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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Translational Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1544456
This article is part of the Research Topic Targeting Adipose Tissue for the Treatment of Metabolic Alterations View all articles

Sex Differences in Metabolic Regulation by Gi/o-coupled Receptor Modulation of Exocytosis

Provisionally accepted
Montana Young Montana Young 1*Ryan P Ceddia Ryan P Ceddia 2David Reyes David Reyes 1Jackson B Cassada Jackson B Cassada 1*Analisa Thompson-Gray Analisa Thompson-Gray 1*Julio E Ayala Julio E Ayala 3*Owen P Mcguinness Owen P Mcguinness 3*Sheila Collins Sheila Collins 2,3Heidi Hamm Heidi Hamm 1
  • 1 Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee, United States
  • 2 Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • 3 Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, Indiana, United States

The final, formatted version of the article will be published soon.

    Presynaptic Gi/o coupled GPCRs can act as negative feedback regulators of neurotransmitter release via Gβγ effector modulation through two mechanisms: decreased calcium influx and direct inhibition of membrane fusion by soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE). Previously, we discovered that truncation of the last three C-terminal amino acids of SNAP25 (SNAP25Δ3) prevents Gβγ-SNARE interaction, effectively removing the braking mechanism on neurotransmitter release. We have demonstrated enhanced metabolic protection in male SNAP25 Δ3/Δ3 mice housed at room temperature (22°C), including increased adipose tissue beiging and glucose uptake and enhanced insulin sensitivity, rendering them resistant to diet-induced obesity (DIO). When male SNAP25 Δ3/Δ3 mice were housed at thermoneutrality (30°C), all metabolic protection was abolished, suggesting sympathetic tone is important for the phenotypes. Here, we found SNAP25 Δ3/Δ3 female mice exhibited the same metabolic protection at RT (22°C) and displayed enhanced metabolic protection from DIO compared to standard chow just as males did. However, female SNAP25 Δ3/Δ3 mice display persistent metabolic protection even when housed at thermoneutrality. In this study, we investigate the mechanisms behind this sex dependent persistent phenotype. Thermoneutral set point did not differ between sexes nor genotype, suggesting that metabolic protection is not due to a difference in hypothalamic temperature regulation. Metabolic protection in SNAP25 Δ3/Δ3 persisted in ovariectomized mice despite increased weight gain compared to mice receiving sham operations. Therefore, we posit that there is a sex hormone independent mechanism driving the persistent metabolic protection of female SNAP25 Δ3/Δ3 mice housed in thermoneutrality.

    Keywords: G protein coupled receptor (GPCR), sex hormone, Metabolism, Norepinephrene, Diet induced obesity (DIO), Exocytosis, SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor), G protein beta gamma

    Received: 12 Dec 2024; Accepted: 07 Feb 2025.

    Copyright: © 2025 Young, Ceddia, Reyes, Cassada, Thompson-Gray, Ayala, Mcguinness, Collins and Hamm. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Montana Young, Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, 37240-7933, Tennessee, United States
    Jackson B Cassada, Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, 37240-7933, Tennessee, United States
    Analisa Thompson-Gray, Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, 37240-7933, Tennessee, United States
    Julio E Ayala, Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, 37232, Indiana, United States
    Owen P Mcguinness, Department of Molecular Physiology and Biophysics, School of Medicine, Vanderbilt University, Nashville, 37232, Indiana, United States

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