Efeito do tratamento com Vesículas extracelulares do leite bovino em alterações ósseas e metabólicas na Obesidade induzida por Dieta em Camundongos

Abstract

Obesity is a chronic disease resulting from a positive energy balance associated with bone alterations and is involved in the pathophysiology of several metabolic disorders. Treatments for bone loss include calcium and vitamin D supplementation, as well as medication, but current therapies are not fully effective, requiring new strategies. Bovine milk extracellular vesicles (MEVs) are nanoparticles formed from the plasma membrane with significant immunomodulatory activity. These particles are composed of proteins, lipids, ribonucleic acids (RNA), and microRNAs, which play a role in cell signaling. Recent studies have demonstrated the positive effects of MEVs on bone cell function in vitro and in vivo, showing benefits in maintaining bone health in various pathological contexts, such as experimental models of osteoporosis induced by obesity, ovariectomy, and glucocorticoids. Therefore, the objective of this study was to evaluate the effect of oral administration of MEVs on bone loss and metabolic alterations in mice with obesity induced by a diet rich in refined carbohydrates (HC) and saturated fat (HF). Eight-week-old male BALB/c and C57BL/6 mice were fed an HC or HF diet, respectively, throughout the experimental period (12 weeks) and treated with MEVs from week 9 until the end of the experiment. MEVs were offered in the animals' drinking water at a dose of 14.3 x 106 particles/mL. Our results demonstrated that both obesogenic diets led to metabolic alterations of obesity in the mice, such as adipose cell hypertrophy, hyperglycemia, hyperlipidemia, and liver alterations. Associated with this, a significant reduction in bone mass and quality was observed, as well as alterations in tissue cell function, both in the maxilla and femur of the animals. In contrast, animals fed the HC diet and treated with MEVs demonstrated a reversal of bone damage, in addition to a reduction in osteoclast activity at the expense of an increase in osteoblasts, osteocytes, and the expression of the RUNX2 marker, associated with a reduction in the RANKL/OPG ratio. These results were combined with a reduction in adipocyte hypertrophy, leptin, and the inflammatory marker PTX3, in addition to an increase in adiponectin. These animals also showed improvements in glucose and lipid metabolism, as well as in liver histopathological scores. In contrast, animals fed the HF diet and treated with MEVs demonstrated no protective effects on femoral bone mass, adipose tissue, or systemic metabolism, but showed a reduction in maxillary bone loss and a significant effect on hepatic fat deposition. Therefore, MEVs may act as both a treatment and a prevention in models of moderate obesity, but not fully in severe obesity. The reversal or reduction of bone damage may be related to the improvement in the metabolic profile, as observed after treatment with MEVs in the model of obesity induced by an HC diet. However, further studies are essential to elucidate the metabolic pathways involved in the action of MEVs and, thus, define more assertive interventions in the context of obesity.