Hypothalamic AMPK-induced autophagy ameliorates hypercatabolism in septic rats by regulating POMC expression

Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that activ...

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Published in:Biochemical and biophysical research communications 2018-03, Vol.497 (4), p.1089-1096
Main Authors: Cao, Chun, Gao, Tao, Cheng, Yan, Cheng, Minhua, Su, Ting, Xi, Fengchan, Wu, Cuili, Yu, Wenkui
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Autophagy
BLOOD
Hypercatabolism
Hypothalamic AMPK
HYPOTHALAMUS
INJECTION
PATHOGENESIS
PHOSPHOTRANSFERASES
POMC
RATS
Sepsis
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Summary:Hypercatabolism plays a critical role in the pathogenesis of post-critical care debility in critical patients. Central nervous system may exerte a critical role in the regulation of hypercatabolism. However, little is known about the exact mechanisms of the central role. Here, we reported that actived hypothalamic AMP-activated protein kinase (AMPK)-induced autophagy modulated the expression of POMC to ameliorate hypercatabolism in septic rats. Firstly, rats were i.c.v. injected with the lentiviral vector containing shRNA against POMC. Two weeks after injections, rats were intraperitoneally injected with LPS or saline. Twenty-four hours later, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism markers and neuropeptides expression were detected. Then, rats were injected with AICAR or saline into third ventricle and promptly intraperitoneally injected with LPS or saline. Twenty-four hours after infection, blood, skeletal muscle and hypothalamus tissues were obtained. Hypercatabolism, hypothalamic AMPK-induced autophagy markers and neuropeptides expression were also detected. Results showed that sepsis would decrease the level of hypothalamic autophagy accompany with the alterations of POMC expression and hypercatabolism. Knocking out hypothalamus POMC expression could significantly ameliorate hypercatabolism. Moreover, Central activation of AMPK-induced autophagy pathway via third ventricle injection of AICAR, an AMPK activator, could efficiently ameliorate hypercatabolism as well as attenuate the elevated POMC expression rather than other neuropeptides. Taken together, these results suggested that hypothalamic AMPK-autophagy pathway as a regulatory pathway for POMC expression was essential for hypercatabolism during sepsis. And hypothalamic AMPK-autophagy activation could attenuate the POMC expression to ameliorate hypercatabolism. Pharmaceuticals with the ability of activating hypothalamic AMPK-autophagy pathway may be a therapeutic potential for hypercatabolism in septic patients. •Sepsis decreases hypothalamic AMPK-autophagy and increases POMC.•Hypercatabolism is associated with hypothalamic autophagy and POMC.•Central activation of AMPK-autophagy ameliorates elevated POMC during sepsis.•Central activation of AMPK-autophagy ameliorates hypercatabolism during sepsis.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.02.184