[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 corresponding to amino acid residues 116-130 of secreted mouse leptin is contained in a restricted sequence at the amino terminus of the peptide, between residues 116-122 (Ser-Cys-Ser-Leu-Pro-Gln-Thr, OB3). Substitution of the Leu residue at position 4 of OB3 with its D-isomer ([D-Leu-4]-OB3) enhanced the ability of OB3 (1 mg/day, ip, 7 days) to reduce body weight gain, food and water intake, and serum glucose in female C57BL/6J ob/ob mice. In the present study, we have utilized a pair-feeding approach to demonstrate that the antihyperglycemic action of [D-Leu-4]-OB3 is not solely due to its effects on caloric intake. One group of female C57BL/6J ob/ob mice (n=6) was fed ad libitum, and two additional groups (n=6 per group) were allowed 3.0 g food/mouse 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 libitum 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 1 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 same sex and age. After 2 days of treatment with [D-Leu-4]-OB3, however, blood glucose was reduced to levels comparable to those seen in wild-type nonobese mice. [D-Leu-4]-OB3 also lowered serum insulin levels by 53% when compared to mice fed ad libitum. Neither pair-feeding nor [D-Leu-4]-OB3 treatment had any apparent effect on thermogenesis. These results suggest that [D-Leu-4]-OB3 exerts its effects on serum glucose not only by suppressing caloric intake, but also through a separate effect on glucose metabolism which may involve increased tissue sensitivity to insulin.
Grasso
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P
Department of Medicine, Division of Endocrinology and Metabolism, MC-141, Albany Medical College, Albany, NY 12208, USA. GrassoP@mail.amc.edu
Rozhavskaya-Arena
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Leinung
M C
MC
Lee
D W
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D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D005260:Female; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D020738:Leptin / Q000008:administration & dosage / Q000819:agonists* / Q000494:pharmacology*; D016555:Matched-Pair Analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D022722:Thermogenesis / Q000187:drug effects; D013997:Time Factors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D020738:Leptin; D010446:Peptide Fragments; C410793:leptin (116-130)