[D-LEU-4]-OB3, a synthetic leptin agonist, improves hyperglycemic control in C57BL/6J ob/ob mice

We have recently shown that the activity of a synthetic peptide correspondi ng to amino acid residues 116-130 of secreted mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residue s 116-122 (Ser-Cys-Ser-Leu-Pro-Gln-Thr, OB3). Substitution of the Leu resid ue at position 4 of OB3 with its D-isomer ([D-Leu-4]-OB3) enhanced the abil ity of OB3 (1 mg/day, ip, 7 days) to reduce body weight gain, food and wate r intake, and serum glucose in female C57BL/6J ob/ob mice. In the present s tudy, we have utilized a pair-feeding approach to demonstrate that the anti hyperglycemic action of [D-Leu-4]-OB3 is not solely due to its effects on c aloric intake. One group of female C57BL/6J ob/ob mice (n=6) was fed ad lib itum, and two additional groups (n=6 per group) were allowed 3.0 g food/mou se daily, an amount previously determined to satisfy [D-Leu-4]-OB3-treated mice. At the end of the 7-day test period, vehicle-injected mice fed ad lib itum were approximately 10% heavier than their initial body weights, while pair-fed mice injected with vehicle and [D-Leu-4]-OB3-treated mice lost 5% of their initial body weights, After I day of treatment, blood glucose was reduced by 20% in pair-fed vehicle-injected mice, and by 40% in mice given [D-Leu-4]-OB3. Food restriction reduced blood glucose throughout the 7-day study, but not to levels seen in wild-type nonobese C57BL/6J mice of the sa me sex and age. After 2 days of treatment with [D-Leu-4]-OB3, however, bloo d glucose was reduced to levels comparable to those seen in wild-type nonob ese mice. [D-Leu-4]-OB3 also lowered serum insulin levels by 53% when compa red to mice fed ad libitum. Neither pair-feeding nor [D-Leu-4]-OB3 treatmen t had any apparent effect on thermogenesis. These results suggest that [D-L eu-4]-OB3 exerts its effects on serum glucose not only by suppressing calor ic intake, but also through a separate effect on glucose metabolism which m ay involve increased tissue sensitivity to insulin. (C) 2001 Elsevier Scien ce B.V. All rights reserved.