Adropin transgenesis improves recognition memory in diet-induced obese LDLR-deficient C57BL/6J mice

Peptides. 2021 Dec:146:170678. doi: 10.1016/j.peptides.2021.170678. Epub 2021 Oct 22.

Abstract

Obesity-related metabolic dysregulation causes mild cognitive impairment and increased risk for dementia. We used an LDLR-deficient C57BL/6J mouse model (LDLRKO) to investigate whether adropin, a neuropeptide linked to neurodegenerative diseases, improves cognitive function in situations of metabolic dysregulation. Adropin transgenic mice (AdrTG) were crossed with LDLRKO; male and female progeny were fed a high fat diet for 3-months. Male chow-fed wild type (WT) mice were used as controls. Diet-induced obesity and LDLR-deficiency caused severe dyslipidemia, irrespective of sex. The AdrTG prevented reduced adropin protein levels in LDLRKO cortex. In males, metabolic dysregulation and AdrTG genotype significantly and bi-directionally affected performance in the novel object recognition (NOR) test, a declarative hippocampal memory task (discrimination index mean ± SE for WT, 0.02 ± 0.088; LDLRKO, -0.115 ± 0.077; AdrTG;LDLRKO, 0.265 ± 0.078; genotype effect, p = 0.009; LDLRKO vs. AdrTG;LDLRKO, P < 0.05). A 2-way ANOVA (fixed variables: sex, AdrTG genotype) indicated a highly significant effect of AdrTG (P = 0.003). The impact of the diet-genotype interaction on the male mouse brain was investigated using RNA-seq. Gene-ontology analysis of transcripts showing fold-changes of>1.3 or <-1.3 (P < 0.05) indicated metabolic dysregulation affected gene networks involved in intercellular/neuronal signaling, immune processes, angiogenesis, and extracellular matrix organization. The AdrTG selectively attenuated the impact of metabolic dysregulation on intercellular/neuronal signaling pathways. Intercellular/neuronal signaling pathways were also the predominant processes overrepresented when directly comparing AdrTG;LDLRKO with LDRKO. In summary, adropin overexpression improves cognitive function in severe metabolic dysregulation through pathways related to cell-cell communication and neuronal processes, and independently of preventing inflammatory responses.

Keywords: Cognitive function; Dementia; Dyslipidemia; Learning; Obesity; Peptide therapy; Transgenic models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet*
  • Disease Models, Animal
  • Gene Transfer Techniques*
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Memory*
  • Mice
  • Mice, Inbred C57BL
  • Obesity / etiology
  • Obesity / psychology*
  • Receptors, LDL / genetics*

Substances

  • Enho protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Receptors, LDL