[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice

• Published in: Peptides (New York, N.Y. : 1980) Vol. 101; pp. 51 - 59
• Main Authors: Wang, Anke, Anderson, Brian M., Novakovic, Zachary M., Grasso, Patricia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018
• Subjects: Animals; Biomimetic Materials - chemistry; Biomimetic Materials - pharmacology; Diet-induced obesity; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Disease Models, Animal; Glucose Tolerance Test; Glycemic control; Insulin - blood; Insulin resistance; Leptin - chemistry; Leptin mimetics; Leptin resistance; Male; Mice; Mice, Obese; Obesity - blood; Obesity - chemically induced; Obesity - drug therapy; Peptides - chemistry; Peptides - pharmacology; Prediabetes; PBS; Glycemic control; AD; BBB; Leptin mimetics; CNS; DIO; DDM; Prediabetes; AUC; Leptin resistance; Diet-induced obesity; Insulin resistance; LF; OGTT; HF; BMI
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2017.12.012

•Oral delivery of MA-[D-Leu-4]-OB3 in dodecyl maltoside is feasible in DIO mice.•MA-[D-Leu-4]-OB3 improves glucose tolerance in DIO mice.•The effects of MA-[D-Leu-4]-OB3 on glycemic control are independent of its effects on energy balance.•MA-[D-Leu-4]-OB3 may slow the progression of prediabetes to overt diabetes in DIO mice. We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high-fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their influence on glycemic control, may prevent the pre-diabetic state associated with most cases of common obesity from escalating into overt type 2 diabetes mellitus.