Hepatic transcriptomic changes following equivalent weight loss by calorie restriction or vertical sleeve gastrectomy in mice with hepatic steatosis

Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to transcriptomically profile hepatic changes in mice undergoing VSG. Methods: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). Results: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p=0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p=0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p=0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acyl, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. Conclusion: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG. Overall design: Mice with Diet Induced Obesity were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Four samples from each treatment group were selected for NGS sequencing, followed by Gene Set Enrichment Analysis.

袖状胃切除术（Sleeve gastrectomy, VSG）可改善肝脏脂肪变性，且该改善与体重减轻相关。本研究旨在探究两点：其一，对于饮食诱导肥胖（Diet-induced obesity, DIO）小鼠，袖状胃切除术是否可实现不依赖体重减轻的肝脏脂肪变性改善；其二，对接受袖状胃切除术的小鼠的肝脏变化进行转录组学分析。方法：将饮食诱导肥胖小鼠分为三组，分别接受袖状胃切除术、假手术后进行食物限制以匹配袖状胃切除术组的体重（Sham-WM组）、假手术后恢复自由进食（Sham-Ad lib组）。于研究期末开展肝脏转录组学检测，并将各处理组与仅接受假手术的自由进食小鼠（Sham-Ad lib组）进行对照比较。结果：袖状胃切除术组的肝脏脂肪变性改善程度显著优于Sham-WM组（Sham-Ad lib、Sham-WM及VSG组的肝脏甘油三酯水平分别为2.5 ± 0.1、2.1 ± 0.2、1.6 ± 0.1 mg/mg，p=0.003）。仅VSG组的胰岛素抵抗稳态模型评估指数得到显著改善（Sham-Ad lib、Sham-WM及VSG组分别为51.2 ± 8.8、36.3 ± 5.3、22.3 ± 6.1，p=0.03）。作为胰高血糖素抵抗的评估指标，胰高血糖素-丙氨酸指数在VSG组中下降，但在Sham-WM组中显著升高（Sham-Ad lib、Sham-WM及VSG组分别为9.8 ± 1.7、25.8 ± 4.6、5.2 ± 1.2，p=0.0003）。调控脂肪酸合成的胰高血糖素受体信号通路下游基因（Acaca、Acacb、Me1、Acyl、Fasn及Elovl6）在VSG组中表达下调，而在Sham-WM组中表达上调。结论：胰高血糖素敏感性的改变可能参与了袖状胃切除术后不依赖体重减轻的肝脏脂肪变性改善。整体实验设计：将饮食诱导肥胖小鼠分为三组，分别接受袖状胃切除术、假手术后进行食物限制以匹配VSG组体重（Sham-WM组）、假手术后恢复自由进食（Sham-Ad lib组）。每组选取4个样本进行二代测序（NGS sequencing），随后开展基因集富集分析（Gene Set Enrichment Analysis, GSEA）。