Short-term overfeeding of zebrafish with normal or high-fat diet as a model for the development of metabolically healthy versus unhealthy obesity.
BACKGROUND
Obese individuals differ in their risk of developing metabolic and cardiovascular complications depending on fat distribution (subcutaneous versus visceral) and adipose tissue (AT) phenotype (hyperplasic versus hypertrophic). However, the exact mechanisms which determine whether an obese individual is metabolically healthy or unhealthy are not clear, and analyses of the underlying pathomechanisms are limited by the lack of suitable in vivo models in which metabolically healthy versus metabolically unhealthy AT accumulation can be specifically induced. In the current study, we aimed to establish a protocol for the use of zebrafish as a model for obesity-related metabolically healthy versus metabolically unhealthy AT accumulation.


METHODS
We overfed adult male zebrafish of the AB strain with normal fat diet (NFD) or high fat diet (HFD) for 8 weeks and compared parameters related to obesity, i.e. body weight, body mass index, condition index and body fat percentage, to control zebrafish fed under physiological conditions. In addition, we investigated the presence of early obesity-related metabolic alterations by quantifying blood glucose levels, plasma triglyceride and cholesterol levels, and by assessing ectopic lipid accumulation in the liver of zebrafish. Finally, we determined gene expression levels of marker genes related to lipid metabolism, inflammation and fibrosis in visceral AT and liver.


RESULTS
We show that 8-weeks overfeeding with either NFD or HFD leads to a significant increase in body weight and AT mass compared to controls. In contrast to NFD-overfed zebrafish, HFD-overfed zebrafish additionally present metabolic alterations, e.g. hyperglycemia and ectopic lipid accumulation in the liver, and a metabolically unhealthy AT phenotype with adipocyte hypertrophy especially in the visceral AT depot, which is accompanied by changes in the expression of marker genes for lipid metabolism, inflammation and fibrosis.


CONCLUSIONS
In summary, we have established a method for the specific induction of metabolically distinct obesity phenotypes in zebrafish. Our results indicate that zebrafish represents an attractive model to study regulatory mechanisms involved in the determination of AT phenotype during development of metabolically healthy versus metabolically unhealthy obesity.
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany. Kathrin.Landgraf@medizin.uni-leipzig.de.|Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany. Kathrin.Landgraf@medizin.uni-leipzig.de.
Kathrin
http://orcid.org/0000-0002-6878-6033
K
Landgraf
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany.
Susanne
S
Schuster
Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
Andrej
A
Meusel
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany.
Antje
A
Garten
Institute of Medical Physics and Biophysics, University of Leipzig, Leipzig, Germany.
Thomas
T
Riemer
Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
Dorit
D
Schleinitz
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany.
Wieland
W
Kiess
Center for Pediatric Research Leipzig (CPL), University Hospital for Children & Adolescents, University of Leipzig, Liebigstraße 21, 04103, Leipzig, Germany.|Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.
Antje
A
Körner
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D007249:Inflammation / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D009765:Obesity / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism; D015027:Zebrafish
D001786:Blood Glucose; D014280:Triglycerides
Adipocyte hypertrophy; Adipose tissue; Fatty liver; High fat diet; Hyperglycaemia; Metabolic syndrome; Obesity; Zebrafish