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

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 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice 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 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses. [Display omitted] •Constitutive 16p11.2 haploinsufficiency leads to increased brain glucose uptake•Changes in brain metabolite flux suggest altered glycolysis or intracellular shuttling•Brain endothelial cells from 16p11.2-deficient mice lack the NT-PGC-1α protein•Endothelial-specific 16p11.2 haploinsufficiency leads to increased brain glucose uptake A mouse model of 16p11.2 deletion syndrome displays altered brain metabolism. Béland-Millar et al. show dysregulation of metabolite flux in the cerebral cortex, without concomitant differences in oxygen saturation or glucose transporters. Reduced mitochondrial biogenesis in 16p11.2-deficient brain endothelial cells appears associated with these brain metabolic changes.