Ventromedial hypothalamus glucose‐inhibited neurones: A role in glucose and energy homeostasis?

Abstract

The ventromedial hypothalamus (VMH) plays a complex role in glucose and energy homeostasis. The VMH is necessary for the counter‐regulatory response to hypoglycaemia (CRR) that increases hepatic gluconeogenesis to restore euglycaemia. On the other hand, the VMH also restrains hepatic glucose production during euglycaemia and stimulates peripheral glucose uptake. The VMH is also important for the ability of oestrogen to increase energy expenditure. This latter function is mediated by VMH modulation of the lateral/perifornical hypothalamic area (lateral/perifornical hypothalamus) orexin neurones. Activation of VMH AMP‐activated protein kinase (AMPK) is necessary for the CRR. By contrast, VMH AMPK inhibition favours decreased basal glucose levels and is required for oestrogen to increase energy expenditure. Specialised VMH glucose‐sensing neurones confer the ability to sense and respond to changes in blood glucose levels. Glucose‐excited (GE) neurones increase and glucose‐inhibited (GI) neurones decrease their activity as glucose levels rise. VMH GI neurones, in particular, appear to be important in the CRR, although a role for GE neurones cannot be discounted. AMPK mediates glucose sensing in VMH GI neurones suggesting that, although activation of these neurones is important for the CRR, it is necessary to silence them to lower basal glucose levels and enable oestrogen to increase energy expenditure. In support of this, we found that oestrogen reduces activation of VMH GI neurones in low glucose by inhibiting AMPK. In this review, we present the evidence underlying the role of the VMH in glucose and energy homeostasis. We then discuss the role of VMH glucose‐sensing neurones in mediating these effects, with a strong emphasis on oestrogenic regulation of glucose sensing and how this may affect glucose and energy homeostasis.

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

“…Overexpression of a dominant negative form of the kinase or genetic inactivation of both AMPK α1 and α2 genes suppressed GI activity. These observations are in agreement with published data showing that AMPK is required for hypoglycemia detection by GI neurons of the VMH ( 17 ). They, however, extend these previous data by showing that both α1 and α2 isoforms similarly contribute to GI neurons glucose sensing.…”

“…In this circuit, it is usually assumed that hypoglycemia sensing by VMN GI neurons plays an essential role in triggering the counterregulatory response. However, supporting evidence is only circumstantial, based on various, non–cell-specific pharmacological or gene-silencing approaches ( 15 – 17 ). Thus, the relative importance in triggering the counterregulation response of VMN GI neurons and of GI neurons present at other locations of the afferent limb is not established ( 11 ).…”

17β-estradiol promotes acute refeeding in hungry mice via membrane-initiated ERα signaling

“…Acute refeeding is partially evoked by hypoglycemia during starvation, which regulates activities of the glucose-sensing neurons in the brain to stimulate appetite [ 21 , [25] , [26] , [27] ]. Both the ARH and vlVMH contain abundant glucose-sensing neurons and are implicated in the regulation of food intake and glucose balance [ 20 , [22] , [23] , [24] , [25] , 28 ]. In this study, we further examined the glucose-sensing functions of the ERα ARH and ERα vlVMH neurons in response to hypoglycemia.…”

“…We and others demonstrated that ERα expressed by hypothalamic neurons, including in the arcuate nucleus (ARH) and ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH), is essential to mediate estrogenic actions to prevent body weight gain in females [ [16] , [17] , [18] , [19] ]. Notably, the ARH and vlVMH are also enriched with glucose-sensing neurons [ [20] , [21] , [22] , [23] , [24] , [25] ], which play important roles in energy homeostasis [ 20 , 21 , [25] , [26] , [27] , [28] ]. In particular, we recently found that ERα neurons in the vlVMH (ERα vlVMH neurons) have strong glucose-sensing capability and can maintain normal glucose balance in female mice [ 29 ].…”

AMPK in the Ventromedial Nucleus of the Hypothalamus: A Key Regulator for Thermogenesis

“…Furthermore, AMPK within the VMH plays a crucial role in the detection of acute hypoglycemia and the initiation of the glucose counter-regulatory response (159)(160)(161)(162). Thereby, the potential hypoglycemic risk should be taken into consideration before the application of AMPK inhibitors.…”