CXCR3-expressing myeloid cells recruited to the hypothalamus protect against diet-induced body mass gain and metabolic dysfunction

Abstract

AbstractMicrogliosis is an important component of diet-induced hypothalamic inflammation in obesity. A few hours after the introduction of a high-fat diet, the mediobasal hypothalamus resident microglia undergo morphological and functional changes toward an inflammatory phenotype. If the consumption of large amounts of dietary fats persists for long periods, bone marrow- derived myeloid cells are recruited and integrated into a new landscape of hypothalamic microglia. However, it is currently unknown what are the transcriptional signatures and specific functions exerted by either resident or recruited subsets of hypothalamic microglia. Here, the elucidation of the transcriptional signatures revealed that resident microglia undergo only minor changes in response to dietary fats; however, under the consumption of a high-fat diet, there are major transcriptional differences between resident and recruited microglia with a major impact on chemotaxis. In addition, in recruited microglia, there are major transcriptional differences between females and males with an important impact on transcripts involved in neurodegeneration and thermogenesis. The chemokine receptor CXCR3 emerged as one of the components of chemotaxis with the greatest difference between recruited and resident microglia, and thus, was elected for further intervention. The hypothalamic immunoneutralization of CXCL10, one of the ligands for CXCR3, resulted in increased body mass gain and reduced energy expenditure, particularly in females. Furthermore, the chemical inhibition of CXCR3 resulted in a much greater change in phenotype with increased body mass gain, reduced energy expenditure, increased blood leptin, glucose intolerance, and reduced insulin. Thus, this study has elucidated the transcriptional differences between resident and recruited hypothalamic microglia in diet-induced obesity, identifying chemokines as a relevant subset of genes undergoing regulation. In addition, we showed that a subset of recruited microglia expressing CXCR3 has a protective, rather than a detrimental role in the metabolic outcomes promoted by the consumption of a high-fat diet, thus, establishing a new concept in obesity-associated hypothalamic inflammation.