Interferon activated gene 202b (Ifi202b) promotes Zfp432 expression and suppresses the thermogenic gene program resulting in obesity and insulin resistance

Background:

By positional cloning we identified the transcriptional modulator Ifi202b as putative novel obesity gene. Ifi202b is mainly expressed in white adipose tissue of obese NZO but absent in lean B6 mice due to a loss-of-function mutation. The aim of this study was to identify downstream targets of Ifi202b and to clarify the mechanisms how it induces obesity.

Methods:

To characterize the function of Ifi202b in adipose tissue biology we overexpressed the gene in 3T3-L1 fibroblasts and B6 mice which lack an Ifi202b expression. In addition, we analyzed the expression of the human orthologue IFI16 in relation to adipocyte size and inflammatory markers.

Results:

Transcriptome analyses detected Zfp423, an essential functional determinant of preadipocyte commitment to be upregulated in response to Ifi202b. This effect was accompanied by accelerated adipocyte differentiation as indicated by increased expression of adipogenic markers (e.g. Pparg), by an enhancement of whitening, inhibition of adipocyte thermogenic gene program, and elevated triglyceride storage. Human subjects with a high expression of IFI16 exhibited larger adipocytes, elevated CRP plasma levels, and IL-6 expression in adipose tissue. In comparison to B6-controls, Ifi202b-transgenic mice (B6-Tg(Ifi202b)) exhibited a lower body temperature, presumably due to the suppression of brown markers (e.g. Ucp1) and an increase of the expression of the white-selected gene Tcf21 in white adipose tissue. Furthermore, B6-Tg(Ifi202b) mice show adipocyte hypertrophy, adiposity and impaired insulin sensitivity.

Conclusion:

In summary, we conclude that Ifi202b mediates preadipocyte commitment, promotes white adipocyte identity and fat storage, which facilitates the induction of inflammation and insulin resistance.