L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.

Aims: Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment.
Materials and Methods: C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo.
Results: L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway.
Conclusion: L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment.
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