Estrogen receptor-α expressing neurons in the ventrolateral VMH regulate glucose balance

Abstract

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH) or glucose-excited neurons (GE-ERα vlVMH). Hypoglycemia activates GI-ERα vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH to mpARH circuit and inhibition of ERα vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

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

“…Consistent with our previous report [ 29 ], all of the tested ERα vlVMH neurons from the female control mice were glucose-sensing, with 57.6% being GE neurons and 42.4% being GI neurons ( Figure 5 G and Supplemental Figure 3B ). We further demonstrated that all of the tested ERα vlVMH neurons from the ERα-C451A and ERα-AF2 0 mice were also glucose-sensing with similar GE/GI compositions ( Figure 5 G).…”

“…Within the vlVMH, ERα-expressing neurons partially overlap with those expressing steroidogenic factor-1 [ 17 ] and/or vesicular glutamate transporter-2 [ 59 ]. We recently identified a chloride ion channel, anoctamin 4, as a GI-ERα vlVMH marker, and Abcc8, a subunit of the ATP-sensitive potassium channel, as a GE-ERα vlVMH marker [[ 29 ]]. These two ion channels are important for mediating the glucose-sensing functions of GI- and GE-ERα vlVMH neurons, respectively [[ 29 ]].…”

“…We recently identified a chloride ion channel, anoctamin 4, as a GI-ERα vlVMH marker, and Abcc8, a subunit of the ATP-sensitive potassium channel, as a GE-ERα vlVMH marker [[ 29 ]]. These two ion channels are important for mediating the glucose-sensing functions of GI- and GE-ERα vlVMH neurons, respectively [[ 29 ]]. Within the ARH, ERα-expressing neurons partially overlap with those expressing pro-opiomelanocortin [ 17 , 41 ], kisspeptin [ 60 ], or tyrosine hydroxylase [ 61 ].…”

“…Female ERα-ZsGreen, ERα-ZsGreen/ERα-C451A mutant, and ERα-ZsGreen/ERα-AF2 0 mutant mice (12 weeks of age) were used for electrophysiological recordings. The mice were deeply anesthetized with isoflurane and transcardially perfused with a modified ice-cold sucrose-based cutting solution (pH 7.3) containing 10 mM NaCl, 25 mM NaHCO 3 , 195 mM sucrose, 5 mM glucose, 2.5 mM KCl, 1.25 mM NaH 2 PO 4 , 2 mM Na-pyruvate, 0.5 mM CaCl 2 , and 7 mM MgCl 2 bubbled continuously with 95% O 2 and 5% CO 2 [ 29 ]. The mice were then decapitated, and the entire brain was removed and immediately submerged in cutting solution.…”

“…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 ].…”