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.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.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.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.