Reza Rezvani

Complement C3 and cleavage products in cardiometabolic risk.

This review summarizes available evidence on the role of serum complement component 3 (C3), produced by liver, adipocytes and activated macrophages at inflammation sites, and C3 cleavage products linking lipoproteins and metabolism to immunity. C3 and cleavage products are modified in several associated metabolic disorders including obesity, insulin resistance, type-2 diabetes, dyslipidemia, and cardiovascular diseases. Circulating C3 is independently and linearly associated with serum triglycerides, C-reactive protein (CRP), waist circumference and in some populations inversely with current smoking. The complement cascade is activated during myocardial ischemia and likely mediates immune and inflammatory responses in ischemic myocardium. Serum complement activation is elevated in unstable rather than stable angina pectoris suggesting added contribution to damage extension in acute coronary syndromes. In logistic regression models for incident metabolic syndrome (MetS), increasing C3 concentrations predicted MetS in women, after adjusting for continuous values of 3 major MetS components and other confounders, with a relative risk similar in magnitude to an established component suggesting elevated C3 likely constitutes part of the cluster of MetS in women. C3 interacts with MetS in men for independently conferring risk of incident type-2 diabetes and coronary heart disease (CHD). In women, though C3 is equally predictive of cardiometabolic risk, it is less so additively to MetS components or to CRP. Evidence suggests that circulating C3 might serve as a signal for an immune process that enhances - via mediation of increased apolipoprotein (apo) E levels - the development of dysfunctional apoA-I particles rendering them diabetogenic and atherogenic in populations prone to MetS or subsets of populations harboring impaired glucose tolerance. C3 activation also leads to production of chemoattractants C3a and C5a, and acylation stimulating protein (ASP, C3adesArg), a lipogenic hormone, which contribute additionally to the metabolic phenotypes generated. These observations have clinical and public health implications.

Effect of the Mediterranean diet on plasma adipokine concentrations in men with metabolic syndrome.

OBJECTIVE While a Mediterranean dietary pattern (MedDiet) has been associated with favorable changes in several features of metabolic syndrome (MetS), its impact on plasma adipokine concentrations remains largely unknown. The objective of this study was to determine the impact of the MedDiet consumed under controlled feeding conditions, without (-WL) and with weight loss (+WL), on plasma adipokine concentrations in adult men with MetS (NCEP-ATP III). MATERIALS/METHODS The diet of 26 men with MetS (age 24 to 62 yrs) was first standardized to a North American control diet for 5 weeks. Participants then consumed a pre-determined MedDiet for 5 weeks. Both diets were consumed under weight-maintaining isoenergetic feeding conditions. Participants then underwent a 20-week free-living caloric restriction period, after which they consumed the MedDiet again in weight stabilizing, isoenergetic feeding conditions. RESULTS Body weight was reduced by 10.2%±2.9% and waist circumference by 8.6±3.3 cm after the weight loss period and stabilization on MedDiet (P<0.001). MedDiet-WL had no impact on plasma concentrations of leptin, plasminogen activator inhibitor-1, resistin, visfatin, acylation stimulating protein and adiponectin. MedDiet+WL reduced plasma leptin concentrations (P<0.01) and increased plasma adiponectin concentrations (P<0.05) compared with the control diet and MedDiet-WL. CONCLUSION Data from this nutritionally controlled study suggest that short-term consumption of MedDiet has little effect on the concentrations of many adipokines in the absence of weight loss.

Effects of sugar‐sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: Relationships with Metabolic Outcomes

The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined.

Downregulation of complement C3 and C3aR expression in subcutaneous adipose tissue in obese women.

Background The central component of the complement system, C3, is associated with obesity, metabolic syndrome and cardiovascular disease however the underlying reasons are unknown. In the present study we evaluated gene expression of C3, the cleavage product C3a/C3adesArg and its cognate receptor C3aR in subcutaneous and omental adipose tissue in women. Methods Women (n = 140, 21–69 years, BMI 19.5–79 kg/m2) were evaluated for anthropometric and blood parameters, and adipose tissue gene expression. Results Subjects were separated into groups (n = 34–36) according to obesity: normal/overweight (≤30 kg/m2), obese I (≤45 kg/m2), obese II (≤51 kg/m2), and obese III (≤80 kg/m2). Overall, while omental expression remained unchanged, subcutaneous C3 and C3aR gene expression decreased with increasing adiposity (2-way ANOVA, p<0.01), with a concomitant decrease in SC/OM ratio (p<0.001). In subcutaneous adipose, both C3 and C3aR expression correlated with apoB, and apoA1 and inversely with waist circumference and blood pressure, while C3aR also correlated with glucose (p<0.05–0.0001). While omental C3aR expression did not correlate with any factor, omental C3 correlated with waist circumference, glucose and apoB (all p<0.05). Further, while plasma C3a/C3adesArg increased and adiponectin decreased with increasing BMI, both correlated (C3a negatively and adiponectin positively) with subcutaneous C3 and C3aR expression (p<0.05–0.001) or less). Conclusions The obesity-induced down-regulation of complement C3 and C3aR which is specific to subcutaneous adipose tissue, coupled to the strong correlations with multiple anthropometric, plasma and adipokine variables support a potential role for complement in immunometabolism.

