Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance
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 a...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-12-01
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| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877816301600 |
| _version_ | 1818128274126012416 |
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| author | Marina T. DiStefano Rachel J. Roth Flach Ozlem Senol-Cosar Laura V. Danai Joseph V. Virbasius Sarah M. Nicoloro Juerg Straubhaar Sezin Dagdeviren Martin Wabitsch Olga T. Gupta Jason K. Kim Michael P. Czech |
| author_facet | Marina T. DiStefano Rachel J. Roth Flach Ozlem Senol-Cosar Laura V. Danai Joseph V. Virbasius Sarah M. Nicoloro Juerg Straubhaar Sezin Dagdeviren Martin Wabitsch Olga T. Gupta Jason K. Kim Michael P. Czech |
| author_sort | Marina T. DiStefano |
| collection | DOAJ |
| description | 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 × 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. 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 × 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 °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. Keywords: Obesity, Adipocyte, Lipid droplet, Lipolysis, Hypoxia-inducible gene 2 (Hig2) |
| first_indexed | 2024-12-11T07:30:38Z |
| format | Article |
| id | doaj.art-da5c0d463454410a9f92bd4386dce998 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-11T07:30:38Z |
| publishDate | 2016-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-da5c0d463454410a9f92bd4386dce9982022-12-22T01:15:50ZengElsevierMolecular Metabolism2212-87782016-12-0151211491161Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistanceMarina T. DiStefano0Rachel J. Roth Flach1Ozlem Senol-Cosar2Laura V. Danai3Joseph V. Virbasius4Sarah M. Nicoloro5Juerg Straubhaar6Sezin Dagdeviren7Martin Wabitsch8Olga T. Gupta9Jason K. Kim10Michael P. Czech11From the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine and the Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm 89075, GermanyFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine and the Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USAFrom the Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author. Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA, USA. Fax: +1 508 856 1617.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 × 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. 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 × 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 °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. Keywords: Obesity, Adipocyte, Lipid droplet, Lipolysis, Hypoxia-inducible gene 2 (Hig2)http://www.sciencedirect.com/science/article/pii/S2212877816301600 |
| spellingShingle | Marina T. DiStefano Rachel J. Roth Flach Ozlem Senol-Cosar Laura V. Danai Joseph V. Virbasius Sarah M. Nicoloro Juerg Straubhaar Sezin Dagdeviren Martin Wabitsch Olga T. Gupta Jason K. Kim Michael P. Czech Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance Molecular Metabolism |
| title | Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance |
| title_full | Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance |
| title_fullStr | Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance |
| title_full_unstemmed | Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance |
| title_short | Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance |
| title_sort | adipocyte specific hypoxia inducible gene 2 promotes fat deposition and diet induced insulin resistance |
| url | http://www.sciencedirect.com/science/article/pii/S2212877816301600 |
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