Abstract
Shortening of poly(A) tails triggers mRNA degradation; hence, mRNA deadenylation regulates many biological events. In the present study, we generated mice lacking the Cnot1 gene, which encodes an essential scaffold subunit of the CCR4–NOT deadenylase complex in adipose tissues (Cnot1-AKO mice) and we examined the role of CCR4–NOT in adipocyte function. Cnot1-AKO mice showed reduced masses of white adipose tissue (WAT) and brown adipose tissue (BAT), indicating abnormal organization and function of those tissues. Indeed, Cnot1-AKO mice showed hyperinsulinemia, hyperglycemia, insulin resistance, and glucose intolerance and they could not maintain a normal body temperature during cold exposure. Muscle-like fibrous material appeared in both WAT and BAT of Cnot1-AKO mice, suggesting the acquisition of non-adipose tissue characteristics. Gene expression analysis using RNA-sequencing (RNA-seq) showed that the levels of adipose tissue-related mRNAs, including those of metabolic genes, decreased, whereas the levels of inflammatory response-related mRNAs increased. These data suggest that the CCR4–NOT complex ensures proper adipose tissue function by maintaining adipocyte-specific mRNAs at appropriate levels and by simultaneously suppressing mRNAs that would impair adipocyte function if overexpressed.
Highlights
The adipose tissue regulates energy balance and lipid homeostasis [1]
To investigate CNOT1 functions in adipose tissues, we generated Cnot1-AKO mice by crossing adiponectin-cre mice with mice carrying a floxed allele for Cnot1 (Cnot1loxP/loxP) and examined their phenotypes
Masses of eWAT, iWAT, mesenteric White adipose tissue (WAT), perirenal WAT, and brown adipose tissue (BAT) were significantly lower in Cnot1-AKO mice than in control mice, whereas hepatic and pancreatic masses increased in Cnot1-AKO mice (Figure 1E,F)
Summary
The adipose tissue regulates energy balance and lipid homeostasis [1]. White adipose tissue (WAT) provides energy storage, while brown adipose tissue (BAT) dissipates stored energy as heat [1]. Adipose tissue dysfunction or alterations in fat mass result in obesity (excess adipose tissue) or lipodystrophy (loss of adipose tissue). These two conditions are pathologically opposite, both are accompanied by similar metabolic abnormalities, including hepatic steatosis and insulin resistance, leading to increased risk of type 2 diabetes and cardiovascular disease [2,3]. Generalized and partial lipodystrophy are defined on the basis of the degree and location of fat loss [2]. Both genetic and acquired factors are responsible for these conditions [2]. Understanding the mechanism by which lipodystrophy develops will facilitate the development of therapeutic strategies
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