Estrogens modulate ventrolateral ventromedial hypothalamic glucose-inhibited neurons.
OBJECTIVE
Brain regulation of glucose homeostasis is sexually dimorphic; however, the impact sex hormones have on specific neuronal populations within the ventromedial hypothalamic nucleus (VMN), a metabolically sensitive brain region, has yet to be fully characterized. Glucose-excited (GE) and -inhibited (GI) neurons are located throughout the VMN and may play a critical role in glucose and energy homeostasis. Within the ventrolateral portion of the VMN (VL-VMN), glucose sensing neurons and estrogen receptor (ER) distributions overlap. We therefore tested the hypothesis that VL-VMN glucose sensing neurons were sexually dimorphic and regulated by 17β-estradiol (17βE).


METHODS
Electrophysiological recordings of VL-VMN glucose sensing neurons in brain slices isolated from age- and weight-matched female and male mice were performed in the presence and absence of 17βE.


RESULTS
We found a new class of VL-VMN GI neurons whose response to low glucose was transient despite continued exposure to low glucose. Heretofore, we refer to these newly identified VL-VMN GI neurons as 'adapting' or AdGI neurons. We found a sexual dimorphic response to low glucose, with male nonadapting GI neurons, but not AdGI neurons, responding more robustly to low glucose than those from females. 17βE blunted the response of both nonadapting GI and AdGI neurons to low glucose in both males and females, which was mediated by activation of estrogen receptor β and inhibition of AMP-activated kinase. In contrast, 17βE had no impact on GE or non-glucose sensing neurons in either sex.


CONCLUSIONS
These data suggest sex differences and estrogenic regulation of VMN hypothalamic glucose sensing may contribute to the sexual dimorphism in glucose homeostasis.
New Jersey Medical School, Rutgers University, 185 South Orange Ave, Newark, NJ 07103, United States. Electronic address: santiaa1@njms.rutgers.edu.
Ammy M
AM
Santiago
Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, United States. Electronic address: Deborah.Clegg@cshs.org.
Deborah J
DJ
Clegg
New Jersey Medical School, Rutgers University, 185 South Orange Ave, Newark, NJ 07103, United States. Electronic address: routhvh@njms.rutgers.edu.
Vanessa H
VH
Routh
17β-estradiol; 17βE, 17β-estradiol; AICAR, aminoimidazole-4-carboxamide-1-β-d-ribofuranoside; AMP-activated kinase; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; BSA-17βE, bovine serum albumin-conjugated 17βE; CC, compound C; ER, estrogen receptor; GABA, γ-aminobutyric acid; GE, glucose-excited; GI, glucose-inhibited; Glucose excited neurons; Glucose inhibited neurons; HRP, horse radish peroxidase; IR, input resistance; MPP, methylphenolpyrazole; NGS, non-glucose sensing; PHTPP, phenyltrifluoromethylpyrazolophenol; POMC, pro-opiomelanocortin; PVDF, polyvinylidene difluoride; SF-1, steroidogenic factor; Sexual dimorphism; TTX, tetrodotoxin; VL-VMN, ventrolateral VMN; VMH, ventromedial hypothalamus; VMN, ventromedial hypothalamic nucleus; Ventromedial hypothalamic nucleus; Vm, membrane potential
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