Central Nervous System Adaptation Mechanism of Obesity Induced by High-Fat High-Sucrose Diet: Differences in Brain Function Between Obese and Obese Resistant Rats Based on fMRI

The prevalence of metabolic obesity continues to rise, yet its pathogenesis remains controversial. This study focuses on the central neural regulatory differences underlying phenotypic divergence between diet-induced obese (OB) and obesity-resistant (OR) rats following long-term high-fat and high-sucrose diet (HFHSD) exposure. Forty male Wistar rats were randomized to normal diet group (ND, n=8) or HFHSD group (n=32). After 8 weeks, HFHSD rats were split into OB (n=7) and OR (n=8) by weight. OB/OR continued HFHSD for 8 weeks with food intake recorded. At week 15, OGTT and functional magnetic resonance imaging (fMRI) -derived amplitude of low-frequency fluctuations (ALFF) were performed. At week 16, metabolic and somatic parameters were measured. Compared to the OR group, OB rats exhibited persistent hyperphagia, elevated triglycerides, TyG index, and leptin levels, significantly increased liver, heart, and kidney masses, and impaired glucose tolerance (all P<0. 05). fMRI revealed significantly reduced ALFF in the hindbrain (bilateral brainstem and cerebellar molecular layers) and increased ALFF in the right_ dysgranularᵣetrosplenial cortex (RSC) of OB rats. Metabolic load parameters correlated negatively with hindbrain ALFF and positively with RSC ALFF, with a significant negative correlation between hindbrain and RSC activity. Long-term HFHSD induces functional remodeling of the hindbrain–RSC circuit in obese rats, and this neuroplastic alteration is closely associated with systemic metabolic burden, suggesting its involvement in the pathophysiology of obesity. • HFHSD reduces brainstem/cerebellar ALFF but raises RSC ALFF in obese rats. • These ALFF changes correlate closely with systemic metabolic burden indices. • Imbalance between reduced interoceptive and heightened episodic memory sensitivity drives obesity via retrosplenial–hindbrain circuit.