title: Identification of a selective glucocorticoid receptor modulator that prevents both diet-induced obesity and inflammation.
abstract: High-fat diet consumption results in obesity and chronic low-grade inflammation in adipose tissue. Whereas glucocorticoid receptor (GR) antagonism reduces diet-induced obesity, GR agonism reduces inflammation, the combination of which would be desired in a strategy to combat the metabolic syndrome. The purpose of this study was to assess the beneficial effects of the selective GR modulator C108297 on both diet-induced weight gain and inflammation in mice and to elucidate underlying mechanisms.
  
  
  
  Ten-week-old C57Bl/6 J mice were fed a high-fat diet for 4 weeks while being treated with the selective GR modulator C108297, a full GR antagonist (RU486/mifepristone) or vehicle.
  
  
  
  C108297 and, to a lesser extent, mifepristone reduced body weight gain and fat mass. C108297 decreased food and fructose intake and increased lipolysis in white adipose tissue (WAT) and free fatty acid levels in plasma, resulting in decreased fat cell size and increased fatty acid oxidation. Furthermore, C108297 reduced macrophage infiltration and pro-inflammatory cytokine expression in WAT, as well as in vitro LPS-stimulated TNF-α secretion in macrophage RAW 264.7 cells. However, mifepristone also increased energy expenditure, as measured by fully automatic metabolic cages, and enhanced expression of thermogenic markers in energy-combusting brown adipose tissue (BAT) but did not affect inflammation.
  
  
  
  C108297 attenuates obesity by reducing caloric intake and increasing lipolysis and fat oxidation, and in addition attenuates inflammation. These data suggest that selective GR modulation may be a viable strategy for the reduction of diet-induced obesity and inflammation.
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: José K
authors.initials: JK
authors.lastname: van den Heuvel
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mariëtte R
authors.initials: MR
authors.lastname: Boon
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ingmar
authors.initials: I
authors.lastname: van Hengel
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Emma
authors.initials: E
authors.lastname: Peschier-van der Put
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: van Beek
authors.affiliation: Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pereira
authors.affiliation: Corcept Therapeutics, Menlo Park, California, USA.
authors.forename: Hazel
authors.initials: H
authors.lastname: Hunt
authors.affiliation: Corcept Therapeutics, Menlo Park, California, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000067996:RAW 264.7 Cells; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D011965:Receptors, Glucocorticoid; D015735:Mifepristone