title: IEX-1 deficiency induces browning of white adipose tissue and resists diet-induced obesity.
abstract: Chronic inflammation plays a crucial role in the pathogenesis of obesity and insulin resistance. However, the primary mediators that affect energy homeostasis remain ill defined. Here, we report an unexpected role for immediate early response gene X-1 (IEX-1), a downstream target of NF-κB, in energy metabolism. We found that IEX-1 expression was highly induced in white adipose tissue (WAT) in both epidydmal and subcutaneous depots but not in interscapular brown adipose tissue (BAT) in mice fed a high fat diet (HFD). Null mutation of IEX-1 protected mice against HFD-induced adipose and hepatic inflammation, hepatic steatosis, and insulin resistance. Unexpectedly, IEX-1 knockout (IEX-1(-/-)) mice gained markedly less weight on HFD for 20 weeks as compared to wild-type (WT) littermates (37 ± 3 versus 48 ± 2 gm) due to increased energy expenditure. Mechanistically, we showed that IEX-1 deficiency induced browning and activated thermogenic genes program in WAT but not in BAT by promoting alternative activation of adipose macrophages. Consequently, IEX-1(-/-) mice exhibited enhanced thermogenesis (24 ± 0.1 versus 22 ± 0.1 kcal/hour/kg in WT mice) explaining increased energy expenditure and lean phenotype in these mice. In conclusion, the present study suggests that IEX-1 is a novel physiological regulator of energy homeostasis via its action in WAT.
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahid
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.
authors.forename: Ammar A
authors.initials: AA
authors.lastname: Javed
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.
authors.forename: David
authors.initials: D
authors.lastname: Chandra
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Ramsey
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.
authors.forename: Dilip
authors.initials: D
authors.lastname: Shah
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Shriners Hospitals for Children, MGH and HMS, Boston, MA 02114, USA.
authors.forename: Mohammed F
authors.initials: MF
authors.lastname: Khan
authors.affiliation: Department of Molecular Biology, MGH and HMS, Boston, Massachusetts USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhao
authors.affiliation: The Wellman Center for Photomedicine, Massachusetts General Hospital (MGH) and Department of Dermatology, Harvard Medical School (HMS), Boston, Massachusetts 02114 USA.|Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts USA.
authors.forename: Mei X
authors.initials: MX
authors.lastname: Wu
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D002151:Calorimetry; D059305:Diet, High-Fat; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology; D015870:Gene Expression; D005951:Glucose Tolerance Test; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics*; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D022722:Thermogenesis
chemical_list: C518820:IEX-1 protein, mouse; D017874:Immediate-Early Proteins; D007328:Insulin; D012333:RNA, Messenger