Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2026

Homeostatic feeding and reward: investigating the role of a neuronal antenna in obesity (143076)

Adélaïde Bernard 1 2 3 , Xinyu Yue 2 , Francois Mifsud 2 , Irene Ojeda Naharros 2 , Marine Benois 2 , Sumei Zhang 2 , Nicolas F Berbari 4 , Jeremy F Reiter 2 , Maxence V Nachury 2 , Brian G Drew 1 , Christian Vaisse 2 , Robyn Brown 3 , Yi Wang 1 2
  1. Baker Institute, Melbourne, VIC, Australia
  2. UCSF, University of California San Francisco, San Francisco, California, USA
  3. Biochemistry and Pharmacology , University of Melbourne, Melbourne, VIC, Australia
  4. School of Science, IU Indianapolis, Bloomington, Indiana, USA

Background: We have recently shown that the melanocortin-4 receptor (MC4R), a master regulator of hunger, localizes to and functions at the primary cilia of neurons. Primary cilia are single, tiny hairlike structures that protrude from the plasma membrane of most cells, including neurons, and serve as antennae to sense their extracellular environment. Defects in neuronal cilia in adult mice lead to obesity, and in humans, disruptions in primary cilia structure or function leads to a group of diseases collectively termed “ciliopathies”, some of which are associated with obesity. Importantly, we showed that MC4R localization to cilia is necessary to control satiety.

Aim: While this homeostatic control of feeding is aimed at maintaining a stable body weight over time, the motivation to obtain food and food reward are mediated by the dopaminergic system. There’s growing evidence that the melanocortin and dopaminergic systems influence and regulate each other, but how this interplay works is poorly understood. Since MC4R is expressed in a subset of dopamine-sensitive neurons, this project aims at uncovering whether MC4R modulates the dopaminergic system through the primary cilium.

Methods and Results: Weight loss leads to an increased motivation to obtain food to reestablish energy balance. By observing the subcellular localization of MC4R in a mouse model expressing a GFP-tagged MC4R, we showed that MC4R’s accumulation within primary cilia reflects an organism’s energy status, informing the brain about fat loss and regain following refeeding. We used genetic tools combined with CRISPR technology to delete MC4R or primary cilia specifically in hypothalamic dopamine-sensitive neurons and assessed changes in body weight and reward behaviour to determine whether ciliary MC4Rs modulate this neuronal population and reward.

Conclusion: Understanding how the homeostatic (melanocortin) and reward (dopaminergic) systems interact will help uncover the mechanisms that drive feeding beyond caloric needs, which contributes to obesity.