Yuanqing Gao1,1, Nickki Ottaway1, Sonja C. Schriever2, Beata Legutko2, Cristina García‐Cáceres2, Esther de la Fuente2, Clarita Mergen2, Susanne Bour2, Joshua P. Thaler3, Randy J. Seeley1, Jessica A. Filosa4, Javier E. Stern4, Diego Pérez–Tilve1, Michael W. Schwartz3, Matthias H. Tschöp2, Chun‐Xia Yi2
1Division of Endocrinology Diabetes and Metabolism Department of Medicine Metabolic Diseases Institute, University of Cincinnati Cincinnati Ohio
2Institute for Diabetes and Obesity Helmholtz Centre for Health and Environment and Technische Universität München Munich Germany
3Division of Metabolism Endocrinology and Nutrition Diabetes and Obesity Center of Excellence University of Washington Seattle Washington
4Department of Physiology; Georgia Health Sciences University; Georgia
Tóm tắt
The arcuate nucleus (ARC) of the hypothalamus plays a key role in sensing metabolic feedback and regulating energy homeostasis. Recent studies revealed activation of microglia in mice with high‐fat diet (HFD)‐induced obesity (DIO), suggesting a potential pathophysiological role for inflammatory processes within the hypothalamus. To further investigate the metabolic causes and molecular underpinnings of such glial activation, we analyzed the microglial activity in wild‐type (WT), monogenic obese ob/ob (leptin deficient), db/db (leptin‐receptor mutation), and Type‐4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet. Following HFD exposure, we observed a significant increase in the total number of ARC microglia, immunoreactivity of ionized calcium binding adaptor molecule 1 (iba1‐ir), cluster of differentiation 68 (CD68‐ir), and ramification of microglial processes. The ob/ob mice had significantly less iba1‐ir and ramifications. Leptin replacement rescued these phenomena. The db/db mice had similar iba1‐ir comparable with WT mice but had significantly lower CD68‐ir and more ramifications than WT mice. After 2 weeks of HFD, ob/ob mice showed an increase of iba1‐ir, and db/db mice showed increase of CD68‐ir. Obese MC4R KO mice fed a SC diet had comparable iba1‐ir and CD68‐ir with WT mice but had significantly more ramifications than WT mice. Intriguingly, treatment of DIO mice with glucagon‐like peptide‐1 receptor agonists reduced microglial activation independent of body weight. Our results show that diet type, adipokines, and gut signals, but not body weight, affect the presence and activity levels of hypothalamic microglia in obesity. GLIA 2013;62:17–25
