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Hypothalamic glucose hypersensitivity induced insulin secretion in the obese Zücker rat is reversed by central ghrelin treatment
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Edité par CCSD ; Mary Ann Liebert -
Published ahead of print: 7 March 2023. International audience. AIMS: Part of hypothalamic (MBH) neurons detect changes in blood glucose level that coordinate in return the vagal control of insulin secretion. This control cascade requires the production of mitochondrial reactive oxygen species (mROS) which is altered in models of obesity and insulin resistance. Obese, insulin-resistant Zücker rats are characterized by hypothalamic hypersensitivity to glucose. This initiates an abnormal vagus-induced insulin secretion, associated to an overproduction of mROS in response to a low glucose dose. Here, we hypothesized that ghrelin, known to buffer ROS via mitochondrial function, may be a major component of the hypothalamic glucose hypersensitivity in the hypoghrelinemic obese Zücker rat. RESULTS: Hypothalamic glucose hypersensitivity induced insulin secretion of Zücker obese rats was reversed by ghrelin pretreatment. The overproduction of MBH mROS in response to a low glucose load no longer occured in obese rats that had previously received the cerebral ghrelin infusion. This decrease in mROS production was accompanied by a normalization of oxidative phosphorylation (OXPHOS). Conversely, blocking the action of ghrelin with a growth hormone secretagogue receptor antagonist in a model of hyperghrelinemia (fasted rats) completely restored hypothalamic glucose sensing induced insulin secretion that was almost absent in this physiological situation. Accordingly, ROS signaling and mitochondrial activity were increased by the ghrelin receptor antagonist. CONCLUSIONS: Ghrelin, through its action on OXPHOS, modulates mROS signaling in response to cerebral hyperglycemia and the consequent vagal control of insulin secretion. In insulin-resistant obese states, brain hypoghrelinemia could be responsible for the nervous defect in insulin secretion.
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