[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, Small Molecule Synthetic Peptide Leptin Mimetics, Improve Energy Balance and Glycemic Control in Diet-Induced Obese (DIO) Mice

Presentation Number: MON 590
Date of Presentation: April 3rd, 2017

Patricia Grasso*, Anke Wang, Brian M Anderson and Zachary M Novakovic
Albany Medical College, Albany, NY

Abstract

We have previously shown that [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, regulate energy balance and glucose homeostasis in genetically obese ob/ob and db/db mice, and in streptozotocin-induced hyperglycemic non-obese Swiss Webster mice. In a manner similar to leptin, [D-Leu-4]-OB3 activates STAT3 via phosphorylation of ERK 1/2 and PI-3K suggesting that these signals may ultimately result in peptide effects on transcriptional and translational events associated with energy balance and glycemic regulation. Most recently, we have demonstrated in that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 cross the blood-brain barrier (BBB) in Swiss Webster, C57BL/6 wild-type, ob/ob, and diet-induced obese (DIO) mice following oral administration, and localize in the arcuate nucleus, an area of the hypothalamus known to contain leptin–responsive anorexigneic and anorexigenic first order neurons. In the present study, we show that oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 in dodecyl maltoside (trade name Intravail®) (1) reduces food and water intake and body weight gain in DIO mice fed a high-fat diet; (2) augments the weight-reducing effects of a low-fat diet in this mouse model; and (3) improves glucose tolerance. These results suggest that [D-Leu-4]-OB3 and its myristic acid conjugate, in addition to their potential usefulness in treating those rare cases of human obesity resulting from a genetic defect in the production of functional leptin, may have an application in the management of the majority of cases of common obesity characterized by leptin resistance due to defects in leptin transport across the BBB. They further suggest that [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, via their influence on glucose homeostasis, may help to prevent the pre-diabetic state associated with most cases of common obesity from escalating into full-blown type 2 diabetes mellitus.

 

Nothing to Disclose: PG, AW, BMA, ZMN