Estrogen Blocks Appetite-Suppressing Effects of VIP Peptide but Not PACAP in Postmenopausal Rat Model | Research

The takeaway

Estradiol treatment blocked VIP-induced appetite suppression and hypothalamic cell activation in ovariectomized rats but did not affect PACAP's appetite-reducing effects, revealing differential estrogen-peptide interactions in appetite regulation.

VIP appetite suppression blocked by estrogen
Estradiol completely prevented VIP from reducing food intake and activating hypothalamic neurons, while PACAP's appetite-suppressing effects were preserved

What the researchers found

Estradiol-treated ovariectomized rats showed reduced VPAC2 receptor mRNA in the PVN. VIP-induced appetite suppression was completely blocked by estradiol, while PACAP still reduced food intake in both estrogen-treated and untreated groups. VIP-induced cell activation in the ARC and PVN was blocked by estradiol, but PACAP still activated ARC cells in both groups (PVN activation was blocked only in estrogen-treated rats). VIP increased plasma glucose in both groups; PACAP increased glucose only without estrogen. VIP decreased free fatty acids only with estrogen present.

Why it matters

Menopause is associated with weight gain and changes in appetite regulation, partly due to declining estrogen. Understanding how estrogen interacts with specific appetite-regulating peptides helps explain these changes and could guide the development of targeted therapies. The finding that PACAP maintains its appetite-suppressing effect regardless of estrogen status makes it a potentially more reliable therapeutic target for postmenopausal weight management.

How the study worked

Female Wistar rats underwent ovariectomy and intracerebroventricular cannulation surgery. They received daily subcutaneous injections of either corn oil (vehicle) or 10 μg estradiol cypionate. VIP or PACAP was administered by intracerebroventricular microinjection. Researchers measured food intake, plasma glucose and free fatty acids, VPAC2 and PAC1 receptor mRNA expression, and hypothalamic cell activation (c-Fos) in the ARC and PVN nuclei.

What this study cannot tell us

This is a rat study using surgical menopause (ovariectomy), which is more abrupt than natural menopause in humans. The neuropeptides were delivered directly into the brain, which doesn't reflect physiological signaling. Only one dose of estradiol was tested. The study examined acute effects; chronic peptide exposure may produce different results. The small sample sizes typical of such studies limit statistical power.

How to read the evidence

This is a preclinical rat study using an ovariectomy model with intracerebroventricular peptide delivery. It provides detailed mechanistic insights but at an early translational stage, with no direct human relevance established.

When this study was published

Published in 2025, this study addresses the timely intersection of sex hormones and neuropeptide biology in metabolic regulation, relevant to growing interest in sex-specific approaches to obesity treatment.

The bigger picture

VIP and PACAP are closely related neuropeptides that were thought to have overlapping functions. This study reveals a fundamental difference: their appetite effects are differentially regulated by sex hormones. This has implications far beyond appetite — it suggests that sex hormone status may determine which peptide pathways are active at any given time, which matters for understanding and treating metabolic disorders differently in pre- vs. postmenopausal women.

Questions still open

Could PACAP-based therapies be developed as appetite-regulating treatments that remain effective regardless of menopausal status?
Does the estrogen-VIP interaction explain some of the weight gain commonly experienced during the menopausal transition?
Are there other sex hormone-dependent switches in neuropeptide function that affect metabolism?

Common questions

What are VIP and PACAP and how do they affect appetite?

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides that act in brain regions controlling energy balance. Both can reduce food intake when they activate neurons in the hypothalamus. This study shows their appetite effects are differently regulated by estrogen — a distinction that may matter for understanding weight changes during menopause.

Why might this matter for menopausal weight gain?

During menopause, declining estrogen levels are linked to increased appetite and weight gain. This study reveals that estrogen selectively disrupts VIP's ability to suppress appetite while leaving PACAP's effect intact. Understanding these hormone-peptide interactions could explain why appetite regulation changes after menopause and help identify better therapeutic targets for managing postmenopausal weight.

Read the original research

Estrogens impair hypophagia and hypothalamic cell activation induced by vasoactive intestinal peptide, but not by pituitary adenylate cyclase-activating polypeptide.

Peptides, 183, 171325

View on PubMed ↗Publisher’s paper ↗

Citation

Garnica-Siqueira, Marcela Cristina; Martins, Andressa Busetti; Monteiro, Érica Cristina Alves Munhoz; Oliveira, Maria Heloisa Bernardes de; Baratto, Carolina Dos Reis; Tsutsui, Fabiano Takeo Komay; Oliveira, Lucas Leonardo França de; Stopa, Larissa Rugila Dos Santos; Souza, Camila Franciele de; Wunderlich, Ana Luiza Machado; Zaia, Dimas Augusto Morozin; Leite, Cristiane Mota; Zaia, Cássia Thaïs Bussamra Vieira; Uchoa, Ernane Torres. (2025). Estrogens impair hypophagia and hypothalamic cell activation induced by vasoactive intestinal peptide, but not by pituitary adenylate cyclase-activating polypeptide.. Peptides, 183, 171325. https://doi.org/10.1016/j.peptides.2024.171325