Loss of ciliary localized ADCY3 leads to obesity in a mouse model

Lindsey Jackson

Authors:  Lindsey Jackson, Kalene Jasso, Brian Lee, Tyler Ten Eyck, Randall Reed, Jeremy McIntyre

Faculty Mentor: Jeremy McIntyre

College:  College of Medicine

Abstract

According to the CDC, 93.3 million adults in the U.S. are affected by obesity. Adenylyl cyclase 3 (ADCY3), an enzyme that catalyzes the formation of cyclic adenosine monophosphate (cAMP) downstream of several G-protein coupled receptor (GPCRs) signaling pathways, has been implicated in regulating feeding behaviors in humans and rodents. Within the brain, ADCY3 is predominantly localized to the neuronal primary cilium, a microtubule-based organelle that projects from the cell surface and contains several GPCRs for modulatory neuropeptides. Here, we show that a novel Adcy3 mutation resulting in deletion of the c-terminus of the protein leads to severe obesity in mice. Using immunohistochemistry, we show that ADCY3 is no longer detectable in neuronal primary cilia. Mutant mice show significantly increased body weight compared to heterozygous and wildtype littermates. Using open field testing we found that locomotor activity was reduced in mutant mice, along with resting respiration rates. However, at 14-16wks of age, mutant mice don’t show differences in food consumption, or preference for sucrose. Further testing will investigate behavioral changes in mutant mice prior to the onset of obesity. This model presents an opportunity to dissect the role of ciliary localization of ADCY3 in activity and feeding circuits.

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Brenda Smith
Brenda Smith (@guest_704)
1 year ago

I am a professor of music., therefore, my comments are not “scientific”. I see a beautifully designed, colorful and tasteful poster. The oral explanation was clearly stated by a very able and enthusiastic researcher. As a poster judge for scientific work in voice, I found the poster well-conceived, logical and informative. As a musician, I respond with “brava” to this fine work.

Lindsey Jackson
Lindsey Jackson (@guest_1812)
Reply to  Brenda Smith
1 year ago

Thank you for coming to take a look!

Nicholas Selgas
Nicholas Selgas (@guest_2038)
1 year ago

Why is it that the deletion of c-terminus of the protein leads to severe obesity in mice? You mention a decrease in locomotor actitivity (presumably movement) was reduced and that respiration rates were also reduced – how could the latter impact the weight gain of the mice, if at all? Is the decrease in locomotor activity the only behavioral change contributing to the weight gain?

Thanks, Nick

Lindsey Jackson
Lindsey Jackson (@guest_3218)
1 year ago

Hi Nick,

Good question! We used the total distance each mouse traveled over a four-hour period to measure their locomotor activity. There was a significantly significant decrease in this activity and a decrease in the basal respiration rates of the mutant mice. However, their food and drink consumption did not appear to have been altered, even though previous studies have suggested that mice lacking ADCY3 are hyperphagic. This led us to the same question you have: Did the increased body weights cause the decrease in locomotor activity, did the decrease in locomotor activity cause the increased body weights, or was it some combination of the two? Before six weeks of age, these mutant mice had not yet begun to increase in body weight more quickly than the wildtype mice. Therefore, we plan to perform similar locomotor and metabolic testing on ADCY3:Del mice before this age in pursuit of an explanation.