Galectin-3 inhibitor selvigaltin dosed therapeutically in vivo in a rabbit model of metabolic syndrome induced by high-fat diet: effects on rabbit differentiated adipocytes

Introduction: Metabolic syndrome (MetS) is an increasingly prevalent condition characterized by visceral obesity, insulin resistance, dyslipidemia, hypertension, and chronic low-grade inflammation. Impaired preadipocyte differentiation contributes to metabolic disturbances, inflammation, and mitochondrial dysfunction. Galectin-3 (Gal-3) plays a key role in promoting visceral adipose tissue (VAT) inflammation, fibrosis, and mitochondrial impairment. In a preclinical rabbit model of MetS, treatment with the Gal-3 inhibitor selvigaltin reduced VAT mass, indicating potential therapeutic value. This study seeks to clarify how selvigaltin influences the metabolic function of differentiation induction medium (DIM)-induced adipocytes mitochondria, potentially offering a new strategy for treating MetS.Methods: Male New Zealand White rabbits were housed individually under standard conditions. Following one week on a regular diet (RD), they were randomly assigned to one of the following groups for 12 weeks: RD with vehicle, high-fat diet (HFD) with vehicle, or HFD with selvigaltin (0.3, 1.0, or 5.0 mg/kg), administered orally once daily, five days a week, starting from week 9. Visceral adipose tissue (VAT) was collected, and preadipocytes were isolated and induced to differentiate in vitro into DIM-differentiated adipocytes. Subsequent experiments examined mitochondrial dynamics and morphology, superoxide production, oxygen consumption, lipid droplets formation, and target genes mRNA expression.Results: HFD in rabbits induces features of metabolic syndrome, including increased visceral fat, mitochondrial dysfunction, oxidative stress, and lipid accumulation in visceral adipose tissue. Treatment with Gal-3 inhibitor selvigaltin reversed many of these changes, specifically, improving DIM-differentiated adipocytes mitochondrial morphology and dynamics, reducing oxidative stress and lipid droplet size. Furthermore, the HFD induced upregulation of inflammatory markers (COX2, IL-1β, IL-6, TLR2, TLR4, TNFα) and immune cell polarization transcription factors (GATA3, TBX21), all noticeably decreased by selvigaltin treatment.Discussion: This study highlights mitochondrial dysfunction as a key factor in VAT impairment. In DIM-differentiated adipocytes, selvigaltin improves mitochondrial structure, dynamics, and function, reduces oxidative stress and lipid droplet size, and lowers the mRNA expression of proinflammatory-related genes. It also promotes a shift toward a healthier, more metabolically active adipocyte phenotype. Selvigaltin restores mitochondrial health, suggesting its potential as a therapeutic option for metabolic disorders involving VAT dysfunction. Further studies are needed to confirm its clinical relevance.