Cover Story Current Issue

Evolutionary forces have wired our brains to prefer and consume energy-dense foods to aid in our survival. While effective during periods of limited access, the ubiquitous nature of high-fat food sources in society leads to obesity and numerous related health complications. Exacerbating this drive to consume more energy-dense, palatable foods is a devaluation of less appetitive, nutritionally-balanced foods. While this preference for calorically-rich foods is well known, significant gaps exist in our understanding of how this develops and leads to devaluation.

Laboratory mice are typically provided with ad libitum access to a well-balanced standard chow diet (SD) in which the macronutrient composition has been formulated for optimal growth. Introduction to ad libitum high fat diet (HFD), but not a high-sucrose diet, leads to rapid weight gain, at least in part due to excessive caloric intake. Interestingly, when mice are given a choice between ad libitum access to both SD and HFD, they strongly prefer consumption of the latter at the expense of the former. While this predilection for HFD over SD during prolonged exposure is well described, how rapidly this transition occurs under physiological or artificial hunger is less known. Removal of HFD from mice given the choice between HFD and SD, akin to a strict human diet, results in rapid weight loss due to the self-restricted consumption of SD. Additionally, mice fed a HFD will forgo SD consumption even in states of physiological or artificially-induced caloric deprivation. While this SD devaluation is robustly conserved between sex and subject and independent of fat mass accrual, the causative nature of this phenomenon is not well understood.

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Current Issue

Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue

Monika Ayten, Nundehui Díaz-Lezama, Hanaa Ghanawi, Felia C. Haffelder, ... Susanne F. Koch

Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue

Objective

Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is unknown how the retinal proteome changes as RP disease progresses, and which changes can be prevented, halted, or reversed by gene therapy.

Methods

Here, we used a Pde6b-deficient RP gene therapy mouse model and performed untargeted proteomic analysis to identify changes in protein expression during degeneration and after treatment.

Results

We demonstrated that Pde6b gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors.

Conclusion

In conclusion, the metabolic demands of the retina differ in our Pde6b-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.

Articles in Press

Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue

Monika Ayten, Nundehui Díaz-Lezama, Hanaa Ghanawi, Felia C. Haffelder, ... Susanne F. Koch

Metabolic plasticity in a Pde6bSTOP/STOP retinitis pigmentosa mouse model following rescue

Objective

Retinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is unknown how the retinal proteome changes as RP disease progresses, and which changes can be prevented, halted, or reversed by gene therapy.

Methods

Here, we used a Pde6b-deficient RP gene therapy mouse model and performed untargeted proteomic analysis to identify changes in protein expression during degeneration and after treatment.

Results

We demonstrated that Pde6b gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors.

Conclusion

In conclusion, the metabolic demands of the retina differ in our Pde6b-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.

You are what you eat

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