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Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet
Ist Teil von
Diabetologia, 2022-03, Vol.65 (3), p.528-540
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2022
Quelle
MEDLINE
Beschreibungen/Notizen
Aims/hypothesis
Despite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells.
Methods
Heterozygous
Wt1
knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with
Wt1
-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes.
Results
Expression of the thermogenic genes
Cpt1b
and
Tmem26
was enhanced and transcript levels of
Ucp1
were on average more than tenfold higher in epididymal WAT of heterozygous
Wt1
knockout mice compared with wild-type mice.
Wt1
heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of
Ucp1
,
Ppargc1a
,
Cidea
,
Prdm16
and
Cpt1b
upon in vitro differentiation by 60–90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered
Aldh1a1
and
Zfp423
transcripts, two key suppressors of the thermogenic program. Conversely,
Aldh1a1
and
Zfp423
mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes.
Conclusion/interpretation
WT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing
Wt1
expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease.
Graphical abstract