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Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.

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.

SUBMITTER: Coan PM

PROVIDER: S-EPMC5548512 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.

Coan Philip M PM Barrier Marjorie M Alfazema Neza N Carter Roderick N RN Marion de Procé Sophie S Dopico Xaquin C XC Garcia Diaz Ana A Thomson Adrian A Jackson-Jones Lucy H LH Moyon Ben B Webster Zoe Z Ross David D Moss Julie J Arends Mark J MJ Morton Nicholas M NM Aitman Timothy J TJ

Hypertension (Dallas, Tex. : 1979) 20170724

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-/- ra ...[more]

PMID: 28739975

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Project description:BackgroundAlthough the increased prevalence and severity of clinical depression and elevated cardiovascular disease risk represent 2 vexing public health issues, the growing awareness of their combined presentation compounds the challenge. The obese Zucker rat, a model of the metabolic syndrome, spontaneously develops significant depressive symptoms in parallel with the progression of the metabolic syndrome and, thus, represents a compelling model for study. The primary objective was to assess the impact on both cardiovascular outcomes, specifically vascular structure and function, and depressive symptoms in obese Zucker rats after aggressive treatment for cardiovascular disease risk factors with long-term exercise or targeted pharmacological interventions.Methods and resultsWe chronically treated obese Zucker rats with clinically relevant interventions against cardiovascular disease risk factors to determine impacts on vascular outcomes and depressive symptom severity. While most of the interventions (chronic exercise, anti-hypertensive, the interventions (long-term exercise, antihypertensive, antidyslipidemia, and antidiabetic) were differentially effective at improving vascular outcomes, only those that also resulted in a significant improvement to oxidant stress, inflammation, arachidonic acid metabolism (prostacyclin versus thromboxane A2), and their associated sequelae were effective at also blunting depressive symptom severity. Using multivariable analyses, discrimination between the effectiveness of treatment groups to maintain behavioral outcomes appeared to be dependent on breaking the cycle of inflammation and oxidant stress, with the associated outcomes of improving endothelial metabolism and both cerebral and peripheral vascular structure and function.ConclusionsThis initial study provides a compelling framework from which to further interrogate the links between cardiovascular disease risk factors and depressive symptoms and suggests mechanistic links and potentially effective avenues for intervention.

Dataset Information

Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.

Publications

Complement Factor B Is a Determinant of Both Metabolic and Cardiovascular Features of Metabolic Syndrome.

Similar Datasets

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