# Uncovering the role of hypothalamic ciliary cAMP signaling in sex-specific control of metabolic homeostasis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $576,810

## Abstract

Project Summary / Abstract
Despite similar obesity rates in both sexes, the underlying biology of excessive weight gain in women and men
is believed to differ significantly. Neurons in the ventromedial nucleus of the hypothalamus (VMH) exhibit
sexually dimorphic characteristics and play a crucial role in energy balance. However, the signaling pathways
within VMH neurons that contribute to sex-specific control of energy balance remain largely unknown.
Recently, the primary cilium, a solitary antenna-like sensory organelle found in most mammalian cells,
including neurons, has emerged as a critical regulator of metabolic homeostasis. Human genetic studies have
identified the cilia-specific adenylate cyclase 3 (Adcy3) as a significant obesity-risk gene and animal studies
have further shown that global Adcy3 knockout mice develop severe obesity, particularly in females. However,
the mechanism underlying Adcy3's contribution to female-biased weight gain remains unknown. Our recent
findings indicate that selective deletion of Adcy3 in VMH neurons leads to female-specific obesity without a
significant increase in food intake. Adcy3 is enriched in estrogen receptor alpha (ERα)- and melanocortin 4
receptor (Mc4r)-expressing neurons in the ventrolateral subdivision of VMH (VMHvl), which are known to affect
energy expenditure (EE) in female mice. Additionally, we found that ERα binds to a putative promoter region of
the Adcy3 gene. Based on these compelling preliminary observations and previous literature suggesting that
Mc4r, a Gαs-coupled receptor enriched in primary cilia, is a direct transcriptional target of ERα within VMHvl
neurons and increases EE specifically in female mice, we propose a novel hypothesis that Adcy3 functions
downstream of ERα-driven Mc4r signaling at the primary cilium of VMHvl neurons to increase EE in females by
modulating the excitability and/or neurotransmission of these neurons. This hypothesis will be tested by
pursuing following three aims: Aim-1) determine if VMHvl Adcy3 is necessary for metabolic homeostasis by
acting downstream of estrogen-ERα and Mc4r signaling, Aim-2) determine if increasing Adcy3 activity in
VMHvl ERα+ neurons is sufficient to protect against obesity, and Aim-3) determine if loss of Adcy3 reduce the
excitability and/or the neurotransmitter release of VMHvl ERα+ neurons. The proposed research aims to
significantly advance our understanding of hypothalamic signaling pathways involved in sex-specific regulation
of energy homeostasis. Additionally, it will provide new insights into the largely unknown mechanisms by which
ciliary cAMP signaling affects the physiology of key hypothalamic neurons that are crucial for metabolic
homeostasis. Such knowledge may ultimately lead to the development of a novel strategy to effectively prevent
or treat obesity in females.

## Key facts

- **NIH application ID:** 10980937
- **Project number:** 1R01DK139062-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Huxing Cui
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $576,810
- **Award type:** 1
- **Project period:** 2024-07-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980937

## Citation

> US National Institutes of Health, RePORTER application 10980937, Uncovering the role of hypothalamic ciliary cAMP signaling in sex-specific control of metabolic homeostasis (1R01DK139062-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10980937. Licensed CC0.

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