Sex differences in the physiological and cognitive-behavioral effects of high fat and ketogenic diets in mice
Authors: Lawrence Zachary , James Shalet , Noto Natalia , Restropo Yazmin , Uribe Iliana , Hernandez Ariana , Wind Eleanor , Tamiya Blanche , Pulido-Correa Victoria , Pandya Meha , Speth Robert , Robison Lisa 
Published: May 2023

Consumption of high fat diet (HFD) contributes to several neurological disorders and metabolic disease. Our previous work has shown that a HFD results in sex-specific effects in C57Bl/6J mice, including adult hippocampal neurogenesis, neuroinflammation, and performance on cognitive-behavioral tasks. In general, females are more negatively impacted compared to males, even when the metabolic effects of HFD are similar amongst the sexes. The ketogenic (Keto) diet is a popular fad diet that involves limiting the intake of carbohydrates to induce a state of “nutritional ketosis.” This state promotes ketogenesis while reducing gluconeogenesis. While the Keto diet is also very high in fat content, it appears to hold potential for neuroprotection against brain aging and neurodegenerative disorders, as well as boost mood and cognitive function in young healthy individuals. Further research on the effects of the Keto diet remains to be underexplored in a sex-specific manner. Also, most prior research using animal models has generally used a very strict Keto diet that is not ideal for translational relevance (~0% carbohydrates). Thus, the goal of this study is to compare the physiological and cognitive-behavioral effects of both a high fat and translationally relevant Keto diet to a low-fat control diet in adult male and female mice. Male and female C57Bl/6J mice were fed either a low fat (LF; 10% fat, 70% carbs), high fat (HF; 60% fat, 20% carbs), or Keto (Keto; 80% fat, 5% carbs) diet beginning at 2-3 months of age. Body weight, food intake, and fluid intake were measured weekly throughout the experiment. Five months into the diet intervention, mice underwent a battery of behavioral tests to assess potential changes in general activity levels, anxiety-like behavior, and several domains of cognitive function. Diabetic status and ketosis were assessed, and tissues and organs were collected and weighed at the end of the experiment to further determine physiological effects of the various diets. As expected, HFD resulted in increased weight gain and glucose intolerance compared to LF diet in both males and females. Sex-specific changes in fat accumulation and organ mass were also noted in response to HF diet. Keto diet induced a state of mild ketosis to a similar degree amongst the sexes, with fewer physiological alterations compared to HFD. While HF and Keto diets tended to reduce exploratory behavior in males, this effect was not seen in females. Of note, preliminary data suggests that while spatial working memory is not affected by any of these diet interventions, Keto diet may improve long-term spatial memory in male mice only. Taken together, these findings demonstrate the physiological and cognitive-behavioral effects of a HFD vs. Keto diet in males and females. Even a Keto diet that produces only a mild state of ketosis may improve some aspects of cognition in adulthood, albeit potentially in a sex-specific manner that favors males. Nova Southeastern University President's Faculty Research and Development Grant (LSR), Nova Southeastern University College of Psychology Faculty Research Fellowship (LSR), American Heart Association Award #946666 (LSR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.