Mark A Febbraio

Aim Acyl‐coenzyme A dehydrogenase family member 10 (ACAD10) is a mitochondrial protein purported to be involved in the fatty acid oxidation pathway. Metformin is the most prescribed therapy for type 2 diabetes; however, its precise mechanisms of action(s) are still being uncovered. Upregulation of ACAD10 is a requirement for metformin's ability to inhibit growth in cancer cells and extend lifespan in Caenorhabditis elegans . However, it is unknown whether ACAD10 plays a role in metformin's metabolic actions. Materials and Methods We assessed the role for ACAD10 on whole‐body metabolism and metformin action by generating ACAD10KO mice on a C57BL/6J background via CRISPR‐Cas9 technology. In‐depth metabolic phenotyping was conducted in both sexes on a normal chow and high fat‐high sucrose diet. Results Compared with wildtype mice, we detected no difference in body composition, energy expenditure or glucose tolerance in male or female ACAD10KO mice, on a chow diet or high‐fat, high‐sucrose diet ( p ≥ .05). Hepatic mitochondrial function and insulin signalling was not different between genotypes under basal or insulin‐stimulated conditions ( p ≥ .05). Glucose excursions following acute administration of metformin before a glucose tolerance test were not different between genotypes nor was body composition or energy expenditure altered after 4 weeks of daily metformin treatment ( p ≥ .05). Despite the lack of a metabolic phenotype, liver lipidomic analysis suggests ACAD10 depletion influences the abundance of specific ceramide species containing very long chain fatty acids, while metformin treatment altered clusters of cholesterol ester, plasmalogen, phosphatidylcholine and ceramide species. Conclusions Loss of ACAD10 does not alter whole‐body metabolism or impact the acute or chronic metabolic actions of metformin in this model.

Obesity has been linked to a range of pathologies, including dementia. In contrast, regular physical activity is associated with the prevention or reduced progression of neurodegeneration. Specifically, physical activity can improve memory and spatial cognition, reduce age-related cognitive decline, and preserve brain volume, but the mechanisms are not fully understood. Accordingly, we investigated whether any detrimental effects of high-fat diet (HFD)-induced obesity on cognition, motor behavior, adult hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) could be mitigated by voluntary exercise training in male C57Bl/6 mice. HFD-induced impairment of motor function was not reversed by exercise. Importantly, voluntary wheel running improved long-term memory and increased hippocampal neurogenesis, suggesting that regular physical activity may prevent cognitive decline in obesity.