Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.
Addiction can be viewed as a form of drug-induced neural plasticity. One of the best-established molecular mechanisms of addiction is upregulation of the cAMP second messenger pathway, which occurs in many neuronal cell types in response to chronic administration of opiates or other drugs of abuse. This upregulation and the resulting activation of the transcription factor CREB appear to mediate aspects of tolerance and dependence. In contrast, induction of another transcription factor, termed DeltaFosB, exerts the opposite effect and may contribute to sensitized responses to drug exposure. Knowledge of these mechanisms could lead to more effective treatments for addictive disorders.
1Here we report multiple lines of evidence for a comprehensive model for retinal 2 energy metabolism. Metabolic flux, locations of key enzymes and our finding that 3 glucose enters the neural retina almost entirely through photoreceptors support a 4 conceptually new model for retinal metabolism. In this model, glucose from the 5 choroidal blood supply passes through the retinal pigment epithelium to the retina 6 where photoreceptors convert it to lactate. Photoreceptors then export the lactate 7 as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. A 8 key feature of this model is that aerobic glycolysis in photoreceptors produces 9 lactate to suppress glycolysis in the neighboring retinal pigment epithelium. That 10 enhances the flow of glucose to the retina by minimizing consumption of glucose 11 within the retinal pigment epithelium. This framework for metabolic relationships 12 in retina provides new insights into the underlying causes of retinal disease, age-13 related vision loss and metabolism-based therapies.
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