SUN-722 - Cnaβ1 Regulates Substrates Preferences and Metabolic Flexibility in Mice

Energy expenditure encompasses the total energy utilized by the organism to sustain basal physiological processes, physical activity, and nutrient metabolism, with higher basal energy expenditure being associated with increased glucose uptake. In addition, metabolic flexibility allows improved adaptation of glucose uptake under changing metabolic conditions. In this context, we aimed to establish the relationship between the loss of CnAβ1 function, the preferential use of glucose as a metabolic substrate, and its association with basal energy expenditure.
CnAβ1Δi12 mice were generated by deletion of the CnAβ1-specific C-terminal domain. Male and female mice (n = 10) were used at both young (3 months) and old (18 months) ages, together with C57BL/6J control mice. Animals were fed a normal diet (ND), and body weight and food intake were monitored. Basal metabolism was assessed by indirect calorimetry, measuring energy expenditure (EE), activity, and food consumption, as well as metabolic flexibility through respiratory exchange ratio (RER) measurements following a switch to a high-fat diet (HFD). Positron emission tomography (PET) using 18F-fluorodeoxyglucose (18F-FDG) was performed to evaluate glucose metabolism in 3-month-old mice fed an ND. Finally, Type I Diabetes (T1D) was induced in young mice using streptozotocin (STZ), and serum glucose levels (mg/dL) were measured ad libitum at 2- and 4-weeks post-induction.
CnAβ1Δi12 mice exhibited significantly lower body weight at both 3 and 18 months of age compared to C57BL/6J mice. This sustained reduction in body weight was associated with increased EE, which reached statistical significance in aged CnAβ1Δi12 mice. However, total activity was lower in the CnAβ1Δi12 group. RER values were higher in CnAβ1-deficient mice; nevertheless, upon exposure to an HFD, CnAβ1Δi12 mice displayed improved fatty acid utilization as a metabolic substrate. Although RER values approached 0.7 in both groups, they were significantly lower in 18-month-old CnAβ1Δi12 mice. PET analysis revealed increased glucose uptake in highly metabolically demanding tissues in the CnAβ1-deficient group, with statistically significant differences observed in skeletal muscle of young mice fed an ND. Finally, following STZ administration, circulating glucose levels were significantly lower in CnAβ1Δi12 mice at both 2 and 4 weeks.
In conclusion, CnAβ1Δi12 mice exhibit a higher affinity for glucose as a preferred metabolic substrate, despite displaying greater metabolic flexibility under stress conditions such as HFD. Moreover, in the absence of insulin, these mice enhance glucose uptake in highly demanding tissues via insulin-independent mechanism, thereby promoting higher basal energy expenditure and sustaining lower body weight.

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