Deficits in hippocampal neurogenesis in obesity-dependent and -independent type-2 diabetes mellitus mouse models

Sci Rep. 2020 Oct 1;10(1):16368. doi: 10.1038/s41598-020-73401-9.

Abstract

Hippocampal neurogenesis plays an important role in learning and memory function throughout life. Declines in this process have been observed in both aging and Alzheimer's disease (AD). Type 2 Diabetes mellitus (T2DM) is a disorder characterized by insulin resistance and impaired glucose metabolism. T2DM often results in cognitive decline in adults, and significantly increases the risk of AD development. The pathways underlying T2DM-induced cognitive deficits are not known. Some studies suggest that alterations in hippocampal neurogenesis may contribute to cognitive deterioration, however, the fate of neurogenesis in these studies is highly controversial. To address this problem, we utilized two models of T2DM: (1) obesity-independent MKR transgenic mice expressing a mutated form of the human insulin-like growth factor 1 receptor (IGF-1R) in skeletal muscle, and (2) Obesity-dependent db/db mice harboring a mutation in the leptin receptor. Our results show that both models of T2DM display compromised hippocampal neurogenesis. We show that the number of new neurons in the hippocampus of these mice is reduced. Clone formation capacity of neural progenitor cells isolated from the db/db mice is deficient. Expression of insulin receptor and epidermal growth factor receptor was reduced in hippocampal neurospheres isolated from db/db mice. Results from this study warrant further investigation into the mechanisms underlying decreased neurogenesis in T2DM and its link to the cognitive decline observed in this disorder.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation / physiology
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / physiopathology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Hippocampus / physiopathology*
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / physiology
  • Neurogenesis / physiology*
  • Neurons / physiology*
  • Obesity / genetics
  • Obesity / physiopathology*
  • Receptor, IGF Type 1 / genetics
  • Receptors, Leptin / genetics

Substances

  • Igf1r protein, mouse
  • Receptors, Leptin
  • Receptor, IGF Type 1