title: Hormones and diet, but not body weight, control hypothalamic microglial activity.
abstract: 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.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Technische Universität München, Munich, Germany; Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Gao
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Schriever
authors.forename: Beata
authors.initials: B
authors.lastname: Legutko
authors.forename: Cristina
authors.initials: C
authors.lastname: García-Cáceres
authors.forename: Esther
authors.initials: E
authors.lastname: de la Fuente
authors.forename: Clarita
authors.initials: C
authors.lastname: Mergen
authors.forename: Susanne
authors.initials: S
authors.lastname: Bour
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: Jessica
authors.initials: J
authors.lastname: Filosa
authors.forename: Javier E
authors.initials: JE
authors.lastname: Stern
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D003583:Cytokinins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D000077270:Exenatide; D006728:Hormones / Q000494:pharmacology*; D020738:Leptin / Q000172:deficiency / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency; D023062:Receptors, Interleukin-8A / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013495:Supraoptic Nucleus / Q000166:cytology*; D014688:Venoms / Q000494:pharmacology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003583:Cytokinins; D000077270:Exenatide; D006728:Hormones; D020738:Leptin; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D023062:Receptors, Interleukin-8A; D054411:Receptors, Leptin; D014688:Venoms; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C574273:MC4R protein, mouse
keywords: high calorie diet; leptin; obesity