Dietary administration of D-chiro-inositol attenuates sex-specific metabolic imbalances in the 5xFAD mouse model of Alzheimer’s disease

• Published in: Biomedicine & pharmacotherapy 2022-06, Vol.150, p.112994-112994, Article 112994
• Main Authors: López-Gambero, Antonio J., Pacheco-Sánchez, Beatriz, Rosell-Valle, Cristina, Medina-Vera, Dina, Navarro, Juan Antonio, Fernández-Arjona, María del Mar, de Ceglia, Marialuisa, Sanjuan, Carlos, Simon, Vincent, Cota, Daniela, Rivera, Patricia, Rodríguez de Fonseca, Fernando, Suárez, Juan
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Animals; D-chiro-inositol; Disease Models, Animal; Fatty liver disease; Female; Humans; Hypothalamus; Inflammation; Inositol - pharmacology; Inositol - therapeutic use; Insulin - metabolism; Insulin Resistance - physiology; Insulin signaling; Life Sciences; Male; Mice; Mice, Transgenic; Neurons and Cognition; Weight Loss
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2022.112994

Increasing evidence shows that hypothalamic dysfunction, insulin resistance, and weight loss precede and progress along with the cognitive decline in sporadic Alzheimer’s Disease (AD) with sex differences. This study aimed to determine the effect of oral dietary administration of D-Chiro-inositol (DCI), an inositol used against insulin resistance associated with polycystic ovary, on the occurrence of metabolic disorders in the transgenic 5xFAD mouse model of AD (FAD: Family Alzheimer's Disease). DCI was administered from 6 to 10 months of age to male and female 5xFAD mice and control (non-Tg) littermates. Energy balance and multiple metabolic and inflammatory parameters in the hypothalamus, liver and plasma were evaluated to assess the central and peripheral effects of DCI. Results indicated that weight loss and reduced food intake in 5xFAD mice were associated with decreased neuropeptides controlling food intake and the appearance of a pro-inflammatory state in the hypothalamus. Oral administration of DCI partially restored energy balance and hypothalamic parameters, highlighting an increased expression of Npy and Agrp and female-specific downregulation of Gfap and Igf1. DCI also partially normalized impaired insulin signaling and circulating insulin, GLP-1, and GIP deficiencies in 5xFAD mice. Principal component analysis of metabolic parameters indicated the presence of a female-specific fatty liver in 5xFAD mice: DCI administration reversed hepatic fat accumulation, β-oxidation, inflammation and increased GOT and GPT levels. Our study depicts that metabolic impairment along with the cognitive decline in a mouse model of AD, which is exacerbated in females, can be ameliorated by oral supplementation with insulin-sensitizing DCI. [Display omitted] •Hypothalamic dysfunction and insulin resistance may contribute to Alzheimer’s Disease.•D-Chiro-inositol (DCI) is a natural inositol acting as insulin signaling sensitizer.•DCI restores altered energy balance in Familiar Alzheimer’s Disease (FAD) mouse model.•DCI normalizes circulating insulin and liver insulin signaling in FAD mouse model.•DCI lessens female-specific liver fatty accumulation and inflammation in FAD mice.