Background & Aims: Human epidemiological studies have consistently revealed a strong association of baseline C-reactive protein (CRP) elevation with obesity, but direct evidence demonstrating that CRP plays a causal role is still lacking. It has been challenging to demonstrate experimental proof of causality of the CRP elevation for the development and diabetes.
Methods: Here we generated transgenic rats that express the human CRP gene at baseline level. Human CRP is produced at 10-20 ug/ml in the circulation. Rats were examined for body weight, fat mass, and glucose tolerance. Fecal samples were collected from transgenic and non-transgenic rat lines.
Results: Univariate linear regression analysis showed that CRP causes the adult-onset obesity. After the age of 11-week old in the rats, CRP dramatically increases the growth rates of body weight by around two-folds (11.8 and 9.5 for transgenic lines vs. 5.0 for non-transgenic littermates). The whole-body magnetic resonance imaging (MRI) showed that the total fat mass is increased by 6-9 folds in the transgenic rats. The glucose tolerance test showed that these rats have glucose intolerance. The 16S rRNA high-throughput sequencing showed that the composition of gut microbiota is altered consistently in both transgenic lines. The abundances of Akkermansia muciniphila (13.2-fold) and Bilophila (3.1-fold) are dramatically reduced, and the abundances of Butyrivibrio (11.6-fold) and Peptococcus (1.8-fold) are increased.
Conclusions: Our data established a causal role of CRP elevation in the development of adult-onset obesity.