Association of Immune and Metabolic Receptors C5aR and C5L2 with Adiposity in Women

Adipose tissue receptors C5aR and C5L2 and their heterodimerization/functionality and interaction with ligands C5a and acylation stimulating protein (ASP) have been evaluated in cell and rodent studies. Their contribution to obesity factors in humans remains unclear. We hypothesized that C5a receptors, classically required for host defense, are also associated with adiposity. Anthropometry and fasting blood parameters were measured in 136 women divided by body mass index (BMI): normal/overweight (≤30 kg/m2; n = 34), obese I (≤45 kg/m2; n = 33), obese II (≤51 kg/m2; n = 33), and obese III (≤80 kg/m2; n = 36). Subcutaneous and omental adipose tissue C5aR and C5L2 expression were analysed. C5L2 expression was comparable between subcutaneous and omental across all BMI groups. Plasma ASP and ASP/omental C5L2 expression increased with BMI (P < 0.001 and P < 0.01, resp.). While plasma C5a was unchanged, C5aR expression decreased with increasing BMI in subcutaneous and omental tissues (P < 0.01 and P < 0.05, resp.), with subcutaneous omental depots. Omental C5L2/C5aR ratio increased with BMI (P < 0.01) with correlations between C5L2/C5aR and waist circumference, HDL-C, and adiponectin. Tissue and BMI differences in receptors and ligands, particularly in omental, suggest relationship to metabolic disturbances and highlight adipose-immune interactions.

Cross-sectional associations of acylation stimulating protein (ASP) and adipose tissue gene expression with estradiol and progesterone in pre- and postmenopausal women

Sex steroid hormones play an important regulatory role in fat metabolism and obesity. We hypothesized involvement of interactions between ovarian hormones with acylation stimulating protein (ASP).

Complement Receptors C5aR and C5L2 Are Associated with Metabolic Profile, Sex Hormones, and Liver Enzymes in Obese Women Pre- and Postbariatric Surgery

Objective. Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation. We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2) would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. Materials and Methods. Fasting plasma (hormone, lipid, and enzyme analysis) and liver biopsies (RT-PCR gene expression) were obtained from 91 women during surgery. Results. Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P < 0.01) and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P < 0.05). While plasma ASP was lower in pre- versus postmenopausal women (P < 0.01), the hepatic C5L2/C5aR mRNA ratio was increased (P < 0.001) and correlated positively with estrone (P < 0.01) and estradiol (P < 0.001) and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P < 0.05). Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P < 0.05, AST and GGT, P < 0.001 2-way-ANOVA). Conclusion. C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function.

Effects of Sugar-sweetened Beverages on plasma Acylation Stimulating Protein, Leptin & Adiponectin and Metabolic Parameters

The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined.

Downregulation of complement C3 and C3aR expression in subcutaneous adipose tissue in obese Caucasian women

Background: The central component of the complement system, C3, is associated with obesity, type 2 diabetes and cardiovascular disease however the underlying reasons are unknown. In the present study we evaluated gene expression of C3, the cleavage product C3a and its cognate receptor C3aR in subcutaneous and omental adipose tissue in women. Methods: Women (n=140, 21-69 years, BMI 19.5-79 kg/m 2 ) were evaluated for anthropometric and blood parameters, and adipose tissue gene expression. Results: Subjects were separated into groups (n=33-36) according to obesity: normal/overweight (≤ 30kg/m 2 ), obese I (≤45 kg/m 2 ), obese II (≤51 kg/m 2 ), and obese III (≤80 kg/m 2 ). Overall, while omental expression remained unchanged, subcutaneous C3 and C3aR gene expression decreased with increasing adiposity (2-way ANOVA, p<0.01), with a concomitant decrease in SC/OM ratio (p<0.001). In subcutaneous adipose, both C3 and C3aR expression correlated with apoB, and apoA1 and inversely with waist circumference and blood pressure, while C3aR also correlated with glucose (p<0.050.0001). While omental C3aR expression did not correlate with any factor, omental C3 correlated with waist circumference, glucose and apoB (all p<0.05). Further, while plasma C3a/C3adesArg increased and adiponectin decreased with increasing BMI, both correlated (C3a negatively and adiponectin positively) with subcutaneous C3 and C3aR expression (p<0.05-0.001) or less). Conclusions: The obesity-induced down-regulation of complement C3 and C3aR which is specific to subcutaneous adipose tissue, coupled to the strong correlations with multiple anthropometric, plasma and adipokine variables support a potential role for complement in immunometabolism.

Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: Relationships with Metabolic Outcomes: Sugar Consumption Effect on Adipokines

The effects of fructose and glucose consumption on plasma acylation stimulating protein (ASP), adiponectin, and leptin concentrations relative to energy intake, body weight, adiposity, circulating triglycerides, and insulin sensitivity were determined.