Lipocalin 2 Deficiency Diminishes the Metabolic Effect of 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; there is no one-size-fits-all approach. In recent years, the ketogenic diet (KD) has become a popular approach for weight loss and metabolic health promotion. The main mechanism of weight loss caused by this diet is to promote the body to use fat as its primary form of energy by drastically reducing carbohydrate intake. Understanding the molecular mechanisms that contribute to the metabolic effect of the KD is critical for determining the appropriateness of this dietary approach. At the cellular and molecular level, the KD has been known to activate mitochondrial function and thermogenesis in thermogenic adipose tissue to stimulate fat utilization. However, specific molecules and genes that are involved in this metabolic regulation remain largely unknown. Lipocalin-2 (LCN2) has been characterized as an adipokine by our group and others. In our previous studies, LCN2 has been suggested as a critical regulator of mitochondrial function and thermogenesis in energy metabolism. LCN2 knockout (KO) mice exhibit impaired thermogenesis as well as exacerbated diet-induced obesity and adipose tissue inflammation. It is of interest to know if LCN2 plays a role in KD-induced energy metabolism. In this study, wild type (WT) and LCN2 KO female mice at 10 months of age were fed either a ketogenic diet or regular chow diet (RCD) for 10 weeks, followed by 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 WT and LCN2 KO mice under either the RCD or KD. However, we did find thatafter 10 weeks of KD, WT mice had significant loss of body weight by ~15% as well as significantly decreased inguinal and gonadal fat mass when compared with control mice fed a RCD. Interestingly, this effect on body weight and fat mass was not observed in LCN2 KO mice; the body weight and inguinal and gonadal fat depots were not significantly different between RCD- and KD-fed LCN2 KO mice. From the histology of the liver and adipose tissue, the KD led to significantly increased small adipocytes in the inguinal adipose tissue of WT mice, suggesting a healthy remodeling of this tissue. Intriguingly, this remodeling effect was completely absent in LCN2 KO mice. Moreover, we found that in WT mice the KD caused increased lipid accumulation in the liver compared to RCD. This reflects increased utilization of fatty acids and production of ketones. More strikingly, the KD resulted in liver lipid accumulation more profoundly in LCN2 KO mice, which may be due to mitochondrial dysfunction and defective fatty acid oxidation in the absence of LCN2. Together, we demonstrate that LCN2 deficiency diminishes the metabolic effect of the KD. This suggests that the role of LCN2 in regulating mitochondrial metabolism, thermogenesis, and other unknown physiological activities may be an important mechanism by which the KD leads to weight loss and improved metabolic health.