Abstract
Leptin resistance and co-existing insulin resistance is considered as hallmark of diet-induced obesity. Here, we investigated therapeutic potential of hesperidin to improve leptin and insulin resistance using high fat diet (HFD)-induced obese experimental animal model. We also performed in silico studies to validate therapeutic effectiveness of hesperidin by performing protein-ligand docking and molecular dynamics simulation studies. Group 1 was identified as control group receiving vehicle only. Group 2 was marked as non-treated group receiving 60% HFD. While, other groups were treated daily with orlistat (120 mg/kg/d), hesperidin (55 mg/kg/d), combination of hesperidin (55 mg/kg/d) + orlistat (120 mg/kg/d). Hesperidin alone (P<0.001) and particularly in combination with orlistat (P<0.001), resulted in controlling the levels of HFD-altered biomarkers including random and fasting state of glycemia, leptin and insulin resistance. Similarly, hesperidin also improved the serum and tissue levels of leptin, interleukin-6 and tumor necrosis factor-alpha more significantly (P<0.05) when compared with that of orlistat. These results were found to be in accordance with the results of histopathological examination of pancreas, liver and adipose tissues. In-silico studies also proved that hesperidin binds to leptin receptor with higher affinity as compared to that of orlistat and induces the favorable variations in geometrical conformation of leptin receptor to promote its association with leptin which may lead to the cascades of reactions culminating the lipolysis of fats that may ultimately lead to cure obesity. The results of this study may be a significant expectation among the forthcoming treatment strategies for leptin and insulin resistance.
Highlights
Leptin, a hormonal peptide is known to control the body weight
We found that high fat diet (HFD) significantly increased (P
There is an increased secretion of leptin from white adipose tissue, but this leptin does not bind with its receptor (LEP-R) present on hypothalamus in brain, causing resistance to the leptin and increasing the body weight which leads to the obesity [1]
Summary
A hormonal peptide is known to control the body weight. Leptin is produced primarily by white adipose tissues. Other factors that may contribute in increasing the secretion of leptin includes reduce food intake and/or excess utilization of body energy through hypothalamicpituitary-gonadal axis [1]. Any change in the level of leptin secretion may have a direct influence on metabolic functions of the body. This may be because of the contribution of leptin for oxidation of free fatty acids (FFAs) in periphery, which in turn results in the decreased accumulation of body fat. Hyperleptinemia and leptin resistance in turn may cause disturbances in lipid metabolism causing reduction in FFAs oxidation and increasing the levels of triglycerides (TGs) [5]. Makeover of leptin sensitivity has been suggested to be helpful in ameliorating the disturbances in lipid profile and associated conditions like DM [6,7,8]
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