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. 2020 Oct 15:737:135284.
doi: 10.1016/j.neulet.2020.135284. Epub 2020 Aug 25.

Sex-dimorphic aromatase regulation of ventromedial hypothalamic nucleus glycogen content in euglycemic and insulin-induced hypoglycemic rats

Mostafa M H Ibrahim  1 , Md Main Uddin  1 , Khaggeswar Bheemanapally  1 , Karen P Briski  2
Affiliations

Sex-dimorphic aromatase regulation of ventromedial hypothalamic nucleus glycogen content in euglycemic and insulin-induced hypoglycemic rats

Mostafa M H Ibrahim et al. Neurosci Lett. .

Abstract

Estrogen receptors control hypothalamic astrocyte glycogen accumulation in vitro. Glycogen metabolism impacts metabolic transmitter signaling in the ventromedial hypothalamic nucleus (VMN), a key glucoregulatory structure. Aromatase, the enzyme that converts testosterone to estradiol, is expressed at high levels in the VMN. Here, the aromatase inhibitor letrozole (Lz) was used alongside high-resolution microdissection/UPHLC-electrospray ionization-mass spectrometric methods to determine if neuroestradiol imposes sex-specific control of VMN glycogen content during glucostasis and/or glucoprivation. Testes-intact male and estradiol-replaced ovariectomized female rats were pretreated by lateral ventricular letrozole (Lz) infusion prior to subcutaneous insulin (INS) injection. Vehicle-treated female controls exhibited higher VMN glycogen content compared to males. Lz increased VMN glycogen levels in males, not females. INS-induced hypoglycemia (IIH) elevated (males) or diminished (females) rostral VMN glycogen accumulation. Induction of IIH in Lz-pretreated animals reduced male VMN glycogen mass, but augmented content in females. Data provide novel evidence for regional variation, in both sexes, in glycogen reactivity to IIH. Results highlight sex-dimorphic neuroestradiol regulation of VMN glycogen amassment during glucostasis, e.g. inhibitory in males versus insignificant in females. Locally-generated estradiol is evidently involved in hypoglycemic enhancement of male VMN glycogen, but conversely limits glycogen content in hypoglycemic females. Further research is needed to characterize mechanisms that underlie the directional shift in aromatase regulation of VMN glycogen in eu- versus hypoglycemic male rats and gain in negative impact in hypoglycemic females.

Keywords: Aromatase; Glycogen; Insulin-induced hypoglycemia; Letrozole; Sex differences; Ventromedial hypothalamic nucleus.

