Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation.

Abstract

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.

• Authors: Chan Hee Lee, Hyo Jin Kim, Yong-Soo Lee, Gil Myoung Kang, Hyo Sun Lim, Seung-Hwan Lee, Do Kyeong Song, Obin Kwon, Injae Hwang, Myeongjoo Son, Kyunghee Byun, Young Hoon Sung, Seyun Kim, Jae Bum Kim, Eun Young Choi, Young-Bum Kim, Keetae Kim, Mi-Na Kweon, Jong-Woo Sohn, Min-Seon Kim
• Journal: Cell reports (Cell Rep) Vol. 25 Issue 4 Pg. 934-946.e5 (10 23 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 30355499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Nitric Oxide Synthase Type II
• Glucose

Topics

• Animals
• Arcuate Nucleus of Hypothalamus (pathology)
• Blood-Brain Barrier (pathology)
• Cell Proliferation
• Diet, High-Fat
• Glucose (metabolism)
• Hypothalamus (pathology)
• Inflammation (enzymology, pathology)
• Macrophage Activation
• Macrophages (enzymology)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Obesity (enzymology, pathology)
• RAW 264.7 Cells