Item Details

title

Characterizing a Protein-Coding Mutation in the Transmembrane Domain of Adenylate Cyclase 3 in a Rat Model

author

Fitzpatrick, Mackenzie Katherine

abstract

Global rates of both obesity and depression are steadily increasing, and research has shown that these two diseases are bi-directionally linked. A multitude of genetic and environmental factors influence this association, and shared biological causes (including altered cyclic AMP (cAMP) signaling) have even been identified. Despite this, few studies have attempted to identify candidate genes/mutations that contribute to obesity and depression simultaneously. Furthermore, few studies have investigated associated protein-coding mutations, which may be more translatable to humans than rodent knockout models.In a genome-wide association study of adiposity in rats, we identified a protein-coding mutation in the transmembrane (TM) domain of Adenylate cyclase 3 (Adcy3). Adcy3 is an established human candidate gene for obesity and depression separately. The goal of this dissertation was to investigate if this mutation can cause simultaneous obesity-like and depression-like phenotypes in a rat model, and if so, how. We generated a rat model of this mutation (F122delV123L, “Adcy3mut/mut”) and placed wild-type and Adcy3mut/mut rats on a high-fat diet. We conducted three in vivo studies: an initial study to assess metabolism and behavior, a second study to investigate thermogenesis and lipolysis, and a third study to more comprehensively assess behavior in Adcy3mut/mut. We also investigated the mechanisms by which Adcy3mut/mut impairs ADCY3 function. We found that Adcy3mut/mut rats had increased adiposity but that adiposity was driven by increased food intake in males and by decreased energy expenditure in females. We also found sex differences in specific emotion-like behaviors affected by Adcy3mut/mut. However, Adcy3mut/mut rats of both sexes had impaired hypothalamic AMP-activated protein kinase (AMPK) and reduced peripheral lipolysis. Adcy3mut/mut impaired enzymatic function without affecting ADCY3 localization, reducing cAMP in the hypothalamus in both sexes and also in white adipose tissue in females. This work shows that a TM mutation in Adcy3 can influence both adiposity and behavior and that Adcy3 may contribute to the relationship between obesity and depression. We show that biological sex influences these signaling pathways and that the TM domain of ADCY3 is essential for protein function. Future studies will shed light on the translational implications of these findings for human disease.

subject

adenylate cyclase 3

cyclic AMP

depression

genetic variants

obesity

rat model

contributor

Solberg Woods, Leah (advisor)

Chen, Rong (committee member)

Lowther, Todd (committee member)

McClain, Donald (committee member)

Weiner, Jeffrey (committee member)

date

2025-06-24T08:36:30Z (accessioned)

2025 (issued)

degree

Molecular Medicine and Translational Science (discipline)

embargo

2026-06-23 (terms)

2026-06-23 (liftdate)

identifier

http://hdl.handle.net/10339/111014 (uri)

language

en (iso)

publisher

Wake Forest University

type

Dissertation