Chlorogenic acid (CGA) has been shown to stimulate glucose uptake in skeletal muscle through the activation of AMPK. However, its effect on other metabolic pathways and likewise its effects after long-term consumption have yet to be understood. We investigated the effects of CGA on glucose tolerance, insulin sensitivity, hepatic gluconeogenesis, lipid metabolism and skeletal muscle glucose uptake in Lepr(db/db) mice. Hepatoma HepG2 was used to investigate CGA's effect on hepatic glucose production and fatty acid synthesis. Subsequently, we attempted to evaluate whether these effects of CGA are associated with the activation of AMPK. In Lepr(db/db) mice, acute treatment with CGA lowered AUCglucose in an OGTT. Chronic administration of CGA inhibited hepatic G6Pase expression and activity, attenuated hepatic steatosis, improved lipid profiles and skeletal muscle glucose uptake, which in turn improved fasting glucose level, glucose tolerance, insulin sensitivity and dyslipidemia in Lepr(db/db) mice. CGA activated AMPK, leading to subsequent beneficial metabolic outcomes, such as suppression of hepatic glucose production and fatty acid synthesis. Inhibition and knockdown of AMPK abrogated these metabolic alterations. In conclusion, CGA improved glucose and lipid metabolism, via the activation of AMPK.
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