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Sex-dimorphic Rostro-caudal Patterns of 5′-AMP-activated Protein Kinase Activation and Glucoregulatory Transmitter Marker Protein Expression in the Ventrolateral Ventromedial Hypothalamic Nucleus (VMNvl) in Hypoglycemic Male and Female Rats: Impact of Estradiol

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Abstract

The ventromedial hypothalamic nucleus-ventrolateral part (VMNvl) is an estradiol-sensitive structure that controls sex-specific behavior. Electrical reactivity of VMNvl neurons to hypoglycemia infers that cellular energy stability is monitored there. Current research investigated the hypothesis that estradiol elicits sex-dimorphic patterns of VMNvl metabolic sensor activation and gluco-regulatory neurotransmission during hypoglycemia. Rostral-, middle-, and caudal-VMNvl tissue was separately micropunch-dissected from letrozole (Lz)- or vehicle-injected male and estradiol- or vehicle-implanted ovariectomized (OVX) female rats for Western blot analysis of total and phosphorylated 5′-AMP-activated protein kinase (AMPK) protein expression and gluco-stimulatory [neuronal nitric oxide synthase (nNOS); steroidogenic factor-1 (SF1) or -inhibitory (glutamate decarboxylase65/67 (GAD)] transmitter marker proteins after sc insulin (INS) or vehicle injection. In both sexes, hypoglycemic up-regulation of phosphoAMPK was estradiol-dependent in rostral and middle, but not caudal VMNvl. AMPK activity remained elevated after recovery from hypoglycemia over the rostro-caudal VMNvl in female, but only in the rostral segment in male. In each sex, hypoglycemia correspondingly augmented or suppressed nNOS profiles in rostral and middle versus caudal VMNvl; these segmental responses persisted longer in female. Rostral and middle segment SF1 protein was inhibited by estradiol-independent mechanisms in hypoglycemic males, but increased by estradiol-reliant mechanisms in female. After INS injection, GAD expression was inhibited in the male rostral VMNvl without estradiol involvement, but this hormone was required for broader suppression of this profile in the female. Neuroanatomical variability of VMNvl metabolic transmitter reactivity to hypoglycemia underscores the existence of functionally different subgroups in that structure. The regional distribution and estradiol sensitivity of hypoglycemia-sensitive VMNvl neurons of each neurochemical phenotype evidently vary between sexes.

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Abbreviations

AMPK:

5′-AMP-activated protein kinase

ER:

Estrogen receptor

ERα:

Estrogen receptor-alpha

ERβ:

Estrogen receptor-beta

GABA:

γ-Aminobutyric acid

GAD:

Glutamate decarboxylase65/67

INS:

Insulin

IIH:

Insulin-induced hypoglycemia

LZ:

Letrozole

nNOS:

Neuronal nitric oxide synthase

OVX:

Ovariectomy

pAMPK:

PhosphoAMPK

SF1:

Steroidogenic factor-1

VMN:

Ventromedial hypothalamic nucleus

VMNvl:

Ventromedial hypothalamic nucleus–ventrolateral part

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NIH DK-109382

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  1. Ayed A. Alshamrani and Khaggeswar Bheemanapally are co-first authors of this paper.

Authors and Affiliations

  1. School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, 356 Bienville Building 1800 Bienville Drive, Monroe, 71201, USA

    Ayed A. Alshamrani, Khaggeswar Bheemanapally, Abdulrahman Alhamyani, Md. Haider Ali, Prabhat R. Napit, Md. Main Uddin, A.S.M. Hasan Mahmood, Mostafa M. H. Ibrahim & Karen P. Briski

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  1. Ayed A. Alshamrani
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  3. Abdulrahman Alhamyani
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Correspondence to Karen P. Briski.

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Alshamrani, A.A., Bheemanapally, K., Alhamyani, A. et al. Sex-dimorphic Rostro-caudal Patterns of 5′-AMP-activated Protein Kinase Activation and Glucoregulatory Transmitter Marker Protein Expression in the Ventrolateral Ventromedial Hypothalamic Nucleus (VMNvl) in Hypoglycemic Male and Female Rats: Impact of Estradiol. J Mol Neurosci 71, 1082–1094 (2021). https://doi.org/10.1007/s12031-020-01730-5

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