Hepatocyte Adenosine Kinase Aggravates the Effect of Ketogenic Diet on Increasing Body Weight and Metabolic Dysregulation in Mice

Author : Honggui Li, Xiaojing Li, Miaoyun Chen, Chaodong Wu

Abstract : Adenosine kinase (ADK) catalyzes the phosphorylation of adenosine to adenosine monophosphate. Hepatocyte-specific ADK overexpression (Hep-ADKTg) has been shown to increase adiposity and systemic insulin resistance in mice. While the ketogenic diet (KD) is often utilized for weight management, its efficacy remains controversial across different models. This study investigated the metabolic impact of long-term KD on Hep-ADKTg mice in two distinct phases: Study 1 focused on young mice before obesity onset (5-6 weeks old), and Study 2 targeted mid-aged mice with preexisting obesity (7 months old). In Study 1, seven months of KD feeding induced significantly greater weight gain and glucose intolerance in both Hep-ADKTg and wild-type (WT) mice compared to low-fat diet (LFD) controls. Notably, this obesogenic response was substantially more severe in the Hep-ADKTg group. In Study 2, the detrimental effects were further exacerbated, with KD-fed Hep-ADKTg mice exhibiting maximal weight gain and peak severity of hepatic steatosis and inflammation. In conclusion, long-term KD feeding promotes weight gain and exacerbates metabolic dysfunction in both WT and Hep-ADKTg mice. These deleterious effects are significantly amplified by ADK-driven obesity, indicating that genetic background and preexisting metabolic status are critical determinants of KD-mediated physiological outcomes.

Keywords : This work is supported, in part or in whole, by NIDDK grant (DK124854 to CW).

Conference Name : International Conference on Immunometabolism and Energy Homeostasis (ICIMEH-26)

Conference Place : Kuala Lumpur, Malaysia

Conference Date : 29th Jun 2026