Mehmood Ali, Arvind Gupta, Rahul Dev Verma, Sariyah Akhtar, Jimut Kanti Ghosh
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引用次数: 0
Abstract
Leptin is an adipokine, which plays key roles in regulation of glucose-metabolism and energy-homeostasis. Therefore, identification of a short peptide from Leptin which improves glucose-metabolism and energy-homeostasis could be of significant therapeutic importance. Mutational studies demonstrated that N-terminal of human Leptin-hormone (LH) is crucial for activation of Leptin-receptor while its C-terminal seems to have lesser effects in it. Thus, for finding a metabolically active peptide and complimenting the mutational studies on Leptin, we have identified a 17-mer (Leptin-1) and a 16-mer (Leptin-2) segment from its N-terminal and C-terminal respectively. Consistent with the mutational studies, Leptin-1 improved glucose-metabolism by increasing glucose-uptake, GLUT4 expression and its translocation to the plasma-membrane in L6-myotubes, while Leptin-2 was mostly inactive. Leptin-1-induced glucose-uptake is mediated through activation of AMPK, PI3K and AKT proteins since inhibitors of these proteins inhibited the event. Leptin-1 activated leptin-receptor immediate downstream target protein, JAK2 reflecting its possible interaction with leptin-receptor while Leptin-2 was less active. Furthermore, Leptin-1 increased mitochondrial-biogenesis and ATP-production, and increased expression of PGC1α, NRF1 and Tfam proteins, that are important regulators of mitochondrial-biogenesis. The results suggested that Leptin-1 improved energy-homeostasis in L6-myotubes, whereas, Leptin-2 showed much lesser effects. In diabetic, db/db mice, Leptin-1 significantly decreased blood glucose level and improved glucose-tolerance. Leptin-1 also increased serum adiponectin and decreased serum TNF-α and IL-6 level signifying the improvement in insulin-sensitivity and decrease in insulin-resistance, respectively in db/db mice. Overall, the results show the identification of a short peptide from the N-terminal of human LH which significantly improves glucose-metabolism and energy-homeostasis.
期刊介绍:
The Journal of Biological Chemistry welcomes high-quality science that seeks to elucidate the molecular and cellular basis of biological processes. Papers published in JBC can therefore fall under the umbrellas of not only biological chemistry, chemical biology, or biochemistry, but also allied disciplines such as biophysics, systems biology, RNA biology, immunology, microbiology, neurobiology, epigenetics, computational biology, ’omics, and many more. The outcome of our focus on papers that contribute novel and important mechanistic insights, rather than on a particular topic area, is that JBC is truly a melting pot for scientists across disciplines. In addition, JBC welcomes papers that describe methods that will help scientists push their biochemical inquiries forward and resources that will be of use to the research community.