MASLD model using female Wistar rats fed an obesogenic diet, with assessments of insulin resistance, glucose tolerance, liver damage, oxidative stress, and the expression of genes related to metabolic function. Results: MASLD CDP-treated rats showed low visceral adipose tissue (VAT) content, improved insulin responsiveness and glucose tolerance, reduced steatosis, and reversed oxidant stress and the NRF2, GPX1, and GCLC expression. Furthermore, MASLD-related dysregulation of genes involved in lipid metabolism was restored, including vLDL transport (MTTP, APOB, and RASAL2), β-oxidation (PPAR-α, ACOX1, and FOXO1), lipogenesis (ACC1 and SREBP 1C), and fatty acid transport (PSD3 and CD36). In accordance, genes of key signaling pathways were also restored, including mTOR, TSC1, and TSC2, along with fibrosis and inflammation TGF-β, Fas, NF-κB, and IL-6. In VAT of MASLD animals, crown-like structures and adiposity density were diminished by CDP treatment, with increased expression of genes associated with beige-like adipose tissue remodeling, including PGC-1α, UCP1, NRF1, ATP6v1, CEBP-α, COX4i1, PPARγ, and CS. Consistently, the UCP1 and PGC-1α protein expression was increased in the VAT of MASLD animals treated with CDPs. Conclusions: The anti-MASLD effects of CDPs were associated with reversal of key pathogenic markers in the liver and VAT, suggesting remodeling of white adipose tissue (WAT) toward a beige-like adipose tissue phenotype. The findings suggest that CDPs may modulate adipose tissue structure and adipogenesis, underscoring their therapeutic relevance for MASLD.