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The gut–brain axis provides a pathway for the interaction between gut microbiota and methamphetamine (METH) addiction. However, the gut microbial signatures during different phases of METH use remain unclear. In the present study, we established models of acquisition, extinction, and reinstatement of METH‐induced conditioned place preference (CPP) in male mice and detected the gut microbiome profiles of the fecal samples at the three phases by 16S rRNA gene sequencing. Our results revealed that the richness of the gut microbiome increased following repeated METH administration, and it decreased after 4 weeks of abstinence. The microbial richness remained at a low level after one METH challenge at the reinstatement phase. The abundance of several genera including Prevotella, Bacteroides, and Lactobacillus differentially altered among phases of METH‐induced CPP. The co‐occurrence networks of the gut microbiome became weaker and more unstable during the development of METH‐induced CPP at the extinction and reinstatement phases. Notably, the predicted gene functions of short‐chain fatty acid metabolism, which were correlated with the abundance of Prevotella, Bacteroides, and Lactobacillus, were found differentially enriched among phases of METH‐induced CPP. Our findings highlight a potential association between perturbations of the gut microbiome and different phases of METH use.

Scope: Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose-stimulated insulin secretion and glucose uptake via PI3K-Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear. Methods and results: ApoA4-knockout (KO) aggravates diet-induced obesity, hepatic steatosis, and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA-seq data. Conversely, liver-specific overexpression of ApoA4 via AAV-ApoA4 transduction reverses the effect in ApoA4-KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short-term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS-PI3K-Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity. Conclusion: ApoA4 restricts hepatic steatosis by inhibiting SREBF1-mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS-PI3K-Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity-associated NAFLD.