| Popis: |
Hypothalamus is the key region in regulating energy and glucose homeostasis. Now more and more evidence shows that not only neurons, but also glial cells represent important components in this regulatory center. In the current study, we investigated how microglia and astrocytes contribute to the control of energy homeostasis and the pathologies of diet-induced obesity. Microglia are resident macrophages in the brain. Microglia induced innate immune responses have been linked with hypothalamic inflammation and metabolic syndromes. Here, we used genetic and pharmacological approaches to analyze the metabolic causes of hypothalamic microglial activation in metabolic disorders, demonstrating that microglia respond to nutrients, adipokines and gut hormones but not to body weight changes per se. We then analyzed dietary effects on microglia. After comparing a standard chow diet, a high carbohydrate high-fat diet, a low carbohydrate, high fat diet and a ketogenic diet, we found that only the high carbohydrate high fat diet resulted in reactive microglia in hypothalamus. We further discovered that the presence of advanced glycation end products (AGEs) in hypothalamus on high carbohydrate high fat diet might be an important mediator of hypothalamic microgliosis. Mice lacking receptors for AGEs had significant less hypothalamic microgliosis and improved metabolic phenotypes when exposed to high carbohydrate high fat diet. Astrocytes are the other predominant glia population in the brain. Their contributions in neuroendocrine control by responding to hormones and nutrients were underestimated. In this study, we investigated the role of astrocytes in nutrient sensing by generating an inducible and astrocytes-specific and loss of function model for lipoprotein lipase. We found that lipoprotein lipase controls lipid content in astrocytes and contributes to maintaining systemic glucose and energy homeostasis. When animals were exposed to high-fat diet, mice lacking lipoprotein lipase on astrocytes exhibited accelerated weight gain and impaired glucose homeostasis. Together, these data show essential roles of hypothalamic glial cells in diet-induced obesity and systemic metabolic regulation, which shed light on understanding pathologies of metabolic syndromes. |
