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Publication
Sex differences in metabolic regulation by Gi/o-coupled receptor modulation of
exocytosis.
Authors Young M, Ceddia RP, Thompson-Gray A, Reyes D, Cassada JB, Ayala JE, McGuinness
OP, Collins S, Hamm HE
Submitted By Submitted Externally on 8/28/2025
Status Published
Journal Frontiers in pharmacology
Year 2025
Date Published
Volume : Pages 16 : 1544456
PubMed Reference 40176888
Abstract Presynaptic Gi/o coupled GPCRs can act as negative feedback regulators of
neurotransmitter release via Gß? 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 (SNAP25?3) prevents Gß?-SNARE interaction, effectively removing
the braking mechanism on neurotransmitter release. We have demonstrated enhanced
metabolic protection in male SNAP25?3/?3 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?3/?3 mice were housed at thermoneutrality (30°C), all metabolic
protection was abolished, suggesting sympathetic tone is important for the
phenotypes., We housed male and female mice at either standard room temperature
(21°C) or at thermoneutrality (30°C) and fed them a high fat diet (HFD) for
8 weeks. Glucose tolerance tests were performed before and after the 8 weeks of
HFD along with body composition analyses. Organs were then dissected for mass
analysis as well as immunohistochemistry. Additionally, we ovariectomized female
mice to investigate the role of sex hormones in our phenotypes. Finally, we
housed mice in Sable Promethion chambers at various environmental temperatures
to investigate the effect of environmental temperature on basal metabolic
rates., We found SNAP25?3/?3 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?3/?3 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?3/?3 persisted in
ovariectomized mice despite increased weight gain compared to mice receiving
sham operations., This study has identified that there is not a sex-dependent
difference for thermoneutral set point in mice. Additionally, there is a sex
hormone independent mechanism driving the persistent metabolic protection of
female SNAP25?3/?3 mice housed in thermoneutrality.




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