Abstract
Adenylyl cyclase 3 (Adcy3), a member of the mammalian adenylyl cyclase family responsible for generating the second messenger cAMP, has long been known to play an essential role in olfactory signal transduction. Here, we demonstrated that Adcy3 heterozygous null mice displayed increased visceral adiposity in the absence of hyperphagia and developed abnormal metabolic features characterized by impaired insulin sensitivity, dyslipidemia, and increased plasma levels of proinflammatory cytokines on both chow and high-fat diet (HFD). Of note, HFD decreased the Adcy3 expression in white adipose tissue, liver, and muscle. We also report for the first time that Adcy3 haploinsufficiency resulted in reduced expression of genes involved in thermogenesis, fatty acid oxidation, and insulin signaling, with enhanced expression of genes related to adipogenesis in peripheral tissues of mice. In conclusion, these findings suggest that cAMP signals generated by Adcy3 in peripheral tissues may play a pivotal role in modulating obesity and insulin sensitivity.
Highlights
Et al recently found that the gain-of-function mutation of Adenylyl cyclases (Adcys)[3] gene had increased Adcy[3] activity and cyclic AMP (cAMP) production and the mutant mice had significantly lower total body weights and fat mass compared to wild type controls after 12 weeks of HFD feeding[15]
Hepatic triglyceride (55% for male, p < 0.001; 60% for female, p < 0.001), cholesterol (77% for male, p < 0.001; 79% for female, p < 0.001), and fatty acid (216% for male, p < 0.001; 234% for female, p < 0.001) levels were significantly higher in Adcy3+/− mice relative to levels observed in WT mice on HFD (Fig. 2d–f,m–o)
There was no significant difference in plasma levels of TG, total cholesterol (TC), free fatty acid (FFA), and proinflammatory cytokines between Adcy3+/− and WT mice fed chow irrespective of gender (Fig. 2a–c,g–i,j–l,p–r)
Summary
Et al recently found that the gain-of-function mutation of Adcy[3] gene had increased Adcy[3] activity and cAMP production and the mutant mice had significantly lower total body weights and fat mass compared to wild type controls after 12 weeks of HFD feeding[15]. It has been established that cAMP signaling, in addition to its involvement in regulating feeding behavior and leptin sensitivity in the hypothalamus[16,17], has a role in controlling adipose tissue development and function through regulating the expressions of genes related to adipogenesis, lipolysis, and thermogenesis[18,19,20]. Hepatic Adcy[3] was reported to play a protective role in insulin resistance and obesity in mice with HFD-induced obesity[22]. The present study was aimed at determining whether Adcy[3] functions in peripheral tissues related to metabolic disorders by regulating the development of adiposity and insulin resistance in mice
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