ESPEYB19 11. Obesity and Weight Regulation New findings in adipose tissue biology (5 abstracts)
11.7. Leptin resistance before and after obesity: evidence that tissue glucose uptake underlies adipocyte enlargement and liver steatosis/steatohepatitis in Zucker rats from early-life stages
Guzzardi MA , Guiducci L , Campani D , La Rosa F , Cacciato Insilla A , Bartoli A , Cabiati M , De Sena V , Del Ry S , Burchielli S , Bonino F & Iozzo P
Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy
patricia.iozzo@ifc.cnr.it Int J Obes (Lond) 2022, 46(1):50–58. doi: 10.1038/s41366-021-00941-z
Brief Summary: This experimental study was conducted with fa/fa rats that have a homozygous defect in the leptin receptor and therefore severe leptin resistance. The animals develop extreme obesity, diabetes and metabolic syndrome. The study of young, still normal-weight animals showed that the initial hyperglycemia due to hepatic glucose overproduction is a first metabolic feature of early, severe leptin resistance. Glucose intolerance seems to be causal for the development of insulin resistance and obesity, which appear later.
Leptin is a key regulator of appetite and weight gain but most people with obesity show leptin resistance. This work addresses the fundamental question of the sequence of events in obesity development. Does the lack of action of leptin lead to the initiation of obesity and the metabolic consequences or is obesity the cause of leptin resistance? The answer is ultimately fundamental to define early intervention options and time windows for prevention and treatment.
The results show that hyperglycemia is one of the first events of early manifestation of leptin resistance. Consistent with this observation is the finding that the molecular changes leading to the expansion of adipose tissue in fa/fa rats (e.g., upregulation of glucose-6-phosphate dehydrogenase, acetyl-coenzyme A carboxylase, fatty acid synthetase) are reversible through transplantation of fat tissue from healthy rats [1]. Therefore, the molecular dysfunctions in adipose tissue are secondary rather than primary and possibly triggered by circulating rather than intrinsic factors. Increased glucose uptake by the liver plays a role in these early stages and subsequently leads to the development of NASH. Increased hepatic glucose uptake and in NASH could thus be biomarkers or diagnostic markers for leptin resistance.
Reference: 1. Ashwell M. The use of the adipose tissue transplantation technique to demonstrate that abnormalities in the adipose tissue metabolism of genetically obese mice are due to extrinsic rather than intrinsic factors. Int J Obes. 1985;9:77–82.
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