Hypoglycemia-Sensing Neurons of the Ventromedial Hypothalamus Require AMPK-Induced Txn2 Expression but Are Dispensable for Physiological Counterregulation

摘要

The ventromedial nucleus of the hypothalamus (VMN) is involved in the counterregulatory response to hypogly-cemia. VMN neurons activated by hypoglycemia (glucose-inhibited [Gl] neurons) have been assumed to play a critical although untested role in this response. Here, we show that expression of a dominant negative form of AMPK or inactivation of AMPK α1 and α2 subunit genes in Sf1 neurons of the VMN selectively suppressed Gl neuron activity. We found that Txn2, encoding a mito-chondrial redox enzyme, was strongly downregulated in the absence of AMPK activity and that reexpression of Txn2 in Sf1 neurons restored Gl neuron activity. In cell lines, Txn2 was required to limit glucopenia-induced reactive oxygen species production. In physiological studies, absence of Gl neuron activity after AMPK suppression in the VMN had no impact on the counterregulatory hormone response to hypoglycemia or on feeding. Thus, AMPK is required for Gl neuron activity by controlling the expression of the antioxidant enzyme Txn2. However, the glucose-sensing capacity of VMN Gl neurons is not required for the normal counterregulatory response to hypoglycemia. Instead, it may represent a fail-safe system in case of impaired hypoglycemia sensing by peripherally located glucose detection systems that are connected to the VMN.