Emerging data demonstrate that microglial inflammatory signaling plays a pivotal role in the development of obesity induced-hypothalamic inflammation. In the early stages of hypothalamic inflammation, cells from microglia recognize the excess of saturated fatty acids (SFAs) from the diet and activate an important inflammatory response. Due to fenestrated nature of the blood-brain barrier (BBB) surrounding the mediobasal hypothalamus, bone-marrow-derived myeloid cells can cross BBB in response to this excessive consumption of SFAs, magnifying hypothalamic inflammation. However, a major limitation in understanding SFAs-induced metabolic dysfunction is a lack of knowledge of direct involvement of hypothalamic microglial cells or bone marrow-derived myeloid cells on the development of hypothalamic inflammation (at the early stage during over-nutrition). To address this, Aim 1 will determine whether modulation of hypothalamic microglial activity can affect hypothalamic inflammation and energy metabolism. Aim 2 will determine the contribution of microglial cells or bone marrow-derived myeloid cells in regulating SFAs-induced hypothalamic inflammation. To accomplish these aims, we will use state-of-the-art technologies, including DREADD (designer receptors exclusively activated by designer drugs) to directly modulate hypothalamic microglia cells, CX3CR1-Cre and CD169-Cre mice to test cellular mechanisms of fat-induced hypothalamic inflammation in an in vivo context. These studies provide a unique opportunity to establish a new paradigm in which microglial cell or bone marrow-derived myeloid cells is a key determinant of fat-induced metabolic disorders, and may offer a novel target for the treatment of obesity and its co-morbidities.
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