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

Abstract

Obesity-related metabolic dysregulation causes mild cognitive impairment and increased risk for dementia. We used an LDLR-deficient C57BL/6\u2009J 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\u2009±\u2009SE for WT, 0.02\u2009±\u20090.088; LDLRKO, -0.115\u2009±\u20090.077; AdrTG;LDLRKO, 0.265\u2009±\u20090.078; genotype effect, p\u2009=\u20090.009; LDLRKO vs. AdrTG;LDLRKO, P\u2009<\u20090.05). A 2-way ANOVA (fixed variables: sex, AdrTG genotype) indicated a highly significant effect of AdrTG (P\u2009=\u20090.003). 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\u2009<\u20090.05) 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.