[D-Leu-4]-OB3, an orally bioavailable leptin-related synthetic peptide insulin sensitizer: A study comparing the efficacies of [D-Leu-4]-OB3 and metformin on energy balance and glycemic regulation in insulin-deficient male Swiss Webster mice

A Synthetic Fragment of Leptin Increase Hematopoietic Stem Cell Population and Improve Its Engraftment Ability

“…Previously, several reports have shown that a region encompassing the amino acids from 98 to 122 of the leptin molecule is important for its activity. Some short fragment sequences on this region apparently possess bioactivity similar to intact leptin [Grasso et al, 1997, 2001; Oliveira et al, 2005, 2012; de Oliveira et al, ; Martins et al, ; Leinung and Grasso, ; Dias et al, ; Novakovic et al, ; Lin et al, ].…”

“…Moreover, their sequences have been recognized by the leptin receptor present in human pituitary HP‐75 cell lineage [de Oliveira et al, ]. In other studies involving the use of leptin‐based fragments, [D‐Leu 4 ]‐OB3 and OB3 regulated the energy balance and glucose homeostasis, and also activated Stat‐3 [Grasso et al, 1997, 2001; Novakovic et al, ; Lin et al, ].…”

Myristic acid conjugation of [D-Leu-4]-OB3, a biologically active leptin-related synthetic peptide amide, significantly improves its pharmacokinetic profile and efficacy

“…On-going efforts in the design, development, and preclinical application of lepin-related synthetic peptide agonists and antagonists [4][5][6][7][8][9][10][12][13][14][15][16][17][18][19][20][21][22][23] indicates that the apparent failure of leptin in the clinic to satisfy the therapeutic needs of the majority of obese humans has acted as a catalyst in efforts to develop novel peptide therapeutics targeted at reducing the pandemic proportions of this disease and its associated metabolic dysfunctions. In this regard, small-molecule peptide therapeutics have the potential to overcome the limitations of recombinant leptin, since their uptake into the central nervous system (CNS) is not dependent on saturable transport across the blood-brain barrier (BBB).…”

“…Defective transport into the CNS has been identified as the cause of leptin resistance in the majority of cases of human obesity [1][2][3]. [D-Leu-4]-OB3 has been shown to be biologically active in genetically obese diabetic ob/ob and db/db mouse models, and in non-obese streptozotocin-induced insulin-deficient Swiss Webster mice [7,10,19,20,23,25]. It is worthy of special note that demonstration of the anti-obesity and anti-hyperglycemic effects of [D-Leu-4]-OB3 in leptin-resistant db/db mice indicates a mechanism of action that involves recruitment of signaling pathways that achieve leptin-like effects independent of activation of the long isoform of the leptin receptor.…”

“…More recently, we have shown that oral delivery of [D-Leu-4]-OB3, when given in combination with a number of FDA-approved anti-diabetes drugs, exenatide, pramlintide, and metformin, augments the effects of these therapeutics in both insulin-resistant and insulin-deficient mouse models [10,20]. Given the fact that the majority of clinically obese humans are leptin-resistant because of defects in transport of leptin across the blood-brain barrier (BBB) [3], the relevance of these results in leptin-resistant rodent models of obesity and diabetes to the clinical management of human metabolic disease may be highly significant.…”