title: Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
abstract: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis.
  
  
  
  White and brown adipocyte-deficient (Hig2fl/fl× Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl× Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process.
  
  
  
  Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl× Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes.
  
  
  
  We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Marina T
authors.initials: MT
authors.lastname: DiStefano
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Roth Flach
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Senol-Cosar
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Laura V
authors.initials: LV
authors.lastname: Danai
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Virbasius
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nicoloro
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Juerg
authors.initials: J
authors.lastname: Straubhaar
authors.affiliation: From the Program in Molecular Medicine and the Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sezin
authors.initials: S
authors.lastname: Dagdeviren
authors.affiliation: From the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Olga T
authors.initials: OT
authors.lastname: Gupta
authors.affiliation: From the Program in Molecular Medicine and the Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.affiliation: From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: Michael.Czech@umassmed.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D018149:Glucose Intolerance / Q000378:metabolism; D007333:Insulin Resistance; D066292:Lipid Droplets / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics
chemical_list: C000601089:HIG2 protein, mouse; D009363:Neoplasm Proteins
keywords: Adipocyte; BAT, brown adipose tissue; FFA, free fatty acid; GTT, glucose tolerance test; HFD, high fat diet; Hig2, Hypoxia-inducible gene 2; Hypoxia-inducible gene 2 (Hig2); ITT, insulin tolerance test; LD, lipid droplet; Lipid droplet; Lipolysis; NEFA, non-esterified fatty acid; Obesity; RER, respiratory exchange ratio; SGBS, Simpson-Golabi-Behmel syndrome; SVF, stromal vascular fraction; TG, triglyceride; Ucp1, uncoupling protein 1; WAT, white adipose tissue; eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue