Type 2 Diabetes, Metabolic Syndrome, Lipid Metabolism

Abstract

Background: Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. Methods: To directly address such issues, the authors generated POMC-␣ 2 /KO and POMC-␣ 2 /KO mice lacking AMPK-␣ 2 in proopiomelanocortin (POMC)-and agouti-related protein (AgRP)-expressing neurons, key regulators of energy homeostasis. Results: POMC-␣ 2 /KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, POMC-␣ 2 /KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK-␣ 2 -deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Conclusion(s): Taken together with the divergent phenotypes of POMC-␣ 2 /KO and AgRP-␣ 2 /KO mice, the data suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.Using genetically modified mice, this paper demonstrates that AMP-kinase is not a general sensor for the regulation of energy homeostasis in the hypothalamus as it mediates glucose-sensing signaling mechanisms but is not involved in the leptin and insulin pathways. AMPK is an enzyme involved in pathways that generate ATP, and participates in energy homeostasis in response to nutrients and hormonal signals. In peripheral tissues, it is involved in catabolic pathways (fat oxidation, lipolysis and suppression of hepatic glucose production). In the central nervous system, AMPK is seen as a general integrator of energy homeostasis. Anorexigenic signals such as leptin, insulin and glucose inhibit AMP activity, promoting food intake ( fig. 1). The different neuronal populations were not identified in the hypothalamus. The generation of two specific-KO mouse models (deficient in AMPK activity in POMC and AgRP neurons) shows two different phenotypes, indicating a clear dissociation between the signaling mechanisms by which POMC and AgRP neurons sense glucose and hormonal signals: the effects of leptin and insulin were not affected by AMPK activity suppression. Electrophysiological studies confirm that APMK is not necessary for the effects of leptin and insulin. Conversely, glucose sensing is abolished in both neuron populations when AMPK activity is suppressed and the mechanism for this remains unknown but does not appear to be only a general protective one. Glucose levels in the hypothalamus are involved in the orexigenic process via GLUT2, K-ATP channels and glucokinase [...