Effects of Whole-Body Adenylyl Cyclase 5 (Adcy5) Deficiency on Systemic Insulin Sensitivity and Adipose Tissue

Abstract

Genome-wide association studies have identified adenylyl cyclase type 5 (ADCY5) as candidate gene for diabetes-related quantitative traits and an increased risk of type 2 diabetes. Mice with a whole-body deletion of Adcy5 (Adcy5–/–) do not develop obesity, glucose intolerance and insulin resistance, have improved cardiac function and increased longevity. Here, we investigated Adcy5 knockout mice (Adcy5–/–) to test the hypothesis that changes in adipose tissue (AT) may contribute to the reported healthier phenotype. In contrast to previous reports, we found that deletion of Adcy5 did not confer any physiological or biochemical benefits. However, this unexpected finding allowed us to investigate the effects of Adcy5 depletion on AT independently of lower body weight and a metabolically healthier phenotype. Adcy5–/– mice exhibited an increased number of smaller adipocytes, lower mean adipocyte size and a distinct AT gene expression pattern with midline 1 (Mid1) as the most significantly downregulated gene compared to control mice. Our Adcy5–/– model challenges previously described beneficial effects of Adcy5 deficiency and suggests that targeting Adcy5 does not improve insulin sensitivity and may therefore limit the relevance of ADCY5 as potential drug target.

Identification of SNPs in MITF associated with beak color of duck

“…As the main regulator of melanin, MITF can regulate the transcription of TYR, TRP-1 and TRP-2 by binding the promoter factor region (Otreba et al, 2012;Wang et al, 2014;Jia et al, 2021). Moreover, as the key genes on the WNT signaling pathway and CAMP signaling pathway (Kim et al, 2018;Chen et al, 2020;Pallotti et al, 2020;Dommel et al, 2021;Pruller et al, 2022) all the other selected genes have been confirmed to regulate MITF expression (Khaled et al, 2002;Huber et al, 2003;Otreba et al, 2012;Lee et al, 2016). Furthermore, MITF have been found to play key regulatory roles in multiple pigmentrelated traits.…”

Association of MARC1, ADCY5, and BCO1 Variants with the Lipid Profile, Suggests an Additive Effect for Hypertriglyceridemia in Mexican Adult Men

“…However, our findings of the sex-specific association agree with a previous study using the MARC1 knockout mice model that described a sex-dependent phenotype [ 30 , 48 ]. A recent study using the ADCY5 -/- mice model reported significant differences in the total cholesterol, HDL-c, and LDL-c serum profile between male and female mice, without significant differences reported for triglyceride levels [ 49 ]. The authors suggest that ADCY5 could work as a signaling switch for the apoprotein A1-mediated cholesterol efflux pathway [ 50 ].…”

“…The authors suggest that ADCY5 could work as a signaling switch for the apoprotein A1-mediated cholesterol efflux pathway [ 50 ]. Furthermore, they concluded that cAMP, produced by ADCY5 , may regulate cholesterol exocytosis to remove excessive cellular lipids and could increase aromatase expression, a key enzyme involved in estrogen production, promoting distinct phenotypes between males and females [ 49 ].…”

Type 2 diabetes is more closely associated with risk of colorectal cancer based on elevated DNA methylation levels of ADCY5

“…Furthermore, ADCY3 of the same family is at present a promising target for anti-obesity therapeutics. Although it was reported that intervention with ADCY5 in rodents does not improve insulin sensitivity ( 18 ), evidence is still lacking in primates, particularly in humans.…”