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.

Graphical abstract

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Data availability

Data related to this manuscript are available on request from the authors.

Abbreviations

CNS:

Central nervous system

CRP:

C-reactive protein

EHC:

Euglycaemic–hyperinsulinaemic clamp

GIR:

Glucose infusion rate

GDR:

Glucose disposal rate

hCRP:

Human C-reactive protein

HFD:

High-fat diet

HGP:

Hepatic glucose production

ICV:

Intracerebroventricular

InsR:

Insulin receptor

KO:

Knockout

LPS:

Lipopolysaccharide

NCD:

Normal chow diet

RER:

\( \dot{V}{\mathrm{O}}_2 \)/\( \dot{V}\mathrm{C}{\mathrm{O}}_2 \)

STAT3:

Signal transducer and activator of transcription 3

TALEN:

Transcription activator-like effector nuclease

WT:

Wild-type

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Acknowledgements

Some of the data were presented as an abstract at the 56th EASD Annual Meeting in 2020.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

This work was supported by research grants from the National Natural Science Foundation of China (81800755 to MY, 81630021 to AZZ); the national Key R&D Program of China (2018YFa0800600 to AZZ); the Key research and development program of Guangdong Province for ‘innovative drug creation’ (2019B020201015 to FL); and the Guangdong Innovative Research Team Program (2016ZT06Y432 to AZZ and FHL).

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MY and SQ designed and performed experiments, analysed results, and wrote and edited the manuscript. YH, TW and LL performed and analysed the results obtained from the EHC experiments in addition to editing the manuscript. ND and FL helped with interpretation and analyses of the data from Crp KO rats, and edited the manuscript. AZZ and GY conceived the study, designed and performed experiments, analysed results, and wrote and edited the manuscript. All authors read and approved the final manuscript. AZZ and GY are the guarantors of this work.

Corresponding authors

Correspondence to Allan Z. Zhao or Gangyi Yang.

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Yang, M., Qiu, S., He, Y. et al. Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05384-9

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Keywords

  • Central nervous system
  • C-reactive protein
  • Insulin resistance
  • Leptin resistance