Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy.
Department of Surgical, Medical, Molecular Pathology and Critical Care Medicine, Division of Pathology, Pisa University Hospital, Pisa, Italy.
Int J Obes (Lond). 2022 Jan;46(1):50-58. doi: 10.1038/s41366-021-00941-z. Epub 2021 Sep 6.
Leptin resistance occurs in obese patients, but its independent contribution to adiposity and the accompanying metabolic diseases, i.e., diabetes, liver steatosis, and steatohepatitis, remains to be established. This study was conducted in an extreme model of leptin resistance to investigate mechanisms initiating diabetes, fat expansion, liver steatosis, and inflammatory disease, focusing on the involvement of glucose intolerance and organ-specific glucose uptake in brown and subcutaneous adipose tissues (BAT, SAT) and in the liver.
We studied preobese and adult Zucker rats (fa/fa, fa/+ ) during fasting or glucose loading to assess glucose tolerance. Relevant pancreatic and intestinal hormonal levels were measured by Milliplex. Imaging of F-fluorodeoxyglucose by positron emission tomography was used to quantify glucose uptake in SAT, BAT, and liver, and evaluate its relationship with adipocyte size and biopsy-proven nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH).
Preobese fa/fa pups showed impaired glucose tolerance, adipocyte enlargement, hepatic microsteatosis, and lobular inflammation, with elevated hepatic post-glucose load glucose uptake and production. Adult fa/fa rats had more severe glucose intolerance, fasting hyperglycemia, hormonal abnormalities, elevated glucose uptake in SAT and BAT, and more markedly in the liver, together with macrosteatosis, and highly prevalent hepatic inflammation. Organ glucose uptake was proportional to the degree of fat accumulation and tissue inflammation and was able to dissect healthy from NAFLD and NAFLD/NASH livers. Most severe NASH livers showed a decline in glucose uptake and liver enzymes.
In fa/fa Zucker rats, leptin resistance leads to glucose intolerance, mainly due to hepatic glucose overproduction, preceding obesity, and explaining pancreatic and intestinal hormonal changes and fat accumulation in adipocytes and hepatocytes. Our data support the involvement of liver glucose uptake in the pathogenesis of liver inflammatory disease. Its potential as more generalized biomarker or diagnostic approach remains to be established outside of our leptin-receptor-deficient rat model.
瘦素抵抗发生于肥胖患者，但它对肥胖和伴随的代谢疾病（如糖尿病、肝脂肪变性和脂肪性肝炎）的独立贡献仍有待确定。本研究在瘦素抵抗的极端模型中进行，旨在研究引发糖尿病、脂肪扩张、肝脂肪变性和炎症性疾病的机制，重点关注葡萄糖耐量以及棕色和皮下脂肪组织（BAT、SAT）和肝脏中葡萄糖摄取的器官特异性。
我们在禁食或葡萄糖负荷期间研究了肥胖前和成年 Zucker 大鼠（fa/fa、fa/+），以评估葡萄糖耐量。通过 Milliplex 测量相关的胰腺和肠道激素水平。通过正电子发射断层扫描（PET）对 F-氟脱氧葡萄糖进行成像，以定量测量 SAT、BAT 和肝脏中的葡萄糖摄取，并评估其与脂肪细胞大小以及经活检证实的非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）的关系。
肥胖前的 fa/fa 幼崽表现出葡萄糖耐量受损、脂肪细胞增大、肝微脂肪变性和小叶炎症，肝葡萄糖负荷后摄取和产生增加。成年 fa/fa 大鼠表现出更严重的葡萄糖耐量受损、空腹高血糖、激素异常、SAT 和 BAT 葡萄糖摄取增加，肝脏更为显著，伴有大脂肪变性和高度普遍的肝炎症。器官葡萄糖摄取与脂肪积累和组织炎症的程度成正比，能够区分健康和非酒精性脂肪性肝病（NAFLD）以及非酒精性脂肪性肝炎（NASH）肝脏。最严重的 NASH 肝脏表现出葡萄糖摄取和肝酶下降。
在 fa/fa Zucker 大鼠中，瘦素抵抗导致葡萄糖耐量受损，主要是由于肥胖前的肝葡萄糖过度产生，解释了胰腺和肠道激素变化以及脂肪细胞和肝细胞中的脂肪堆积。我们的数据支持肝脏葡萄糖摄取参与肝脏炎症性疾病的发病机制。其作为更广泛的生物标志物或诊断方法的潜力仍有待于在我们的瘦素受体缺陷大鼠模型之外得到证实。
