16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice.

Scientists studied mice with a genetic change linked to autism (16p11.2 deletion). They found these mice had different brain sugar (glucose) processing and fewer energy-producing parts (mitochondria) in brain blood vessels. The brain appeared to adapt by changing how it uses energy, possibly to compensate for blood vessel problems. This research helps us understand how genetic changes in autism might affect how the brain gets and uses energy.

This study investigated brain metabolism changes in mice with 16p11.2 deletion, a genetic variant associated with autism. Researchers found that these mice showed elevated brain glucose uptake when anesthetized and altered glucose responses when awake. The study revealed reduced mitochondria number in brain blood vessel cells and defective mitochondrial biogenesis, specifically lacking the NT-PGC-1α protein variant. Enhanced metabolic responses to glucose were observed in brain tissue extracts.

The authors suggest these metabolic changes represent compensatory adaptations to blood vessel dysfunction in the brain, providing new insights into how genetic changes associated with autism may affect brain energy metabolism.

Findings suggest brain metabolism alterations in 16p11.2 deletion may represent adaptive responses to vascular dysfunction. This could inform monitoring of metabolic health in individuals with this genetic variant and highlight potential therapeutic targets focused on mitochondrial function and brain energy metabolism.

Study conducted only in mouse models, limiting direct translation to humans. Sample size not reported. Unknown study design details. No comparison with other autism-related genetic variants. Limited investigation of long-term metabolic consequences or behavioral correlations.

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration.

Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.