Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity. Lee et al. demonstrate in mice that, upon prolonged high-fat diet feeding, hypothalamic macrophages proliferate, expand their pool, and sustain hypothalamic inflammation. Moreover, they show that hypothalamic macrophage iNOS inhibition diminishes macrophage activation, astrogliosis, blood-brain-barrier permeability, and impaired glucose metabolism in diet-induced obese mice.
Bibliographical noteFunding Information:
This study was supported by grants from the National Research Foundation of Korea, South Korea ( 2013M3C7A1056024 , 2015M3A9E7029177 , 2017R1A2B3007123 , and 2018R1C1B6005102 ) and the NIH ( R01DK083567 to Y.-B.K.). We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript.
© 2018 The Authors