Adenylate cyclase 3: a potential genetic link between obesity and major depressive disorder.

Obesity and major depressive disorder (MDD) are both significant health issues that have been increasing in prevalence and are associated with multiple comorbidities. Obesity and MDD have been shown to be bidirectionally associated, and they are both influenced by genetics and environmental factors. However, the molecular mechanisms that link these two diseases are not yet fully understood. It is possible that these diseases are connected through the actions of the cAMP/protein kinase A (PKA) pathway. Within this pathway, adenylate cyclase 3 (Adcy3) has emerged as a key player in both obesity and MDD. Numerous genetic variants in Adcy3 have been identified in humans in association with obesity. Rodent knockout studies have also validated the importance of this gene for energy homeostasis. Furthermore, Adcy3 has been identified as a top candidate gene and even a potential blood biomarker for MDD. Adcy3 and the cAMP/PKA pathway may therefore serve as an important genetic and functional link between these two diseases. In this mini-review, we discuss the role of both Adcy3 and the cAMP/PKA pathway, including specific genetic mutations, in both diseases. Understanding the role that Adcy3 mutations play in obesity and MDD could open the door for precision medicine approaches and treatments for both diseases that target this gene.

Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats.

Objective: Adenylate cyclase 3 (Adcy3) has been linked to both obesity and major depressive disorder (MDD). Our lab identified a protein-coding variant in the 2nd transmembrane (TM) helix of Adcy3 in rats, and similar obesity variants have been identified in humans. The current study investigates the role of a TM variant in adiposity and behavior. Methods: We used CRISPR-SpCas9 to mutate the TM domain of Adcy3 in WKY rats (Adcy3mut/mut). We also created a heterozygous knockout rat in the same strain (Adcy3+/-). Wild-type (WT), Adcy3+/-, and Adcy3mut/mut rats were fed a high-fat diet for 12 weeks. We measured body weight, fat mass, glucose tolerance, food intake, metabolism, emotion-like behaviors, and memory. Results: Adcy3+/- and Adcy3mut/mut rats weighed more than WT rats due to increased fat mass. There were key sex differences: adiposity was driven by increased food intake in males but by decreased energy expenditure in females. Adcy3mut/mut males displayed increased passive coping and decreased memory while Adcy3mut/mut females displayed increased anxiety-like behavior. Conclusions: These studies show that the ADCY3 TM domain plays a role in protein function, that Adcy3 may contribute to the relationship between obesity and MDD, and that sex influences the relationships between Adcy3, metabolism, and behavior.

Differential gene expression profiling implicates altered network development in rat postnatal day 4 cortex following 4-Methylimidazole (4-MeI) induced maternal seizures.

Compromised maternal health leading to maternal seizures can have adverse effects on the healthy development of offspring. This may be the result of inflammation, hypoxia-ischemia, and altered GABA signaling. The current study examined cortical tissue from F2b (2nd litter of the 2nd generation) postnatal day 4 (PND4) offspring of female Harlan SD rats chronically exposed to the seizuregenic compound, 4-Methylimidazole (0, 750, or 2500 ppm 4-MeI). Maternal seizures were evident only at 2500 ppm 4-MeI. GABA related gene expression as examined by qRT-PCR and whole genome microarray showed no indication of disrupted GABA or glutamatergic signaling. Canonical pathway hierarchical clustering and multi-omics combinatory genomic (CNet) plots of differentially expressed genes (DEG) showed alterations in genes associated with regulatory processes of cell development including neuronal differentiation and synaptogenesis. Functional enrichment analysis showed a similarity of cellular processes across the two exposure groups however, the genes comprising each cluster were primarily unique rather than shared and often showed different directionality. A dose-related induction of cytokine signaling was indicated however, pathways associated with individual cytokine signaling were not elevated, suggesting an alternative involvement of cytokine signaling. Pathways related to growth process and cell signaling showed a negative activation supporting an interpretation of disruption or delay in developmental processes at the 2500 ppm 4-MeI exposure level with maternal seizures. Thus, while GABA signaling was not altered as has been observed with maternal seizures, the pattern of DEG suggested a potential for alteration in neuronal network formation.

Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of Krtcap3.

We previously identified Keratinocyte-associated protein 3, Krtcap3, as a novel adiposity gene, but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between Krtcap3, adiposity, and stress, we exposed wild-type (WT) and Krtcap3 knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited metabolic and behavioral responses to chronic stress exposure. Specifically, stress-exposed KO rats gained more weight, consumed more food when socially isolated, and displayed more anxiety-like behaviors relative to control KO rats. Meanwhile, there were minimal differences between control and stressed WT rats. At study conclusion stress-exposed KO rats had increased corticosterone (CORT) relative to control KO rats with no differences between WT rats. In addition, KO rats, independent of prior stress exposure, had an increased CORT response to removal of their cage-mate (psychosocial stress), which was only seen in WT rats when exposed to chronic stress. Finally, we found differences in expression of the glucocorticoid receptor, Nr3c1, in the pituitary and colon between control and stress-exposed KO rats that were not present in WT rats. These data support that Krtcap3 expression affects stress response, potentially via interactions with Nr3c1, with downstream effects on adiposity and behavior. Future work is necessary to more thoroughly understand the role of Krtcap3 in the stress response.