Loss of function of Ifi202b in C57BL/6J mice suppresses 11β-hydroxysteroid dehydrogenase type 1 expression and development of obesity

Aims: Obesity-associated inflammation of adipose tissue is considered to play a role in the pathogenesis of insulin resistance and type 2 diabetes. Increased production of pro-inflammatory cytokines from hypertrophic adipocytes and the accumulation of macrophages are possible factors linking obesity to insulin resistance. In an outcross population of the New Zealand Obese (NZO) mouse, a polygenic model of obesity and type 2 diabetes, with the lean and diabetes-resistant C57BL/6J (B6) strain, we identified a major quantitative trait locus (QTL) for obesity and hyperglycemia (Nob3) on distal mouse chromosome 1. By positional cloning we identified a loss of function mutation of the interferon inducible gene Ifi202b in B6 mice. We hypothesize that Ifi202b participates in obesity and insulin resistance of NZO mice.

Methods: Male mice of a recombinant-congenic strain (B6.NZO-Nob3.38) that express Ifi202b (N/N) or lack Ifi202b (B/B) where fed a high-fat diet and body composition and glucose homeostasis were determined. Furthermore, gene expression and infiltration of macrophages were analyzed in white adipose tissue. The effect of Ifi202b expression on adipogenesis and inflammatory pathways were investigated in 3T3-L1 adipocytes.

Results: Introgression of a 38 Mbp fragment (Nob3.38) from NZO into the B6 background resulted in a markedly increased body weight, fat mass, and lean mass of NZO-allele carriers. Nob3.38^{N / N} mice showed an impaired glucose tolerance in week 20 and a tendency to higher blood glucose levels in week 30. Analysis of white adipose tissue revealed a higher accumulation of macrophages, an increased expression of pro-inflammatory cytokines and a marked induction of 11β-hydroxysteroid dehydrogenase type 1 (11β-Hsd1) expression in mice expressing Ifi202b. Accordingly, siRNA-mediated suppression of Ifi202b in 3T3-L1 adipocytes resulted in decreased levels of inflammatory markers and a significant inhibition of 11β-Hsd1 expression, whereas an adenoviral-mediated overexpression of Ifi202b increased 11β-Hsd1 mRNA levels.

Conclusion: We suggest elevated Ifi202b expression participates in the development of obesity and insulin resistance by modulating expression of adipogenic genes such as 11β-Hsd1 and expression of cytokines.