Abstract
CFB (complement factor B) is elevated in adipose tissue and serum from patients with type 2 diabetes mellitus and cardiovascular disease, but the causal relationship to disease pathogenesis is unclear. Cfb is also elevated in adipose tissue and serum of the spontaneously hypertensive rat, a well-characterized model of metabolic syndrome. To establish the role of CFB in metabolic syndrome, we knocked out the Cfb gene in the spontaneously hypertensive rat. Cfb-/- rats showed improved glucose tolerance and insulin sensitivity, redistribution of visceral to subcutaneous fat, increased adipocyte mitochondrial respiration, and marked changes in gene expression. Cfb-/- rats also had lower blood pressure, increased ejection fraction and fractional shortening, and reduced left ventricular mass. These changes in metabolism and gene expression, in adipose tissue and left ventricle, suggest new adipose tissue-intrinsic and blood pressure-independent mechanisms for insulin resistance and cardiac hypertrophy in the spontaneously hypertensive rat. In silico analysis of the human CFB locus revealed 2 cis-regulated expression quantitative trait loci for CFB expression significantly associated with visceral fat, circulating triglycerides and hypertension in genome-wide association studies. Together, these data demonstrate a key role for CFB in the development of spontaneously hypertensive rat metabolic syndrome phenotypes and of related traits in humans and indicate the potential for CFB as a novel target for treatment of cardiometabolic disease.
Highlights
Metabolic syndrome (MetS) represents a complex clustering of cardiometabolic traits, including hypertension, insulin resistance, glucose intolerance, and dyslipidemia, all of which increase the risk of developing type 2 diabetes mellitus and cardiovascular disease.[1]
Generation of a Cfb Knockout Rat Using data from a quantitative trait transcript analysis of recombinant inbred strains derived from a spontaneously hypertensive rat (SHR)×Brown Norway (BNLx/Cub) cross,[22] we identified Cfb transcript levels as uniquely and strongly correlated significantly across the recombinant inbred strains for metabolically relevant traits (glucose uptake in isolated adipocytes, r2=−0.65, P(adj)=0.0003; basal lipogenesis in epididymal fat, r2=−0.64, P(adj)=0.0002; serum high-density lipoprotein cholesterol, r2=−0.64, P(adj)=0.0005) and significantly differentially expressed in adipose tissue between parental strains (SHR versus Brown Norway, 1.47-fold P
Abolition of Cfb expression was confirmed by quantitative polymerase chain reaction and immunoblot (Figure S1E), and loss of Cfb function was confirmed by ablation of serum alternative pathway (AP) activity (Figure S1F)
Summary
Metabolic syndrome (MetS) represents a complex clustering of cardiometabolic traits, including hypertension, insulin resistance, glucose intolerance, and dyslipidemia, all of which increase the risk of developing type 2 diabetes mellitus and cardiovascular disease.[1]. Because of the complex genetic basis of human MetS, the spontaneously hypertensive rat (SHR), which exhibits hypertension, insulin resistance, and dyslipidemia, has been extensively studied as a MetS model.[11,12,13]. The rat Cfb gene resides within the major histocompatibility region on chromosome 20p12.18 In SHR, this region has been demonstrated to be important in blood pressure regulation,[19] serum cholesterol, adiposity, and glucose tolerance.[20,21] In this study, we knocked out Cfb in SHR to test the hypothesis that Cfb is necessary for the full expression of cardiometabolic pathophysiological traits in this model of MetS
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