Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats

Abstract

Aims/hypothesis Besides serving as a traditional inflammatory marker, C-reactive protein (CRP) is closely associated with the development of obesity, diabetes and cardiovascular diseases as a metabolic and inflammatory marker. We hypothesise that CRP protein directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker, and that genetic deficiency of CRP will lead to resistance to obesity and insulin resistance. Methods Crp gene deletion was achieved by transcription activator-like effector nuclease (TALEN) technology in rats. The Crp knockout animals were placed on either a standard chow diet or a high-fat diet. Phenotypic changes in body weight, glucose metabolism, insulin sensitivity, energy expenditure and inflammation condition were examined. The central impact of CRP deficiency on leptin and insulin hypothalamic signalling, as well as glucose homeostasis, were examined via intracerebral ventricular delivery of leptin and CRP plus glucose clamp studies in the wild-type and Crp knockout rats. Results CRP deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to high-fat diet. Glucose clamp studies revealed enhanced hepatic insulin signalling and actions. Deficiency of CRP enhanced and prolonged the weight-reducing effect of central injected leptin and promoted the central and peripheral roles of leptin. By contrast, reinstatement of CRP into the hypothalamus of the knockout rats attenuated the effects of central leptin signalling on insulin sensitivity and peripheral glucose metabolism.Conclusions/interpretation This study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes but directly regulates energy balance, body weight, insulin sensitivity and glucose homeostasis through direct regulation of leptin's central effect and hypothalamic signalling.

C-Reactive Protein Knock Out Attenuate Temporomandibular Joint Inflammation in Rats

“…In addition, the effect of metabolism should be taken into consideration, since human CRP exacerbated OA development in high-fat diet-fed mice [36]. And in the study of Yang's group, who used the same batch of CRP knockout rats as ours, CRP was found to regulate energy balance and glucose homeostasis through leptin's central effect and hypothalamic signalling [29]. These studies indicated that elevated CRP level during in ammation should be the premise for exploring the effect of CRP on OA, which is in uenced by in ammation progression, genetic variation and metabolism.…”

“…Adult female Sprague Dawley (SD) rats aged 10-12 weeks and weighing 350-400 g were used as controls for CRP-/-rats of the same age and weight. The CRP-/-rats were provided by Professor Zhigang Yang from Chongqing Medical School [29]. DNA sequencing was performed by Sangon Biotech (Shanghai, China) to determine the knockout e ciency in CRP-/-rats.…”

C-Reactive Protein Knock Out Attenuate Temporomandibular Joint Inflammation in Rats

“…In addition, the effect of metabolism should be taken into consideration, since human CRP exacerbated OA development in high-fat diet-fed mice [36]. In the study of Yang's group, who used the same batch of CRP knockout rats as ours, CRP was found to regulate energy balance and glucose homeostasis through leptin's central effect and hypothalamic signalling [29]. These studies indicated that elevated CRP level during in ammation should be the premise for exploring the effect of CRP on OA, which is in uenced by in ammation progression, genetic variation and metabolism.…”

Innate-Immunity Genes in Obesity

“…Experiments on rats indicate that a Crp KO causes both a reduced weight gain on an HFD and smaller food intake. The latter is apparently induced by the recently discovered direct control of leptin signaling by CRP [79]. Carriage of the intron rs1130864 AA genotype and ACCC haplotype for rs1130864 (intron), rs1205 (3 UTR), rs2794521 (2KB upstream), and rs3093062 (2KB upstream) of the CRP gene is associated with a higher BMI in Mexicans [138].…”

“…Higher obesity, increased macrophage infiltration, but with predominance of anti-inflammatory M2 macrophages [76] Ccl2 Protection against obesity [77] Ccr2 Partial protection against diet-induced obesity [78] Crp (Rattus norvegicus) Reduction in weight gain and food intake [79] C3 Reduction in weight gain, but no reduction in WAT inflammation [80] C3aR…”