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.