Objective: High-fat diets (HFD) are thought to disrupt energy homeostasis to drive overeating and obesity. However, weight loss resistance in individuals with obesity suggests that homeostasis is intact. This study aimed to reconcile this difference by systematically assessing body weight (BW) regulation under HFD.Methods: Male C57BL/6 N mice were fed diets with varying fat and sugar in different durations and patterns. BW and food intake were monitored.Results: BW gain was transiently accelerated by HFD (≥40%) prior to plateauing. The plateau was consistent regardless of starting age, HFD duration, or fat/sugar content.Reverting to a low-fat diet (LFD) caused transiently accelerated weight loss, which correlated with how heavy mice were before the diet relative to LFD-only controls.Chronic HFD attenuated the efficacy of single or repetitive dieting, revealing a defended BW higher than that of LFD-only controls.Conclusions: This study suggests that dietary fat modulates the BW set point immediately upon switching from LFD to HFD. Mice defend a new elevated set point by increasing caloric intake and efficiency. This response is consistent and controlled, suggesting that hedonic mechanisms contribute to rather than disrupt energy homeostasis. An elevated floor of the BW set point after chronic HFD could explain weight loss resistance in individuals with obesity.

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3 Risma TB, Alward WLM. Successful long-term management of iris flocculi and miosis in a patient with a strong family history of thoracic aortic aneurysms and dissections associated with an MYH11 mutation.