Acute anti-obesity treatment with celastrol reduces body weight, cerebral inflammation and metabolic imbalances in mice

Background The global rise in obesity is predominantly driven by energy dense foods consumption and sedentary lifestyles that contribute to a growing burden of metabolic and neuroinflammatory comorbidities. Obesity is linked to a chronic low-grade inflammatory profile, as well as to a localized neuroendocrine imbalance and inflammatory response in the brain, including regions regulating energy homeostasis, reward and motivational centers. Anti-obesity medications that reduce body weight are being extensively used across the world, and the specific cerebral mechanisms underlying its action are yet to be clarified. Methods We investigated the cerebral and systemic effects inherent to obesity development and treatment with celastrol, an anti-obesity and anti-inflammatory agent, in a murine model of diet-induced obesity (DIO) using a multimodal approach. We characterized obesity progression and celastrol treatment by comparing body weight, food intake, changes in brain microstructure by in vivo magnetic resonance imaging (MRI) and ex vivo by immunofluorescence, investigated its metabolic rearrangements using ¹ H high-resolution magic angle spinning spectroscopy and draw the hormonal profiles between DIO and control animals, with or without treatment. Results Our findings indicate that obesity induces detectable neuroinflammation, evident through diffusion MRI alterations and increased microglial activation. Treatment resulted in significant body weight reduction, diffusion MRI signal changes, particularly in the hypothalamus, a decrease in microglial activation, a regularization of cerebral osmolyte concentrations, decreased cellular proliferation and astrocytic metabolism markers, and anti-inflammatory cytokine changes. Conclusions These results support the role of celastrol as an anti-obesity treatment, acting through anti-inflammatory mechanisms in the hypothalamus, and prove MRI techniques as valid tools to characterize its effects.