RESUMEN
Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.
Asunto(s)
Alimentos , Gluconeogénesis , Glucosa , Hígado , Proteínas de la Membrana , Mitocondrias Hepáticas , Dinámicas Mitocondriales , Proteínas Mitocondriales , Percepción , Animales , Masculino , Ratones , Técnicas de Sustitución del Gen , Glucosa/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Neuronas/metabolismo , Fosforilación , Proopiomelanocortina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones TransgénicosRESUMEN
Autophagy represents a key regulator of aging and metabolism in sensing energy deprivation. We find that fasting in mice activates autophagy in the liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators, and promotes ketogenesis. AgRP neuron-dependent induction of liver autophagy relies on NPY release in the paraventricular nucleus of the hypothalamus (PVH) via presynaptic inhibition of NPY1R-expressing neurons to activate PVHCRH neurons. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and rewiring of metabolism. AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of liver autophagy in control of metabolic adaptation during nutrient deprivation.