2nd Edition of International Obesity and Metabolism Conference 2026

Abstract

As a liver-abundant enzyme, adenosine kinase (ADK) catalyzes the phosphorylation of adenosine to generate adenosine monophosphate. We recently showed that hepatocyte-specific ADK overexpression in mice brought about excessive fat deposition, e.g., increased adiposity and hepatic steatosis, along with increased severity of systemic insulin resistance. In terms of managing body weight, ketogenic diet (KD) has been implicated as an effective strategy as this is supported by evidence from various mouse models of obesity. However, there also are multiple studies showing contradictory outcomes of KD. Because of this, there is a need to validate effect of KD on altering body weight in mice with or without preexisting obesity. For this purpose, we chose hepatocyte-specific ADK overexpressing (Hep-ADK^Tg) mice for the present study and examined the interplay between ADK and KD in the context of altering body weight and metabolic responses. Since Hep-ADK^Tg mice started to display an obesity phenotype at 5 months of age under a chow diet, we performed two studies. In Study 1 (young mice before obesity onset), male Hep-ADK^Tg mice and its wild-type (WT) control mice, at 5-6 weeks of age, were fed a low-fat diet (LFD, 10% fat calories) or KD (90% fat calories) for 7 months . In Study 2 (mid-aged mice with preexisting obesity), male Hep-ADK^Tg mice and its WT control mice, at 7 months of age, were fed an LFD or KD for 7 months. During dietary feeding, all mice were monitored for their body weight and food intake monthly. In addition, glucose tolerance tests were performed for all mice at one week prior to the end of dietary feeding. At the end of dietary feeding, body weight of all mice was recorded, and tissue samples were harvested. In Study 1, both WT and Hep-ADK^Tg mice exhibited significantly greater weight gain following seven months of KD compared to their respective LFD controls. Notably, this obesogenic response was more pronounced in Hep-ADK^Tg mice, suggesting that ADK overexpression heightens susceptibility to KD-induced weight gain. Consistently, the severity of metabolic dysregulation, including glucose intolerance, hepatic steatosis, and inflammation, was greater in KD-fed mice than in those on an LFD, with these effects being significantly more potent in the Hep-ADK^Tg group. In Study 2, the capacity of KD to promote weight gain and exacerbate metabolic dysfunction was further potentiated. This was evidenced by maximal increases in body weight and peak severity of hepatic steatosis and inflammation in KD-fed Hep-ADK^Tg mice relative to all other groups. Collectively, these results indicate that long-term KD feeding (7 months) significantly increases body weight and metabolic dysregulation in both WT and Hep-ADK^Tg mice; however, these deleterious effects are substantially amplified in the context of ADK-driven obesity. Consequently, both genetic background and pre-existing metabolic status are critical factors that profoundly dictate the metabolic outcomes of a ketogenic diet.