Prophylactic Application of MA-[ d -Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Prevents or Slows the Progression of Obesity, Insulin Resistance, and Cognitive Impairment in a Mouse Model of Type 2 Diabetes Mellitus

Oral delivery of MA-[ d -Leu-4]-OB3 has been shown to significantly improve energy balance, glycemic control, dyslipidemia, and episodic memory in mouse models of fully-expressed T1DM and T2DM. To assess the prophylactic capacity of MA-[ d -Leu-4]-OB3 to prevent or slow the progression of obesity, insulin resistance, and cognitive dysfunction, 3- to 4-week old male C57BL/6J mice were placed on a high-fat diet immediately after weaning, and maintained on this diet, in the absence or presence of orally delivered MA-[ d -Leu-4]-OB3, for 23 weeks. Control mice of the same age and sex were maintained on a low-fat diet. Body weight, caloric and water intake, glucose tolerance, and fasting blood glucose levels were measured. Episodic memory was evaluated by novel object recognition testing. In male C57BL/6J mice maintained on a high-fat diet since weaning, MA-[ d -Leu-4]-OB3 (1) normalized body weight gain for the first 8 weeks of the study, and sustained a significant reduction throughout the remaining 15 weeks; (2) had no effect on caloric or water intake; (3) improved glucose tolerance within 4 weeks; (4) reduced fasting blood glucose to levels approaching or equivalent to those seen in control mice within 3 weeks; and (5) normalized episodic memory within 4 weeks. In addition to its therapeutic potential, MA-[ d -Leu-4]-OB3 may have a prophylactic application to the prevention or progression of many of the dysfunctions associated with metabolic syndrome, Down Syndrome, Alzheimer’s disease (AD), and other AD-like cognitive impairments in humans.