Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance
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Authors
DiStefano, MarinaRoth Flach, Rachel J.
Senol-Cosar, Ozlem
Danai, Laura V.
Virbasius, Joseph V.
Nicoloro, Sarah M.
Straubhaar, Juerg R.
Dagdeviren, Sezin
Wabitsch, Martin
Gupta, Olga T.
Kim, Jason K.
Czech, Michael P.
UMass Chan Affiliations
UMass Metabolic NetworkDepartment of Medicine, Division of Endocrinology, Metabolism and Diabetes
Program in Molecular Medicine
Document Type
Journal ArticlePublication Date
2016-09-28Keywords
AdipocyteBAT
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
Cell Biology
Cellular and Molecular Physiology
Endocrinology
Molecular Biology
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OBJECTIVE: 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. METHOD: White and brown adipocyte-deficient (Hig2fl/fl x Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl x 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. RESULTS: 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 x 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. CONCLUSIONS: 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 degrees 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.Source
Mol Metab. 2016 Sep 28;5(12):1149-1161. eCollection 2016 Dec. Link to article on publisher's siteDOI
10.1016/j.molmet.2016.09.009Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40144PubMed ID
27900258Related Resources
Link to Article in PubMedDistribution License
http://creativecommons.org/licenses/by-nc-nd/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.molmet.2016.09.009
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Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-nd/4.0/