Lipocalin 2 Deficiency Diminishes the Metabolic Effect of The Ketogenic Diet in Female Mice

Abstract

Obesity is a worldwide public health concern, and prevalence in the United States is continuously increasing. Treatment of obesity ranges from dietary approaches to gastric surgery, which can be life-threatening. Research has identified gene expression as a component worthy of consideration when deciding the appropriateness of a dietary approach. Expression of the Lipocalin-2 (Lcn2) gene has been suggested as a potential regulatory mechanism whose expression appears to be correlated to obesity. Identifying a diet that could help regulate the expression of this gene could be beneficial for management of weight and obesity-related diseases. In recent years the ketogenic diet has become popular for weight loss. By eliminating carbohydrates from the diet, it requires the body to use fat as its primary form of energy which is thought to be the cause of the wight loss observed as a result of this diet. Determining the affect the ketogenic diet has in the absence of the LCN2 gene could help identify potential metabolic pathways the ketogenic diet may affect, if any, that leads to weight loss. Both Lcn2 knockout (Lcn2 -/-) and wild type mice were examined after being fed either a normal chow or a ketogenic diet. Tissue weight and metabolic markers were then examined in the attempt to determining the affect, if any, that the ketogenic diet has in the absence of the LCN2 gene. Discovering weather or not there is a difference between these two groups could help identify potential metabolic pathways the ketogenic utilizes that leads to weight loss. In this study, wild type and Lcn2-/- female mice at 10 months of age were fed either a ketogenic diet or normal chow diet for 10 weeks, followed by the metabolic assessments including food intake, body weight, fat mass, and histology of tissues. Our results showed that there was no significant difference in daily food intake between wild type and Lcn2-/- mice under either the normal chow or ketogenic feeding condition. However, we found that after 10 weeks on the ketogenic diet mice has significantly decreased inguinal and gonadal fat mass when compared with control mice fed a normal chow diet. Interestingly, the effect of ketogenic diet on body weight and fat mass was not observed in Lcn2-/- mice; the body weight and tissue weight of inguinal and gonadal fat depots were not significantly different between normal chow- and ketogenic diet-fed Lcn2-/- mice. From the histology of liver and adipose tissue, the ketogenic diet led to significantly increased small adipocytes in inguinal adipose tissue, suggesting a healthy remodeling of inguinal adipose tissue. Intriguingly, this adipose tissue remodeling effect of the ketogenic diet was completely absent in Lcn2-/- mice. Moreover, we found caused increased lipid accumulation in liver of mice fed the ketogenic diet compared to those fed a normal chow diet, which reflects increased utilization of fatty acids and production of ketogenesis. More strikingly, the ketogenic diet resulted in liver lipid accumulation more profoundly in Lcn2-/- mice, which may be caused by mitochondrial dysfunction and defective fatty acid oxidation in the absence of Lcn2. Together, we demonstrate that Lcn2 deficiency diminishes the metabolic effect of ketogenic diet. This suggests that activating the function of Lcn2 gene in regulating mitochondrial metabolism, thermogenesis, and other unknown physiological activities may be an important mechanism by which the ketogenic stimulates the utilization of fat leading to weight loss