Sirtuins are NAD+-dependent protein deacetylases or ADP-ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, metabolism, stress resistance and tumorigenesis. In mammals, sirtuins emerged as key metabolic sensors in various tissues and play a prominent role in metabolic adaptation to energy/nutrient stress. Sirt1 and Sirt6 are believed to act synergistically to prevent liver steatosis, especially under high-fat diet. Sirt1 and Sirt2 inhibit adipogenesis, and Sirt1 promotes the brown remodeling of white adipose tissue to control the metabolic balance in adipose tissue. Sirt7 was postulated to regulate rDNA transcription by associating with RNA polymerase I (Pol I) and maintain oncogenic transformation through deacetylation of histone H3K18, but the role of Sirt7 in metabolic regulation has remained enigmatic. Here, using the Sirt7 knockout mice and Sirt7 knock down approaches, my results describe the role of Sirt7 in maintenance of metabolic homeostasis in liver and the adipocytes differentiation in white adipose tissue. In liver, Sirt7 is required for the stimulation of hepatic rDNA transcription in response to insulin and is necessary for the fasting/refeeding adaptation. The second part of the study demonstrates the essential role of Sirt7 in adipocytes differentiation and white adipose tissue homeostasis. Absence of Sirt7 resulted in increased protein accumulation and activity of Sirt1 and restricted formation of white adipose tissue. In addition, my thesis shows that Sirt7 interacts with Sirt1 and restricts Sirt1 activity by inhibition of Sirt1 auto-deacetylation. These data uncover a new level of complexity in regulation of sirtuin activity and identify autocatalytic posttranscriptional modification as a new principle for regulation of Sirt1 activity. The antagonistic interactions between the two nuclear sirtuins are crucial to establish a well-balanced signalling network required for the maintenance of metabolic homeostasis. In the last part of this thesis, two Sirt1 targeting mouse strains were generated, which allow conditional, tissue specific inactivation of the Sirt1 gene and double knock out Sirt1 and Sirt7 in mice. These mouse models will help to further evaluate the sirtuin functions and the cross-regulatory network between Sirt1 and Sirt7 in the whole body or in the individual tissues.
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