Связь питания и центральной регулирующей роли SIRT1 в энергетическом обмене
SIRT1 играет определенную роль в гипоталамо-гипофизарной оси как один из регуляторов энергетического обмена. Было показано, что CR и временное снижение энергопотребления усиливают экспрессию и активность SIRT1 в гипоталамусе [114]. У мышей, лишенных SIRT1 в мозге, выявляют специфические дефекты клеток переднего гипофиза, изменения в гипофи-зарной сигнализации и двигательной активности в ответ на CR [115], в то время как активация SIRT1 у трансгенных мышей ведет к повышению активности нейронов гипоталамуса [114]. Эти результаты показывают, что SIRT1 в мозге может функционировать в качестве связующего звена между гормонами гипоталамо-гипофизарной системы и состоянием метаболизма. В гипоталамусе нейроны, экспрессирующие проопио-меланокортин (РОМС), обладающие анорексогенной активностью, и нейроны, экспрессирующие агути-связанный белок (AgRP), являются основными регуляторами подачи и расхода энергии [116]. РОМС нейроны продуцируют пептиды насыщения, препятствуя тем самым избыточному потреблению пищи, в то время как AgRP нейроны способствуют потреблению пищи в ответ на голодание и CR. По-видимому, SIRT1 проявляет различные функции в этих двух популяциях нейронов. С одной стороны, ингибирование активности гипотала-мического SIRT1 увеличивает ацетилирование FOXO1, что увеличивает РОМС и снижает AgRP экспрессию, тем самым уменьшая потребление пищи и снижая увеличение массы тела. В соответствии с этими наблюдениями, AgRP нейрон-специфическое разрушение SIRT1 уменьшает AgRP активность нейронов, что, облегчая воздействие ингибирующего сигнала на РОМС нейроны, в свою очередь, приводит к уменьшению потребления пищи и снижению массы тела [117].
С другой стороны, специфическое удаление SIRT1 в РОМС нейронах у мышей вызывает ослабленный ответ на лептиновую сигнализацию и понижение расхода энергии, что приводит к повышенному риску ожирения, индуцированному диетой [118]. Хотя физиологическое значение различных функций SIRT1 до сих пор не ясно, данные исследований подтверждают, что SIRT1 является важным элементом в периферийных и центральных схемах обратной связи, которые опосредуют нормальный ответ на усвояемость пищевых веществ. В целом складывается представление, что активность SIRT1 имеет важное значение в центральной регуляции чувствительности к нутриентам.
Таким образом, можно предположить, что SIRT1 является медиатором эффектов CR на организм. SIRT1 действует как клеточный энергетический сенсор, и это определяет его центральную роль в управлении и модуляции метаболических процессов при изменениях характера питания (рис. 2). Являясь одним из важнейших регуляторов клеточного и системного энергетического гомеоста-за, SIRT1 может представлять интерес как управляющее звено, влияние на которое позволит изменять обменные процессы, моделировать эффекты ограничения калорийности и воздействовать на ключевые патогенетические звенья многих заболеваний, в том числе связанных со старением.
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