(OR17-03-24) Ketogenic Diet Worsens the Yo-Yo Effect Compared With an Isocaloric-Low Fat Diet by Inducing Metabolic Adaptation in Lipid Metabolism

Objectives: Yo-yo effect is a common occurrence of weight cycling in which individuals experience repeated weight loss and gain, a vicious cycle that increases the risk of metabolic diseases such as T2 diabetes, CVD, and all-cause mortality. The ketogenic diet (KD), often combined with calorie restriction (CR), is a popular method for rapid weight loss. Yet, the metabolic consequences of weight cycling via KD remain largely unexplored. This study aims to unravel the effects of repeated weight cycling using KD on weight maintenance, insulin sensitivity, and modulation of lipid metabolism.

Methods: Female mice aged 40 wks underwent yo-yo dieting, alternating between 50% CR feeding and ad libitum feeding of a Western diet (WD, 45% Fat, 35% Carb, 20% Protein), for 2 wks each. Mice were divided into 2 groups for the CR phase: one received a ketogenic diet ration (KD_R, 75% Fat, 5% Carb, 20% Protein), and the other an isocaloric low-fat diet ration (LF_R, 15% Fat, 65% Carb, 20% Protein). A control group was continuously fed WD without CR. After 3 cycles of yo-yo dieting, all groups were fed ad-lib WD for 3 wks more. Parameters measured included body weight, food intake, serum glucose and insulin levels, glucose tolerance test (GTT), and lipid metabolism in adipose tissues, via qPCR.

Results: Post-three cycles of yo-yo dieting, KD_R mice had significant weight gain compared to control, while LF_R showed lower weight regain and better maintenance. Despite no significant food intake increase, visceral fat mass and liver were significantly elevated in KD_R  compared with LF_R or control. Consistently, KD_R were more insulin resistant, evidenced by slower glucose disposal during GTT, elevated serum insulin levels, and increased HOMA-IR scores. Also, KD_R exhibited decreased gene expressions in fatty acid oxidation and increased gene expressions in lipogenesis and inflammation. Reduction in thermogenic gene expression in brown adipose tissue was also observed in KD_R.

Conclusions: Our findings reveal that weight cycling through a KD prompts metabolic adaptations in adipose tissue, reducing energy expenditure, and contributing to enhanced weight gain, and insulin resistance. It underscores that caution is needed when employing KD for weight loss, especially in cyclical dietary patterns, due to its potential adverse metabolic consequences.

Funding Sources: N/A