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Figures

Figure 1.
Figure 1.
Ventromedial Hypothalamic Nucleus (VMN) Micropunch Dissection. The rectangle in the Panel A brain map (−2.85 mm posterior to bregma) depicts the VMN within the mediobasal hypothalamus, and is enlarged (Panel B) to illustrate the location of VMN in that region. The blue circle denotes positioning of a 0.50 mm diameter circular micropunch tool over the center of the elliptical-shaped VMN, enabling sampling of tissue from dorsomedial, central, and ventrolateral divisions of the VMN. Abbreviations in Panel B: ARH: arcuate hypothalamic n.; DMHa,p: anterior, posterior dorsomedial hypothalamic n.; fx: fornix; LHA: lateral hypothalamic area; ME: median eminence; PVi: intermediate periventricular hypothalamic n.; VMHc, dm, vl: central, dorsomedial, ventormlateral ventromedial hypothalamic n.; TU: tuberal n.; V3: third ventricle.
Figure 2.
Figure 2.. Impact of Intracerebroventricular (icv) Administration of the Aromatase Enzyme Inhibitor Letrozole (Lz) on Rostral versus Caudal Ventromedial Hypothalamic Nucleus (VMN) Glycogen Content in Eu- and Hypoglycemic Male and Female Rats.
Groups of Lz- or vehicle (V)- pretreated testes-intact male and estradiol-implanted, ovariectomized (OVX) female rats were injected subcutaneously (sc) with insulin (INS) or V one hour before sacrifice. VMN tissue collected between −2.30 and −2.50 mm posterior to bregma was analyzed by uHPLC-electrospray ionization-mass spectrometry for glycogen content. Data show mean rostral (Figure 2A) and caudal (Figure 2B) VMN glycogen measures ± S.E.M. for groups of male (M; left-hand side; solid or patterned white bars) and female (F; right-hand side; solid or patterned gray bars) rats treated as follows: V infusion/V injection (V/V-M, solid white bars, n=6; V/V-F, solid gray bars; n=6), V infusion/INS injection (V/INS-M; diagonal-striped white bars; n=6; V/INS-F; diagonal-striped gray bars; n=6), Lz infusion/V injection (Lz/V-M; cross-hatched white bars; n=6; Lz/V-F; cross-hatched gray bars, n=6), Lz infusion//INS injection (Lz/INS-M; stippled white bars; n=6; Lz/INS-F; stippled gray bars; n=6). *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
Figure 3.
Figure 3.. Effects of Lz Pretreatment on Insulin-Induced Hypoglycemia in Male versus Female Rats.
Data depict mean plasma glucose levels ± S.E.M. for V/V, V/INS, Lz/V, and Lz/INS groups of male (M; left-hand side) and female (F; right-hand side) rats. *p<0.05; **p<0.01; ***p<0.001; ****p<0.0001.
Figure 4.
Figure 4.. Summary of Singular or Combinatory Effects of Letrozole and Insulin-Induced Hypoglycemia on Male versus Female Rat VMN Glycogen Content.
Abbreviations: IIH, insulin-induced hypoglycemia; Lz, letrozole; N.C., no change. Symbols: ↑, increased glycogen; ↓, decreased glycogen. Top row (rostral VMN): IIH caused divergent changes in glycogen levels in female (reduction) versus male (augmentation) rats. Lz did not affect (female) or increased (male) basal glycogen content, indicating no role versus inhibitory neuroestradiol regulation of this energy reserve. Lz pretreatment promoted hypoglycemic amplification (female) or diminution (male) of rostral VMN glycogen, denoting inhibitory versus stimulatory neuroestradiol regulation during IIH. Bottom row (caudal VMN): IIH did not modify glycogen content in either sex. Lz did not alter (female) or elevated (male) baseline glycogen levels, inferring that neuroestradiol respectively does not regulate or inhibits glycogen mass. Lz-pretreated hypoglycemic rats exhibited increased (female) or unaltered (male) caudal VMN glycogen, inferring neuroestradiol inhibition versus no control of caudal VMN glycogen in those sexes.
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References

    1. Alhamami HN, Alshamrani A, Briski KP KP, Inhibition of glycogen phosphorylase stimulates ventromedial hypothalamic nucleus AMP-activated protein kinase activity and neuronal nitric oxide synthase protein expression in male rats, Physiol. Reports 103 (2018) 236–249. doi: 10.14814/phy2.13484. - DOI - PMC - PubMed
    1. Bheemanapally K, Ibrahim MMH, Briski KP, Combinatory high-resolution microdissection/high-sensitivity high performance liquid chromatographic-mass spectrometry approach for small tissue volume analysis of rat brain glycogen, J. Pharmaceut. Biomed. Anal 178 (2020) 112884. doi: 10.1016/j.jpba.2019.112884. - DOI - PMC - PubMed
    1. Briski KP, Mandal SK, Bheemanapally K, Ibrahim MMH, Effects of acute versus recurrent insulin-induced hypoglycemia on ventromedial hypothalamic nucleus metabolic-sensory neuron AMPK activity: Impact of alpha1-adrenergic receptor signaling, Brain Res. Bull 157 (2020) 41–50. doi: 10.1016/j.brainresbull.2020.01.013. - DOI - PMC - PubMed
    1. Briski KP, Marshall ES, Sylvester PW, Effects of estradiol on glucoprivic transactivation of catecholaminergic neurons in the female rat caudal brainstem, Neuroendocrinology 73 (2001) 369–377. doi: 10.1159/000054655. - DOI - PubMed
    1. Brown AM, Brain glycogen re-awakened, J. Neurochem 89 (2004) 537–552. doi: 10.1111/j.1471-4159.2004.02421.x. - DOI - PubMed

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