Chronic caffeine consumption prevents obesity-induced cognitive and memory impairments by reducing neuroinflammation and enhancing neuronal activity in the hippocampus

Obesity and its associated metabolic disturbances increase the risk of cognitive decline, dementia, and anxiety-related disorders. Chronic caffeine consumption was suggested to prevent synaptic and cognitive deficits, but the underlying mechanisms remain unclear. Here, we investigated whether caffeine protects against cognitive and memory deficits and anxiety induced by a hypercaloric diet, and explored the molecular mechanisms involved. Ten-week-old male Wistar rats were assigned to three groups: normal chow (control), high-fat high-sucrose (HFHSu, 25 weeks), and HFHSu plus caffeine (HFHSuCaff, 1 g/L last 11 weeks). Insulin sensitivity and glucose tolerance were assessed at weeks 14 and 25. Behavioral tests (open field, novel object recognition (NOR), Y-maze, block test, elevated plus maze (EPM)) evaluated memory, cognition, and anxiety. Hippocampal tissues were analyzed by Western blot and immunohistochemistry for insulin signaling, neuronal activity and microglia activation. HFHSu feeding promoted obesity, insulin resistance, and glucose intolerance, accompanied by impaired memory and cognition (reductions in Y-maze, NOR, and block test), increased anxiety (54.5 % time in EPM open arms), reduced hippocampal glutamatergic (41.1 % VGlut) and adenosinergic signaling (22.4 %, 11.1 %, 22.6 % in A1, A2A, A2B receptors), and elevated neuroinflammation (elevated GFAP, IBA-1, IL-6 receptor levels; altered microglial morphology) compared with control. Caffeine intake ameliorated metabolic, cognitive, and neuroinflammatory alterations, except for anxiety. Notably, caffeine increased hippocampal neuronal activity by 25.22, 94.84 and 61.51 % in CA1, CA2 and CA3 areas. In conclusion, chronic caffeine consumption mitigates obesity-induced cognitive and memory deficits via modulation of hippocampal glutamatergic and adenosinergic signaling and reduced neuroinflammation, highlighting its potential as a neuroprotective intervention.