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

Abstract

The ventromedial nucleus of the hypothalamus (VMN) is involved in the counterregulatory response to hypoglycemia. VMN neurons activated by hypoglycemia (glucose-inhibited [GI] 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 GI neuron activity. We found that Txn2 , encoding a mitochondrial redox enzyme, was strongly downregulated in the absence of AMPK activity and that reexpression of Txn2 in Sf1 neurons restored GI neuron activity. In cell lines, Txn2 was required to limit glucopenia-induced reactive oxygen species production. In physiological studies, absence of GI 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 GI neuron activity by controlling the expression of the antioxidant enzyme Txn2. However, the glucose-sensing capacity of VMN GI 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.

New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

“…Although the protection of AMPKα 1 deletion in SF1 neurons against HFD-induced obesity was mainly associated with increased energy expenditure, slight alterations in glucose balance (decreased glycemia and improved glucose tolerance without changes in insulin sensitivity and insulin levels) found in mutant mice fed with an HFD, could be involved [56]. The moderate role of AMPK in glucose sensing by SF1 neurons in the VMH was also reported in a recent study in which AMPK activity suppression led to selective depletion of SF1 glucose inhibitory (GI) neurons, and activated CRR without affecting the presence of glucose excited (GE) neurons [69]. The authors suggested that the primary role of AMPK in SF1 GI neurons is to control the expression of Txn2 (encoding a mitochondrial redox enzyme), providing protection against ROS produced during hypoglycemia.…”

Glucokinase neurons of the paraventricular nucleus of the thalamus sense glucose and decrease food consumption

“…The resulting increase in ATP/ADP ratio closes a K ATP channel, leading to plasma membrane depolarization and, in beta-cells, to insulin secretion or, in neurons, to increased firing activity ( Ashcroft and Rorsman, 2012 ). Activation of GI neurons by hypoglycemia requires the activation of AMP-dependent protein kinase ( Quenneville et al., 2020 ), closure of a chloride channel ( Hirschberg et al., 2020 ), or inhibition of the Na + /K + ATPase as a result of a fall in intracellular ATP levels ( Kurita et al., 2015 ; Silver and Erecinska, 1998 ). However, the mechanisms of gluco-detection by GE and GI neurons are not fully characterized ( Thorens, 2012 ).…”

Neuroestradiol regulation of ventromedial hypothalamic nucleus 5′-AMP-activated protein kinase activity and counterregulatory hormone secretion in hypoglycemic male versus female rats

“…Electrophysiological studies have documented the presence of dedicated metabolic-sensory neurons in the VMN that supply a dynamic cellular energy readout by increasing (‘glucose-inhibited’) or decreasing (‘glucose-excited’) their synaptic firing as ambient energy substrate levels fall [29] , [30] . Recent studies involving genetic manipulation of VMN AMPK α1 and −2 subunit gene expression affirm that both regulatory subunits function to promote increased electrical activity of local ‘glucose-inhibited’ metabolic-sensory neurons during hypoglycemia, but do not regulate ‘glucose-excited’ nerve cell firing [31] . Thus, current documentation of sex differences in neuroanatomical localization of hypoglycemia-associated up-regulation of pAMPK α1 and −2 subunit proteins in the VMN infer that ‘glucose-inhibited’ neurons occur throughout the rostro-caudal length of the female VMN, but are restricted to rostral and middle segments of this structure in males.…”