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Diabetologia

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01-05-2021 | Obesity | Article

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

Authors: Mengliu Yang, Sheng Qiu, Yirui He, Ling Li, Tong Wu, Ning Ding, Fanghong Li, Allan Z. Zhao, Gangyi Yang

Published in: Diabetologia | Issue 5/2021

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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Title: Genetic ablation of C-reactive protein gene confers resistance to obesity and insulin resistance in rats
Authors: Mengliu Yang
Sheng Qiu
Yirui He
Ling Li
Tong Wu
Ning Ding
Fanghong Li
Allan Z. Zhao
Gangyi Yang
Publication date: 01-05-2021
Publisher: Springer Berlin Heidelberg
Keywords: Obesity
Obesity
Insulins
Insulins
Published in: Diabetologia / Issue 5/2021
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-021-05384-9

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