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  • AMPK is a master regulator

    2021-04-17

    AMPK is a master regulator of metabolic homeostasis, its broad spectrum of metabolic activities makes it an attractive target for treatment of metabolic and related disorders including Diabetes and Obesity (Madhavi et al., 2018). It controls lipid metabolism through its target genes PPAR-γ, C/EBP-α and SREBP-1c, which enhances lipid deposition in pre adipocytes during differentiation (Day et al., 2017). HRF treatments induced activation of AMPK by phosphorylation was associated with inhibition of regulatory adipogenic transcription factors PPAR-γ, C/EBP-α and SREBP-1c. Activation of AMPK has led to enhanced ACC phosphorylation thus causing its inactivation. ACC catalyses conversion of acetyl coenzyme A to malonyl coenzyme A, which is crucial in lipid synthesis. Malonyl coenzyme A allosterically inhibits carnitine palmitoyl transferase1 (CPT1), which is involved in transport of activated fatty BIIE 0246 to mitochondria where it is further oxidised, this transport is the rate determing step in mitochondrial fatty acid oxidation (Kurumbail and Calabrese, 2016). Inhibition of ACC activity by HRF treatments not only reduces lipid synthesis as seen in adipogenesis assay and Oil Red O staining but also enhances CPT1 gene expression levels which in turn enhances fatty acid oxidation. In this study AMPK activation by HRF was further confirmed by determining effect of HRF treatments on adipocyte differentiation in the presence of AMPK inhibitor Dorsomorphin. In the presence of Dorsomorphin, HRF treatment has no effect on AMPK phosphorylation and there was no significant reduction in protein expression of master regulator PPAR-γ. On a final note current study provides evidence for potential anti-obesity activity of Hibiscus rosa sinensis flower fraction through activation of AMPK, which reduced pre-adipocyte differentiation to mature adipocytes. Further in vivo obesity studies need to be carried out to ascertain its anti-obesity efficacy and to evaluate its effect on insulin sensitivity.
    Acknowledgements Current research work was funded and supported by Department of Science and Technology, Science and Engineering Research Board [SERB], Government of India, New Delhi [F. No.-SR/YS/LS-82/2013].
    Introduction The brain plays an important role in the evaluation and control of energy homeostasis. Blood concentrations of glucose and fatty acids are sensed by neurons of the hypothalamus, which adjusts feeding behaviour and monitors fatty-acid metabolism. Several laboratories have attempted to design anti-obesity drugs and modulate fatty-acid metabolism to inhibit food intake. C75 is a synthetic inhibitor of fatty-acid synthase (FAS) [1] and has been proposed as an anti-obesity agent since its administration decreases food intake and body weight in rodents [2], [3], [4], [5]. C75 can alter the metabolism of neurons in the hypothalamus, where an increase in the level of malonyl-CoA due to FAS inhibition serves as a secondary messenger of nutrient status, thereby mediating the suppression of food intake [6], [7]. Hypothalamic levels of long-chain fatty acyl-CoA (LCFA-CoA) also signal nutrient availability and control food intake [8]. Malonyl-CoA signals the availability of lipid and carbohydrate fuels [9] and acts as a physiological inhibitor of the enzyme carnitine palmitoyltransferase 1 (CPT1). CPT1 catalyzes the first step in the transport of LCFA from the cytoplasm to the mitochondria, and is the rate-limiting step in β-oxidation. Mammalian tissues express three CPT1 isoforms: CPT1A, CPT1B and CPT1C which differ in their sensitivity to malonyl-CoA and tissue distribution [10], [11]. CPT1A and CPT1C are expressed in the brain. CPT1A is located in the mitochondrial membrane and CPT1C is expressed in the endoplasmic reticulum of neurons where although it has CPT1 activity, it does not participate in mitochondrial fatty-acid oxidation [12]. Interestingly, our group has generated a mutant form of CPT1A insensitive to malonyl-CoA (CPT1A M593S), and a mutant form of carnitine acetyltransferase (CrAT) that swaps its preference from short to LCFA-CoA (CrAT D356A/M564G). These mutants have allowed us to examine the structural requirements of substrates and inhibitors [13], [14], [15].