Increased calorie intake and reduced energy expenditure are the main etiological factors in obesity. On the other hand, increased brown adipose tissue activity and recruitment of beige adipocytes are proposed to antagonize obesity-related complications. miRNAs are important regulators of metabolic processes. These small molecules are generated by a pathway that includes the rate limiting enzyme named DICER, which has been shown to play a key role in adipose tissue thermogenesis and brown/beige adipocyte differentiation and function. Activation of thermogenesis in adipose tissue is mediated by the beta-adrenergic receptors. The signaling cascade mediated by beta-adrenergic agonists occurs through the second messenger cAMP, which promotes a wide range of effector mechanisms to modify cell metabolism, thus promoting lipolysis, thermogenesis, and browning of white fat. Our current results demonstrate that beta-adrenergic signaling robustly induces miRNA/siRNA biogenesis and function, and this participates in the establishment of the oxidative and thermogenic profile induced by beta-adrenergic agonists in adipocytes. However, the mechanisms underlying how beta-adrenergic activation promotes miRNA/siRNA function is unclear. Through this application we propose to study the mechanisms and signaling events involved in the changes of miRNA biogenesis in response to adrenergic stimulation. We intend to do it by a combination of proteomic and functional analyses, which will allow us to identify partners and post-translational modifications in the components of the DICER complex, as well as to investigate the importance of these changes to miRNA biogenesis and adipocyte physiology in response to beta-adrenergic stimulation. This proposal will shed light onto how beta-adrenergic activation contributes to induction of miRNA/siRNA function and promotes DICER activity, and how this mechanism participates in the pathways triggered by beta-adrenergic agonists in the adipocyte.
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