OBJECTIVE: To identify Cald1 as a novel regulator of Linggui Zhugan decoction（苓桂术甘汤） for improving insulin resistance in vivo and in vitro.METHODS: Sprague-Dawley rats were randomly assigned to 3 groups that were received a normal rat chow diet, high-fat diet（HFD）, and an HFD plus LGZGD, respectively. The homeostatic model assessment（HOMA）-insulin resistance（IR） index was used to determine IR. Gene microarray methodology was used to identify differentially expressed genes（DEGs） in the three groups of rats. The DEGs associated with IR were confirmed by quantitative real-time polymerase chain reaction. Additionally,Mouse 3 T3-L1 pre-adipocytes were differentiated into mature 3 T3-L1 adipocytes, which were then treated with tumor necrosis factor（TNF）-α to induce cellular IR. Lipid accumulations were identified by Oil Red O staining. Glucose uptake was assessed using the3 H-2-DG test.RESULTS: In this study, we found Cald1 was further screened to validate its biological function in3 T3-L1 adipocytes induced to develop IR. In vitro experiments showed that insulin-stimulated 3 H-2-DG uptake by IR 3 T3-L1 adipocytes was increased after LGZGD intervention, which was associated with a down-regulation of Cald1 expression.CONCLUSION: LGZGD ameliorates HFD-induced IR in rats and TNF-α induced IR in adipocytes by down-regulating Cald1 expression.