Abstract
In addition to its roles in regulating energy balance and glucose homeostasis, leptin greatly influences hippocampal learning and memory. Because of its tendency to exacerbate autoimmune disease, angiogenesis, and oncogenesis, however, leptin’s usefulness in the treatment of chronic human disease has been severely limited. In the present study, we show that oral delivery of MA-[D-Leu-4]-OB3, a small molecule synthetic peptide leptin mimetic, normalizes glucose utilization and episodic memory in diet-induced obese (DIO) mice, a non-genetic, non-transgenic model of obesity, type 2 diabetes mellitus, and Alzheimer’s Disease (AD)-like cognitive impairment which closely recapitulates human pathology. Oral glucose tolerance and novel object recognition testing indicated that (1) glycemic dysregulation and cognitive impairment are linked in this mouse model; and (2) the ability of MA-[D-Leu-4]-OB3 to normalize glucose utilization systemically appears to be coupled to central effects that are reflected by improvement in episodic memory. Our results suggest that MA-[D-Leu-4]-OB3 may have application not only to the treatment of obesity and diabetes, but also to AD, vascular dementia, mixed dementia, or other forms cognitive impairment which may be associated with the brain’s inability to efficiently utilize glucose and to respond to insulin and insulin-like growth factor (IGF) signaling.
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Acknowledgements
This research was supported by a grant from the Willard B. Warring Memorial Fund, Albany Medical College, Albany, NY, USA. The Intravail® reagent was graciously provided by Aegis Therapeutics, San Diego, CA, USA.
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All authors contributed to the study conception and design. Material preparation and data collection were performed by ZH. Data analysis was performed by ZH and PG. The original and final drafts of the manuscript were written by PG. ZH and ZN reviewed and commented on all versions of the manuscript. All authors read and approved the final manuscript. Funding acquisition, resources, and supervision were provided by Patricia Grasso.
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Zall Hirschstein, Zachary Novakovic, and Patricia Grasso declare that they have no conflict of interest.
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Hirschstein, Z., Novakovic, Z.M. & Grasso, P. MA-[D-Leu-4]-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Normalizes Glucose Tolerance and Episodic Memory in a Mouse Model of Type 2 Diabetes Mellitus and Alzheimer’s Disease-Like Cognitive Impairment. Int J Pept Res Ther 26, 1981–1990 (2020). https://doi.org/10.1007/s10989-019-09995-0
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DOI: https://doi.org/10.1007/s10989-019-09995-0