Early-life metabolic dysfunction impairs cognition and mitochondrial function in mice

• Published in: The Journal of nutritional biochemistry 2023-07, Vol.117, p.109352-109352, Article 109352
• Main Authors: Vilela, Wembley Rodrigues, Bellozi, Paula Maria Quaglio, Picolo, Victor Luna, Cavadas, Bruna Neves, Marques, Keila Valentina Silva, Pereira, Louise Tavares Garcia, Guirao, Ainhoa Rodriguez de Yurre, Amato, Angélica Amorim, Magalhães, Kelly Grace, Mortari, Márcia Renata, Medei, Emiliano Horacio, Goulart, Jair Trapé, de Bem, Andreza Fabro
• Format: Article
• Language: English
• Subjects: Animals; Brown adipose tissue; Cognition; Diet, High-Fat - adverse effects; High-fat diet; Hippocampus; Male; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Obesity - metabolism; Streptozotocin
• ISSN: 0955-2863; 1873-4847; 1873-4847
• DOI: 10.1016/j.jnutbio.2023.109352

The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by a two-hit protocol and their impact on cognitive function in juvenile mice. Three-week-old male C57BL/6 mice received a high-fat diet (HFD) or control diet for 7 weeks, associated with two low doses of streptozotocin (STZ) or vehicle. Despite the absence of obesity, HFD+STZ impaired glucose metabolism and induced a trend towards cholesterol increase. The two-hit protocol impaired recognition and spatial memories in juvenile mice, without inducing a depressive-like behavior. HFD+STZ mice presented increased immunoreactivity for GFAP and a trend towards a decrease in NeuN in the hippocampus. The treatment caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by the two-hit protocol, here verified through the absence of a decrease in O2 consumption after uncoupled protein-1 inhibition and an increase in the reserve respiratory capacity. Impaired mitochondrial function was also observed in the liver of HFD+STZ juvenile mice, but not in their heart. These results indicate that exposure to HFD+STZ early in life has a detrimental impact on the bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment. [Display omitted]