Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.

Related collections

Most cited references 41

Record: found
Abstract: found
Article: found

Is Open Access

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Jing-Jing Xu, David J. B. Lloyd, Clarence Hale … (2009)

OBJECTIVE—Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet–induced obesity (DIO) model. RESEARCH DESIGN AND METHODS—DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques. RESULTS—FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity. CONCLUSIONS—FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.

0 comments Cited 410 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI.

Tayeba Khan, Eric S. Muise, Puneeth Iyengar … (2009)

Adipocytes are embedded in a unique extracellular matrix whose main function is to provide mechanical support, in addition to participating in a variety of signaling events. During adipose tissue expansion, the extracellular matrix requires remodeling to accommodate adipocyte growth. Here, we demonstrate a general upregulation of several extracellular matrix components in adipose tissue in the diabetic state, therefore implicating "adipose tissue fibrosis" as a hallmark of metabolically challenged adipocytes. Collagen VI is a highly enriched extracellular matrix component of adipose tissue. The absence of collagen VI results in the uninhibited expansion of individual adipocytes and is paradoxically associated with substantial improvements in whole-body energy homeostasis, both with high-fat diet exposure and in the ob/ob background. Collectively, our data suggest that weakening the extracellular scaffold of adipocytes enables their stress-free expansion during states of positive energy balance, which is consequently associated with an improved inflammatory profile. Therefore, the disproportionate accumulation of extracellular matrix components in adipose tissue may not be merely an epiphenomenon of metabolically challenging conditions but may also directly contribute to a failure to expand adipose tissue mass during states of excess caloric intake.

0 comments Cited 372 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.

Nils Halberg, Tayeba Khan, Maria Trujillo … (2009)

Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1alpha (HIF1alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1alpha, we determined that HIF1alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1alpha initiates adipose tissue fibrosis, with an associated increase in local inflammation. "Trichrome- and picrosirius red-positive streaks," enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1alpha and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by beta-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.

0 comments Cited 293 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Mol Cell Biol

Journal ID (iso-abbrev): Mol. Cell. Biol

Journal ID (hwp): mcb

Journal ID (pmc): mcb

Journal ID (publisher-id): MCB

Title: Molecular and Cellular Biology

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Print): 0270-7306

ISSN (Electronic): 1098-5549

Publication date (Electronic preprint): 16 November 2015

Publication date (Electronic): 19 January 2016

Publication date Collection: 1 February 2016

Publication date PMC-release: 19 January 2016

Volume: 36

Issue: 3

Pages: 376-393

Affiliations

[a ]Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[b ]Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[c ]Department of Medicine III, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[d ]Department of Ophthalmology, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[e ]Department of Psychiatry, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[f ]Department of Medicine I, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[g ]Department of Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Dresden, Germany

[h ]Department of Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany

[i ]Center for Regenerative Therapies Dresden, Dresden, Germany

[j ]Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Dresden, and German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

Author notes

Address correspondence to Rubén García-Martín, rubenggmm@ 123456hotmail.com , or Triantafyllos Chavakis, triantafyllos.chavakis@ 123456uniklinikum-dresden.de .

Citation García-Martín R, Alexaki VI, Qin N, Rubín de Celis MF, Economopoulou M, Ziogas A, Gercken B, Kotlabova K, Phieler J, Ehrhart-Bornstein M, Bornstein SR, Eisenhofer G, Breier G, Blüher M, Hampe J, El-Armouche A, Chatzigeorgiou A, Chung K-J, Chavakis T. 2016. Adipocyte-specific hypoxia-inducible factor 2α deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation. Mol Cell Biol 36:376–393. doi: 10.1128/MCB.00430-15.

Article

Publisher ID: 00430-15

DOI: 10.1128/MCB.00430-15

PMC ID: 4719429

PubMed ID: 26572826

SO-VID: 6eb62a6a-ca79-4a89-acc8-3eed65ef18f9

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 28 April 2015

Date revision requested : 21 May 2015

Date accepted : 5 November 2015

Page count

Figures: 11, Tables: 0, Equations: 0, References: 59, Pages: 18, Words: 11956

Funding

Funded by: ERC

Award ID: ENDHOMRET

Award Recipient : Triantafyllos Chavakis

Funded by: Center for Regenerative Therapies Dresden

Award Recipient : Monika Ehrhart-Bornstein Award Recipient : Georg Breier Award Recipient : Triantafyllos Chavakis

Funded by: Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659

Award ID: CH279/5-1

Award ID: CH279/6-2

Award Recipient : Triantafyllos Chavakis

Funded by: Else Kröner-Fresenius-Stiftung (EKFS) http://dx.doi.org/10.13039/501100003042

Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation

Read this article at

Abstract

Related collections

Plant MYBs

Most cited references 41

Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice

Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI.

Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.

Author and article information

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 187

Cited by 35

Most referenced authors 985