A peptide derived from the amino terminus of leptin improves glucose metabolism and energy homeostasis in myotubes and db/db mice

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.