Introduction and Objective: Obesity and type 2 diabetes are strongly associated with accelerated cognitive decline. We tested whether chronic high-fat diet (HFD) feeding with sucrose intake impairs cognition in mice and whether TLC-1180, a novel mitochondrial protonophore, improves metabolic and neural deficits.Methods: Male C57BL/6J mice were fed regular chow (RC) or HFD with 1% sucrose water for 16 weeks. A separate HFD group was treated with TLC-1180 for 16 weeks (preventive study). Cognitive performance was assessed using the Open Field Test (OFT) and Novel Object Recognition Test (NORT). Neuronal activation was quantified by c-Fos immunohistochemistry.Results: HFD feeding induced obesity, hyperinsulinemia, and glucose intolerance (all p<0.0001 vs. RC). Behaviorally, HFD mice exhibited reduced exploratory activity in the OFT (decreased distance traveled and time in the center; p<0.05) and impaired recognition memory in the NORT (reduced discrimination index; p<0.05) compared with RC controls. These behavioral deficits were accompanied by reduced thalamic neuronal activation, evidenced by decreased c-Fos-positive cells. Compared with HFD, treatment with TLC-1180 reduced body weight by 14%, body weight gain by 24% (both p<0.01), hyperinsulinemia (p<0.001), and improved glucose tolerance (p<0.05). TLC-1180 also partially restored exploratory behavior and recognition memory performance (both p<0.05). Consistent with these behavioral improvements, TLC-1180 treatment restored neuronal activation in thalamic regions, with c-Fos expression returning to levels comparable to those of RC controls.Conclusion: These findings suggest that metabolic dysfunction associated with HFD feeding disrupts thalamic circuit activity and cognitive behavior, and that pharmacological correction of metabolic parameters with the mitochondrial protonophore TLC-1180 can partially restore thalamocortical engagement and behavioral performance despite partial weight reduction.
R. Calais Gaspar: None. H.N. Morgan: None. S. Parikh: None. J. Furtado: None. J.C. Uribe Isaza: None. J. Zheng: None. F. Sucupira: None. M. Sharma: None. R.P. Myers: Employee; Current; OrsoBio, Inc. G. Subramanian: Employee; Current; OrsoBio. A. Vijayakumar: Employee; Current; OrsoBio, Inc. M. Schneeberger Pane: None. G. Shulman: Consultant; Current; Novo Nordisk A/S. Research Support; Current; Novo Nordisk A/S. Other – collaboration; Current; Ionis Pharmaceuticals. Advisory Panel; Current; ESPERION Therapeutics, Inc. Research Support; Current; Novo Nordisk Foundation. Advisory Panel; Current; Orsobio. Research Support; Current; Orsobio. Advisory Panel; Current; Village S.S.D.
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