Growth Hormone Excess Drives Liver Aging via increased Glycation stress

Abstract

Growth hormone (GH) plays a crucial role in various physiological functions, with its secretion tightly regulated by complex endocrine mechanisms. Pathological conditions such as acromegaly or pituitary tumors result in elevated circulating GH levels, which have been implicated in a spectrum of metabolic disorders, potentially by regulating liver metabolism. In this study, we focused on the liver, a key organ in metabolic regulation and a primary target of GH, to investigate the impact of high circulating GH on liver metabolism. We used bovine GH overexpressing transgenic (bGH-Tg) mice to conduct a comprehensive transcriptomic analysis of hepatic tissues. The bGH-Tg mouse livers exhibit dysregulated fatty acid metabolism and heightened inflammatory responses. Notably, the transcriptomic profile of young bGH-Tg mouse livers resembled that of aged livers and displayed markers of increased cellular senescence. Furthermore, these mice exhibited a significant accumulation of advanced glycation end products (AGEs). Intervention with glycation-lowering compounds effectively reversed the insulin resistance and aberrant transcriptomic signatures in the liver that are associated with elevated GH levels. These findings underscore the potential therapeutic value of glycation-lowering agents in mitigating the deleterious effects of chronic GH overexpression.