Glucagon-Like Peptide 1 (GLP-1) Can Reverse AMP-Activated Protein Kinase (AMPK) and S6 Kinase (P70S6K) Activities Induced by Fluctuations in Glucose Levels in Hypothalamic Areas Involved in Feeding Behaviour

Abstract

The anorexigenic peptide, glucagon-like peptide-1 (GLP-1), reduces glucose metabolism in the human hypothalamus and brain stem. The brain activity of metabolic sensors such as AMP-activated protein kinase (AMPK) responds to changes in glucose levels. The mammalian target of rapamycin (mTOR) and its downstream target, p70S6 kinase (p70S6K), integrate nutrient and hormonal signals. The hypothalamic mTOR/p70S6K pathway has been implicated in the control of feeding and the regulation of energy balances. Therefore, we investigated the coordinated effects of glucose and GLP-1 on the expression and activity of AMPK and p70S6K in the areas involved in the control of feeding. The effect of GLP-1 on the expression and activities of AMPK and p70S6K was studied in hypothalamic slice explants exposed to low- and high-glucose concentrations by quantitative real-time RT-PCR and by the quantification of active-phosphorylated protein levels by immunoblot. In vivo, the effects of exendin-4 on hypothalamic AMPK and p70S6K activation were analysed in male obese Zucker and lean controls 1 h after exendin-4 injection to rats fasted for 48 h or after re-feeding for 2-4 h. High-glucose levels decreased the expression of Ampk in the lateral hypothalamus and treatment with GLP-1 reversed this effect. GLP-1 treatment inhibited the activities of AMPK and p70S6K when the activation of these protein kinases was maximum in both the ventromedial and lateral hypothalamic areas. Furthermore, in vivo s.c. administration of exendin-4 modulated AMPK and p70S6K activities in those areas, in both fasted and re-fed obese Zucker and lean control rats.

PAS Kinase Is a Nutrient and Energy Sensor in Hypothalamic Areas Required for the Normal Function of AMPK and mTOR/S6K1

“…Similar data were observed in VMH, although the differences were not significant. These data are consistent with the results previously described in rodents [21,25,33,34]. However, exendin-4 treatment in fasted animals induced the activation of both metabolic sensors AMPK and S6K1 in a similar way to the re-feed condition, although exendin-4 treatment decreased blood glucose levels.…”

“…We have previously reported an anorexigenic effect of exendin-4 in lean and obese rats [24] and also suggested that this effect can be explained by the regulatory effect exendin-4 has on hypothalamic AMPK and S6K1 activities [25]. Food intake was similar in wild-type and PASK-deficient mice (Fig.…”

“…Hypothalamic AMPK and mTOR/S6K1 pathways respond to changes in glucose and other nutrients in opposite ways, and their effects on the regulation of food intake can overlap. We have also recently reported that the antidiabetogenic and anorexigenic agent exendin-4 counteracts the activation/inactivation of AMPK and mTOR/S6K pathways in hypothalamic areas involved in feeding behaviour, such as VMH and LH, helping to balance the proper activation of these metabolic sensors in lean and obese rats [25].…”

“…Tissues were then exposed immediately to microwave irradiation for 5 s and then homogenized [25]. Total and phosphorylated forms were detected by western blotting using the antibodies described ( Table 1).…”

“…In this sense, we have recently reported that the regulation of AMPK and mTOR/S6K1 pathways in response to changes in nutrient concentration could be modulated by the presence of GLP-1/ exendin-4, which counteracts the activation/inactivation of AMPK and mTOR/S6K1 in the hypothalamic areas involved in feeding behaviour (VMH and LH) [25]. Thus, it seems that exendin-4 might balance the proper activation of these metabolic sensors in lean and obese rats, helping to improve pathophysiological states such as obesity [25].…”