Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation

Autor: James D. Johnson, Nooshin Safikhan, Xiaowei Zheng, Jukka Laine, Mikael Rydén, Earl Albone, Christophe Noll, André C. Carpentier, Subashini Karunakaran, Timothy J. Kieffer, Michelle M. Kwon, Susanne M. Clee, Sergiu-Bogdan Catrina, Kirsi A. Virtanen, Jenny Li-Ying Huang, Tara L. Fernandez, Daniel J. O'Shannessy, Victor Lei, Edward M. Conway, Paul Petrus
Rok vydání: 2019
Předmět:
Adult
Male
0301 basic medicine
medicine.medical_specialty
Panniculitis
Research paper
Adipose Tissue
White
Gene Expression
Adipose tissue
Mice
Transgenic
Inflammation
White adipose tissue
Biology
General Biochemistry
Genetics and Molecular Biology
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Insulin resistance
Metabolic Diseases
Antigens
CD
Antigens
Neoplasm
Fibrosis
Internal medicine
Adipocyte
Brown adipose tissue
medicine
Animals
Humans
Glucose homeostasis
Obesity
Hypoxia
Gene Expression Profiling
General Medicine
Middle Aged
medicine.disease
Immunohistochemistry
Extracellular Matrix
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
chemistry
030220 oncology & carcinogenesis
Female
medicine.symptom
Energy Metabolism
Signal Transduction
Zdroj: EBioMedicine. 44:489-501
ISSN: 2352-3964
DOI: 10.1016/j.ebiom.2019.05.057
Popis: Background A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. Methods The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. Findings CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. Interpretation CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.
Databáze: OpenAIRE
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