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| Author(s): |
Gustavo Aparecido dos Santos
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2013-04-26 |
| Examining board members: |
Marcio Alberto Torsoni;
Dennys Esper Cintra;
Leonardo dos Reis Silveira
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| Advisor: | Marcio Alberto Torsoni |
| Abstract | |
Endotoxic hypoglycaemia has an important role in the survival rates of septic patients. Currently, the hypothalamus is the main area of the brain that regulates glycemic homeostasis. Previous studies have demonstrated that hypothalamic AMP-activated protein kinase (AMPK) activity is sufficient for nutrient-sensing mechanisms to modulate glucose production. However, the role of hypothalamic AMPK in hypoglycaemia associated with endotoxemia is unknown. The aims of this study were to examine hypothalamic AMPK dephosphorylation in lipopolysaccharide (LPS) treated mice and to determine whether pharmacological AMPK activation could reduce the effects of endotoxemia on the liver metabolism of glucose. Fasted Swiss mice and C3H/HeJ (TLR4-receptor mutant) and C3H/HeN (wild type) mices received intraperitoneal injections of LPS (1mg/kg). LPS-treated mice showed reduced food intake and diminished basal glycemia, increased serum TNF? and IL1? levels and hypothalamic p-TAK and TLR4/MyD88 association. These effects were accompanied by hypothalamic AMPK/ACC dephosphorylation and reduction of glucose production in the liver. Interestingly, the LPS treated mice liver also showed diminished expression of PEPCK/G6Pase and reduction in p-FOXO1, p-AMPK, p- STAT3 and p-JNK level. In contrast, the pharmacological hypothalamic AMPK activation blocked the effects of LPS on the hypothalamic AMPK phosphorylation, liver PEPCK expression and glucose production. Furthermore, the effects of LPS were TLR4-dependent because no effect on hypothalamic AMPK phosphorylation, liver PEPCK expression and basal glycemia was detected in C3H/HeJ (TLR4- receptor mutant) mice. These results suggest that hypothalamic AMPK activity may be an important pharmacological target to control glucose homeostasis during endotoxemia (AU) | |
| FAPESP's process: | 10/14034-6 - Modulation of hepatic metabolism of glucose by activation of inflammatory pathway: the role of hypothalamic AMPK and toll like receptor 4 (TLR4)proteins. |
| Grantee: | Gustavo Aparecido dos Santos |
| Support Opportunities: | Scholarships in Brazil - Master |