Nutrition. 2025 Nov 23;143:113037. doi: 10.1016/j.nut.2025.113037. Online ahead of print.

ABSTRACT

OBJECTIVES: We investigated the impact of a ketogenic diet (KD) on feeding behavior, locomotion, and anxiety-like behaviors in mice.

METHODS: Three-month-old male C57BL/6 mice were fed a control diet (C, n = 120) or a diet-inducing obesity and diabetes (high-fat, high-sucrose, HFHS) (Od, n = 120). After 12 wk, mice continued their diet (C1, C4, Od1, Od4) or were switched to a KD for 1 or 4 wk (C/K1, C/K4, Od/K1, Od/K4; n = 30/group). Food-seeking behavior was assessed using the Y-maze test, while locomotion and anxiety-like behavior were evaluated using the Open Field test.

RESULTS: The HFHS diet induced metabolic dysfunction. Body weight increased significantly in Od compared to C, and severe glucose intolerance and insulin resistance were established and maintained throughout the 16 wk in Od4 (P < 0.001). Insulin sensitivity declined across several groups, including Od1, Od4, and C/K1. The Y-maze test revealed significant, time-dependent shifts in dietary preference upon transition (Od1 vs. C1, P = 0.0001; Od/K1 vs. Od/K4, P < 0.0001). Notably, mice transitioned to the KD for 4 wk (Od/K4) showed significantly increased exploratory behavior and total distance traveled in the Open Field test compared to control- and HFHS-maintained groups (C/K4 and Od4).

CONCLUSIONS: Switching to a KD induced rapid neurobehavioral adaptations (altered preferences, increased activity), but it was insufficient to reverse the severe HFHS-induced metabolic dysfunction fully. These findings highlight the differential effects of macronutrient-specific interventions on behavior versus systemic metabolism and warrant further investigation into long-term efficacy and underlying molecular mechanisms.

PMID:41455458 | DOI:10.1016/j.nut.2025.113037

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