Role of the tumour suppressor pathway p53‐p21 in the regulation of metabolism

摘要: Changes in diet and life style caused an alarming increase the incidence of obesity, which is considered a major risk factor for onset metabolic syndrome. One initial events obesity adipocyte hypertrophy, stressful condition that triggers cellular responses like inflammation eventually lead to insulin resistance (IR) hyperinsulinemia, may be link between other obesity-associated disorders such as T2D, cardiovascular diseases, atherosclerosis cancer. The goal this thesis was unravel novel molecular mechanisms underlying development associated IR hyperinsulinemia. We pursued performing two different studies: 1. Analysis role p53/p21 tumour suppressor pathway obesity. 2. effect JNK activation pancreatic ?-cells systemic p21 gene protein expression upregulated adipose tissue (AT) models obesity: leptin-deficient (ob/ob) diet-induced obese (DIO) mice, whereas p21-deficiency protected from adiposity induced by high fat (HFD). Functional genomics analysis showed deficiency did not affect adipogenic genes but highlighted inverse correlation leptin receptor (LepR) AT p21-knockout (KO) compared wild type (WT) mice. Furthermore, mice KO both developed same extent ob/ob Overall, these results indicated mechanism protects depends on properly working leptin/LepR signalling. LepR levels were also increased p53 So, our hypothesis explain at level obesity-protective phenotype HFD conditions, animals have sensitivity due AT, considering overexpression specifically In vivo experiments investigate slightly greater percentage weight decrease WT, with no differences food intake. order establish mechanistic pathway, we performed silico identify putative binding sites E2F transcription gene. can modulate through regulation pRB, turn negatively regulates activity E2F. Supporting idea, pRB deletion DIO. Moreover, has metabolism independently its function cell cycle: regulate propose would one them. Regarding second study, induces locally systemically MKK7D HFD. At time obesity-induced inflammation, generated suffice induce IR. Preserving skeletal muscle seemed sufficient prevent addition, data suggest chronic exposure plasma are required