C-terminal fragment of fibroblast growth factor 23 improves heart function in murine models of high intact fibroblast growth factor 23.

Cardiovascular disease (CVD) is the major cause of death in chronic kidney disease (CKD) and is associated with high circulating fibroblast growth factor (FGF)23 levels. It is unresolved whether high circulating FGF23 is a mere biomarker or pathogenically contributes to cardiomyopathy. It is also unknown whether the C-terminal FGF23 peptide (cFGF23), a natural FGF23 antagonist proteolyzed from intact FGF23 (iFGF23), retards CKD progression and improves cardiomyopathy. We addressed these questions in three murine models with high endogenous FGF23 and cardiomyopathy. First, we examined wild-type (WT) mice with CKD induced by unilateral ischemia-reperfusion and contralateral nephrectomy followed by a high-phosphate diet. These mice were continuously treated with intraperitoneal implanted osmotic minipumps containing either iFGF23 protein to further escalate FGF23 bioactivity, cFGF23 peptide to block FGF23 signaling, vehicle, or scrambled peptide as negative controls. Exogenous iFGF23 protein given to CKD mice exacerbated pathological cardiac remodeling and CKD progression, whereas cFGF23 treatment improved heart and kidney function, attenuated fibrosis, and increased circulating soluble Klotho. WT mice without renal insult placed on a high-phosphate diet and homozygous Klotho hypomorphic mice, both of whom develop moderate CKD and clear cardiomyopathy, were treated with cFGF23 or vehicle. Mice treated with cFGF23 in both models had improved heart and kidney function and histopathology. Taken together, these data indicate high endogenous iFGF23 is not just a mere biomarker but pathogenically deleterious in CKD and cardiomyopathy. Furthermore, attenuation of FGF23 bioactivity by cFGF23 peptide is a promising therapeutic strategy to protect the kidney and heart from high FGF23 activity.NEW & NOTEWORTHY There is a strong correlation between cardiovascular morbidity and high circulating fibroblast growth factor 23 (FGF23) levels, but causality was never proven. We used a murine chronic kidney disease (CKD) model to show that intact FGF23 (iFGF23) is pathogenic and contributes to both CKD progression and cardiomyopathy. Blockade of FGF23 signaling with a natural proteolytic product of iFGF23, C-terminal FGF23, alleviated kidney and cardiac histology, and function in three separate murine models of high endogenous FGF23.

Do we need race-specific resting metabolic rate prediction equations?

BACKGROUND: Resting metabolic rate (RMR) is a key determinant of daily caloric needs. Respirometry, a form of indirect calorimetry (IC), is considered one of the most accurate methods to measure RMR in clinical and research settings. It is impractical to measure RMR by IC in routine clinical practice; therefore, several formulas are used to predict RMR. In this study, we sought to determine the accuracy of these formulas in determining RMR and assess additional factors that may determine RMR. METHODS: We measured RMR in 114 subjects (67% female, 30% African American [AA]) using IC. Along with standard anthropometrics, dual-energy X-ray absorptiometry was used to obtain fat-free mass(FFM) and total fat mass. Measured RMR (mRMR) by respirometry was compared with predicted RMR (pRMR) generated by Mifflin-St.Joer, Cunningham, and Harris-Benedict (HB) equations. Linear regression models were used to determine factors affecting mRMR. RESULTS: Mean age, BMI, and mRMR of subjects were 46 ± 16 years (mean ± SD), 35 ± 10 kg/m2, and 1658 ± 391 kcal/day, respectively. After adjusting for age, gender, and anthropometrics, the two largest predictors of mRMR were race (p < 0.0001) and FFM (p < 0.0001). For every kg increase in FFM, RMR increased by 28 kcal/day (p < 0.0001). AA race was associated with 144 kcal/day (p < 0.0001) decrease in mRMR. The impact of race on mRMR was mitigated by adding in truncal FFM to the model. When using only clinically measured variables to predict mRMR, we found race, hip circumference, age, gender, and weight to be significant predictors of mRMR (p < 0.005). Mifflin-St.Joer and HB equations that use just age, gender, height, and weight overestimated kcal expenditure in AA by 138 ± 148 and 242 ± 164 (p < 0.0001), respectively. CONCLUSION: We found that formulas utilizing height, weight, gender, and age systematically overestimate mRMR and hence predict higher calorie needs among AA. The lower mRMR in AA could be related to truncal fat-free mass representing the activity of metabolically active intraabdominal organs.

Effect of adiposity on tissue-specific adiponectin secretion.

Circulating adiponectin levels are lower in individuals with increased BMI and central adiposity. However, they are paradoxically higher in those with peripheral adiposity. We hypothesized that adiponectin secretion from central and peripheral adipose tissue depots may be associated with adiposity levels and its distribution. A total of 55 subjects (69% women) undergoing elective abdominal surgery (mean age: 53 ± 13 years) were recruited. Health history, anthropometrics, and cardiovascular disease risk factor measurements were obtained. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) samples were obtained and cultured. Media was collected after 24hr and adiponectin released into the medium was measured using ELISA. We found that mean adiponectin levels from SAT and VAT in all subjects were 17.14±15.27 vs. 15.21±14.28 pg/ml/mg of tissue respectively (p = ns). However, adiponectin secretion from VAT correlated negatively with BMI (r = -0.31, p = 0.01), whereas there was no relationship with SAT (r = 0.08 p = 0.61). Similarly, waist circumference and estimated VAT percentage were both negatively correlated with VAT secretion of adiponectin (r = -0.35, p = 0.01 and r = -0.36, p = 0.02 respectively). These negative correlations were significant only in women on gender-stratified analyses. Adiponectin secretion from VAT decreases with increases in adiposity, while SAT secretion remains unchanged, especially in women. This observation may explain lower circulating adiponectin levels in individuals with central obesity. Further studies are needed to explore the mechanism behind this discrepant adiponectin secretion from SAT and VAT with increases in BMI, particularly among women.