Endocrine Abstracts

Introduction: Hypothalamic AMP-activated protein kinase (AMPK) has emerged as a key molecular player in energy homeostasis. It participates of glucose homeostasis modulating liver glucose production. It is known that endotoxin shock presents various complicated metabolic aspects. Among them, in later phase circulatory collapse and hypoglycemia are induced with a deterioration of energy metabolism. Here we evaluated the participation of hypothalamic AMPK in the modulation of hepatic gluconeogenesis by lipopolysaccharide (LPS).

Methods: Swiss mice were used to this study. When necessary the mice were submitted to stereotaxic surgery to implant of guide cannula into the lateral ventricle (I.C.V.). Lypopolissacaride (1 mg/kg) was administered via I.P. in fasted mice and after 4 h it were killed by decapitation and hypothalamus and liver were quickly removed and stored at −80°C. When necessary the food intake was measured during dark period. The protein analyses (AMPK, ACC, PEPCK and STAT3) were performed by western blot and the level of mRNA of PEPCK and G6Pase were evaluated by real time PCR. Blood glucose was determined by glucose oxidase method.

Results: The administration of LPS IP reduced food intake (60%) and glycemia (56%) as well as the AMPK (45%) and ACC (70%) phosphorylation when compared to control mice. Besides, total NFkB expression in the hypothalamus was higher in LPS-mice than control mice. These effects were accompanied by reduced level of mRNA and protein of PEPCK (25 and 40%, respectively) and increase in tyrosine phosphorylation of STAT3 (40%) in the liver. However, the ICV injection of AICAR prevented the dephosphorylation of hypothalamic AMPK and hypoglycemia associated to LPS-IP administration. In TNFR1−/− mice the glycemia was not significantly modified by LPS injection.

Conclusion: These results suggest that hypoglycemia associated to endotoxin shock also can be triggered by TNFα signaling and inactivation of hypothalamic AMPK leading to metabolic complications.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.