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- Regulatory interactions between the metabolic sensors SIRT1 and AMPK in modulating PPARα linked functions, in obesity-dependent type 2 diabetes mellitusPublication . Silvestre, MP; Caton, Paul; Maria Carlota, Maria Carlota; Pinto, Helena Cortez, 1957-Both genetic and environmental influences determine the risk of developing type 2 diabetes mellitus (T2DM). Epidemiological studies indicate that factors influencing the prevalence of T2DM include lifestyle (e.g. inactivity and dietary macronutrient composition), obesity and age. Interestingly maternal protein restriction (Maternal Low Protein; MLP) generates low birth weight (LBW) offspring, who develop insulin resistant and diabetic phenotype in later life. Interferon regulatory factors 3 and 4 (IRF3 and IRF4) are key repressors of adipogenesis. SIRT1, a histone/protein deacetylase, and AMP-activated protein kinase (AMPK) are key enzymes responsible for longevity and energy homeostasis. Through deacetylation and activation of peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC-1α), a transcriptional regulator of fatty acid (FA) oxidation, SIRT1 mediates activation of peroxisome-proliferator-activated receptor α (PPARα), which is a nuclear receptor that controls the expression of genes involved in glucose and lipid homoeostasis. The proposed study aims to investigate whether a positive feed back loop exists in response to AMPK/SIRT1 activation and try to characterize the role of this pathway in the regulatory circuit through which PPARα induces gene expression. C57Bl/6 mice fasted or fed a high fat diet (HF) and rat MLP-offspring were used to understand the importance of nutrient availability in the development of insulin-resistance and T2DM in liver and visceral white adipose tissue (WAT) respectively; specific liver and muscle AMPK α1/2 double null (AMPK-/-) mice were used to understand the role of AMPK on SIRT1 activation and PPARα linked functions; PPARα deficient mice were used to investigate the influence of PPARα deficiency on lipogenesis and β oxidation in mice visceral WAT; H4IIEC3 liver cell line was cultured and treated with a SIRT1 siRNA to better understand the feedback loop between SIRT1 and AMPK; L6 myoblasts were cultured and treated with AMPK agonist adiponectin and with insulin, and 3T3-L1 adipocytes were cultured and treated with PPARα agonists (WY14683) to understand the role of PPARα in IRF3 and IRF4. Using AMPK-/- liver and SIRT1 knockdown H4IIEC3 cells we found that, in the liver, AMPK and SIRT1 regulate each other to prevent lipid accumulation. Studies on HF fed mice, treated with nicotinamide mononucleotide (NMN), linked this 10 AMPK/SIRT1 pathway to phosphorylation of the insulin receptor substrate (IRS-1) at tyrosine residues, suggesting an involvement of the SIRT1/AMPK axis in the insulinsignalling pathway. In skeletal muscle AMPK deficiency impairs the beneficial effects of CR on glucose tolerance. This is linked to decreased SIRT1 gene expression, which could impair insulin signalling pathway, culminating in reduced glucose uptake. Using MLP-offspring visceral WAT, we found that suppression of interferon regulatory factors 3 and 4 (IRF3 and IRF4, respectively) represses fatty oxidation and enhances lipogenesis in MLP-offspring. IRF3 is possibly activated by AMPK, where IRF4 is activated by PPARα. Taken together, our results suggest that AMPK-SIRT1-PGC-1α-SIRT3 axis during fasting/CR is important to prevent metabolic disorders. Regulation of AMPK and PPARα linked functions together with deacetylation catalyzed by the sirtuins may prove to be important for the treatment of T2DM and other disorders associated with aging. Adiponectin (which activates AMPK and PPARα) and NMN (which increases SIRT1 activity) are potential therapeutic targets for the treatment of metabolic disorders.