Delivery of orexigenic neuropeptides caused severe obesity in mice, but removal of AgRP did not result in significant weight loss.
Does brain-targeted AAV delivery of orexigenic neuropeptides induce obesity, and does reversing their expression elicit weight loss in mice?
AAV-mediated delivery of orexigenic peptides to the brain provides a robust preclinical model of obesity, though reversing the hyperphagic stimulus alone is insufficient to drive robust weight loss.
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ABSTRACT Objective This study utilized AAV gene delivery as an approach to induce and reverse hyperphagia in mice. We hypothesized that the delivery of orexigenic neuropeptides to the brain via AAV precipitates obesity and that the implementation of genetic switches to reverse transgene expression would elicit weight loss. Methods We utilized capsid‐modified AAV‐PHP.eB and AAV‐CAP.B10 to deliver AgRP, NPY, a leptin superantagonist, and ghrelin to the mouse brain. Cre‐LoxP, TETOFF, and cumate expression systems were used to alter transgene expression. Results Delivery of three out of four orexigenic neuropeptides to the brain precipitated severe obesity. Cre‐mediated excision of AgRP from the brain caused a return to baseline weight, confounded by tamoxifen‐associated weight loss. Doxycycline‐mediated suppression of AgRP in a TETOFF vector paused weight gain but did not elicit weight loss. Cumate induction of AgRP in the brain was unaffected by systemic administration, suggesting that cumate inadequately penetrates the blood–brain barrier. Conclusions Brain‐targeted delivery of orexigenic peptides induces obesity in mice. This allows for temporally controlled, convenient, and robust preclinical models of obesity. The implementation of genetic switches enabled suppression/removal of AgRP expression, but we unexpectedly observed that removal of hyperphagic stimuli does not elicit robust weight loss.
Sellers et al. (Sun,) reported a other. Delivery of orexigenic neuropeptides caused severe obesity in mice, but removal of AgRP did not result in significant weight loss.