Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 7 different organs that have distinct metabolic demands. Overall our analysis reveled that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. Furthermore, when exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. Accordingly, at the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof has a strong impact on metabolic disorders.
Project description:Constant crosstalk between epigenetic regulators and metabolism homeostasis ensures that several tissues can respond and adapt to environmental cues. Decreased levels of the lysine acetyltransferase (KAT), MOF, was recently associated with cerebral development and syndromic intellectual disability. However, the consequences of having a chronic reduction of MOF levels are still unveiled. Here we characterized by FIA-MS/MS the metabolic profile of Mof heterozygous animals. We generated the profile of 8 different organs that have distinct metabolic demands. Overall, our analysis revealed that Mof heterozygous mice have impaired glucose homeostasis, fatty acids metabolism, and amino acid accumulation. When exposed ad libitum to high-fat diet those animals failed to gain fat mass, while the lean mass remains unalterable. At the molecular level, using the adipocyte model we found that Mof regulates the expression of PPARs and Slc2a4. In summary, we identified the first KAT that shows high-fat diet resistance and we propose that the chronic reduction of Mof impacts metabolic disorders.
Project description:Obesity is associated with low-grade inflammation that leads to insulin resistance and type 2 diabetes via Toll-like Receptor (TLR) and TNF-family cytokine receptor (TNFR) signaling pathways. Ubc13 is an ubiquitin-conjugating enzyme responsible for non-canonical K63-linked polyubiquitination of TNF receptor-associated factor (TRAF)-family adapter proteins involved in TLR and TNFR pathways. However, the relationship between Ubc13 and metabolic disease remains unclear. In this study, we investigated the role of Ubc13 in insulin resistance and high-fat diet (HFD)-induced obesity. We compared wild-type (WT) and Ubc13 haploinsufficient (ubc13(+/-)) mice under normal diet (ND) and HFD, since homozygous knockout mice (ubc13(-/-)) are embryonic lethal. Male and female ubc13(+/-) mice were protected against age-related insulin resistance under ND and HFD compared to WT mice. Interestingly, only female ubc13(+/-) mice were protected against HFD-induced obesity and hepatic steatosis. Moreover, only female HFD-fed ubc13(+/-) mice showed lower expression of inflammatory cytokines that was secondary to reduction in weight gain not present in the other groups. In summary, our results indicate that suppression of Ubc13 activity may play a metabolic role independent of its inflammatory function. Thus, Ubc13 could represent a therapeutic target for insulin resistance, diet-induced obesity, and associated metabolic dysfunctions.
Project description: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.
