Introduction
In an increasingly aged and obese population, diseases such as diabetes, cancer cardiovascular and neurodegenerative diseases are on the rise. Recently, a positive correlation between obesity and cognitive decline and neurodegenerative diseases has been described, offering a new therapeutic target. Among the altered pathways found in obesity, chronic-low grade inflammation stands out for its relevance, since activation of microglia under obesogenic conditions is known to contribute both to the peripheral and central changes in metabolism and cognition.
In this project, we set out to explore the metabolic and central consequences of preventing the activation of nutritional stress-related pathways specifically in microglia in conditions of dietary fatty acids and sugar overload.
Methods
Immortalized microglial BV2 cells were treated with a mixture of glucose, fructose and palmitate to mimic the dietary insults caused by a fatty acids and sugar overload; and used to characterize the mechanisms leading to aberrant microglial activation. Functional consequences of this pathological microglial activation were assessed in vivo feeding High Fat-High Fructose (HFHF) diet to mice specifically depleting in microglia the nutritional stress pathway.
Results
Under chronic dietary insults, microglia specifically activate the nutritional stress response cascade, both in vitro and in vivo. Blunting the activation of this pathway in mice prevents the body weight gain and increased adiposity observed in their control littermates when fed HFHF diet. This protection seems to be due to microglial-mediated increase in energy expenditure, in the absence of differences in overall body temperature, locomotor activity and food intake, or peripheral glucose homeostasis. Microglial BV2 cells inhibited for nutritional stress response activation preserve characteristics of resting microglia, with decreased proliferation and interleukin production, which could contribute to the metabolic protection conferred in vivo.
Discussion
Preventing the activation of nutritional stress pathways specifically in microglial cells might reduce its inflammatory status, helping protect relevant neuronal circuits implicated in the control of energy expenditure, memory and anxiety from the detrimental effects of dietary lipid and sugar overload. Thus, under obesogenic conditions, microglia could act as the link between peripheral alterations and changes in the brain.
Funding
ACA was funded by Juan de la Cierva-Formación, 2020; G.S. is a EMBO YIP member, received funding from the following programmes and organizations: MICIN-FEDER PID2022-138525OB-I00 2023- 26 funded by MICIU/AEI/10.13039/501100011033 and ERDF/UE; Infraestructura de Medicina de Precisión asociada a la Ciencia y Tecnología IMPACT-2021. Instituto de Salud Carlos III., PDC2021-121147-I00.Convocatoria: Proyectos Prueba de Concepto 2021. Ministerio de Ciencia e Innovación.