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Diabetologia. 2019 Feb 9. doi: 10.1007/s00125-019-4813-5. [Epub ahead of print]

Diurnal rhythms in the white adipose tissue transcriptome are disturbed in obese individuals with type 2 diabetes compared with lean control individuals.

Author information

1
Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, room F5-162, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands. d.j.stenvers@amc.uva.nl.
2
Bioinformatics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
3
Department of Endocrinology and Metabolism, Amsterdam UMC, location AMC, University of Amsterdam, room F5-162, P.O. Box 22660, 1100 DD, Amsterdam, the Netherlands.
4
Neurogenetics Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
5
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
6
Department of Clinical Chemistry, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
7
Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience (NIN), Amsterdam, the Netherlands.

Abstract

AIMS/HYPOTHESIS:

Animal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.

METHODS:

In a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3 days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.

RESULTS:

The core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway 'EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.

CONCLUSIONS/INTERPRETATION:

Diurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.

DATA AVAILABILITY:

The raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674).

KEYWORDS:

Circadian rhythms; Clock genes; Glucose tolerance; Lipolysis; Metabolic syndrome; Obesity; RNA sequencing; Transcriptomics; Type 2 diabetes; White adipose tissue

PMID:
30737520
DOI:
10.1007/s00125-019-4813-5

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