Diabetic medicine : a journal of the British Diabetic Association · 2025
Gastric bypass surgery improves lipid metabolism and mitochondrial function through the glutamate receptor Grin3a-mediated CaMKKβ/AMPK pathway in a rat model of type 2 diabetes.
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Zhang Lihai, Wang Jiao, Tan Baihong, Wang Xingquan, Luan Zhenglong
Аннотация
OBJECTIVE: Roux-en-Y gastric bypass (RYGB) procedure offers notable efficacy in treating type 2 diabetes mellitus (T2DM). The research focused on the glutamate receptor gene Grin3a in mediating the metabolic benefits of RYGB, particularly regarding lipid metabolism.
METHODS: Public GEO datasets (GSE2508, GSE12050, and GSE35411) were analysed to assess Grin3a expression and its associated pathways. To assess RYGB efficacy, a T2DM model was induced in rats, with Grin3a knockdown, and AMPK activation. Metabolic parameters, insulin resistance, lipid profiles, adipose tissue morphology, and mitochondrial function in epididymal white adipose tissue (eWAT) were examined. The influence of Grin3a on lipid metabolism and the CaMKKβ/AMPK axis was evaluated in vitro using 3T3-L1 adipocytes.
RESULTS: Bioinformatic analyses revealed that Grin3a was diminished in visceral adipose tissue of obese or diabetic models and up-regulated following RYGB. Its expression was associated with lipid metabolism and oxidative phosphorylation pathways. In vivo, RYGB restored Grin3a levels and improved insulin sensitivity, lipid profiles, mitochondrial function, and adipose browning, while Grin3a knockdown attenuated these effects and AMPK activation partially reversed them. In vitro, Grin3a regulated lipid metabolism and mitochondrial function in adipocytes via the CaMKKβ/AMPK pathway.
CONCLUSION: RYGB improves lipid metabolism and mitochondrial homeostasis in T2DM by activating the Grin3a-CaMKKβ/AMPK axis, offering a potential target for metabolic intervention beyond surgery.
METHODS: Public GEO datasets (GSE2508, GSE12050, and GSE35411) were analysed to assess Grin3a expression and its associated pathways. To assess RYGB efficacy, a T2DM model was induced in rats, with Grin3a knockdown, and AMPK activation. Metabolic parameters, insulin resistance, lipid profiles, adipose tissue morphology, and mitochondrial function in epididymal white adipose tissue (eWAT) were examined. The influence of Grin3a on lipid metabolism and the CaMKKβ/AMPK axis was evaluated in vitro using 3T3-L1 adipocytes.
RESULTS: Bioinformatic analyses revealed that Grin3a was diminished in visceral adipose tissue of obese or diabetic models and up-regulated following RYGB. Its expression was associated with lipid metabolism and oxidative phosphorylation pathways. In vivo, RYGB restored Grin3a levels and improved insulin sensitivity, lipid profiles, mitochondrial function, and adipose browning, while Grin3a knockdown attenuated these effects and AMPK activation partially reversed them. In vitro, Grin3a regulated lipid metabolism and mitochondrial function in adipocytes via the CaMKKβ/AMPK pathway.
CONCLUSION: RYGB improves lipid metabolism and mitochondrial homeostasis in T2DM by activating the Grin3a-CaMKKβ/AMPK axis, offering a potential target for metabolic intervention beyond surgery.