RoseMarie Jones

Obesity is associated with increased levels of circulating hepatocyte growth factor

OBJECTIVES This study evaluated whether obesity in humans was associated with an increase in circulating hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels. BACKGROUND Obesity acts as a cardiovascular risk factor by mechanisms that are not fully understood. Adipose tissue is able to secrete multiple cytokines and growth factors ex vivo. We hypothesized that the increased presence of adipose tissue in obese subjects results in systemic elevations of the mitogenic factors HGF and VEGF. METHODS Blood samples were obtained from lean (n = 21) and obese (n = 44) volunteers. Serum HGF and VEGF levels were assessed by enzyme-linked immunoadsorbent assay. Insulin and fasting glucose levels were measured to evaluate insulin sensitivity. Conditioned medium of adipose cells was assayed for HGF secretion. RESULTS Serum HGF levels in obese subjects were more than three-fold higher than those of lean subjects (2,462 +/- 184 pg/ml vs. 765 +/- 48 pg/ml, p < 0.0001). The VEGF levels were not significantly elevated in obese subjects (135 +/- 31 pg/ml vs. 128 +/- 37 pg/ml). The HGF concentrations, but not VEGF concentrations, were significantly correlated with body mass index (BMI) (p < 0.0001, r = 0.74). The observed increases in HGF concentrations of obese subjects were not secondary to insulin resistance or hypertension. Freshly isolated human adipose cells secreted HGF. CONCLUSIONS Our results indicate that obesity is associated with a marked increase in circulating HGF levels, which correlate linearly with BMI. Because vascular growth factors have been associated with the pathogenesis of atherosclerosis, the possible role of such humoral factors as a link between obesity and cardiovascular disease is very intriguing.

Serum Markers of Bone Turnover Are Increased at Six and 18 Months after Roux-En-Y Bariatric Surgery: Correlation with the Reduction in Leptin

OBJECTIVE The aim of the study was to examine serum markers of bone turnover at 6 and 18 months after Roux-en-Y gastric bypass surgery. PARTICIPANTS Ten women and 10 men [body mass index (BMI), 50.2 +/- 8.4 kg/m(2)] were studied at 6 months; 10 women and nine men (BMI, 47.2 +/- 6.6 kg/m(2)) were studied at 18 months after surgery. MAIN OUTCOME MEASURES Serum osteocalcin, bone specific alkaline phosphatase (BAP), N-telopeptide of type 1 collagen (NTX), PTH, 25-hydroxy vitamin D, and leptin were measured. RESULTS BMI was reduced 32.7 +/- 6.2% at 6 months after surgery. Serum osteocalcin (6.9 +/- 2.4 to 10.9 +/- 2.6 ng/ml; P < 0.0001), BAP (14.2 +/- 3.7 to 16.4 +/- 4.5 ng/ml; P = 0.04), and NTX (10.9 +/- 1.7 to 19.6 +/- 5.3 nm bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (16.0 +/- 8.9 vs. 26.9 +/- 10.6 ng/ml; P <0.0001). The increase in NTX correlated with reduction in serum leptin (r = 0.58; P = 0.007). BMI was reduced 40.9 +/- 7.5% at 18 months after surgery. Serum BAP (17.6 +/- 5.3 to 22.2 +/- 7.8 ng/ml; P = 0.0017) and NTX (10.8 +/- 2.7 to 16.9 +/- 5.5 nm bone collagen equivalents; P < 0.0001) were increased. Calcium, phosphate, and PTH were unchanged, but 25-hydroxy vitamin D increased (17.7 +/- 7.6 to 25.6 +/- 6.8 ng/ml; P < 0.0001). The increase in NTX correlated with reduction in BMI (r = 0.58; P = 0.009) and leptin (r = 0.45; P = 0.04) and the increase in serum 25-hydroxy vitamin D (r = 0.43; P = 0.05). In multiple regression (adjusted model R(2) 0.263; P = 0.013), reduction in leptin was a significant predictor of increase in NTX (P = 0.016), but changes in BMI and 25-hydroxy vitamin D were not. CONCLUSIONS Weight loss after bariatric surgery is associated with long-term increase in serum markers of bone turnover. The increase in NTX is related to the decrease in leptin, which may signal caloric restriction to the skeleton.

Serum Leptin, Parathyroid Hormone, 1,25-Dihydroxyvitamin D, Fibroblast Growth Factor 23, Bone Alkaline Phosphatase, and Sclerostin Relationships in Obesity

BACKGROUND Obesity is associated with hyperparathyroidism and increased bone mass and turnover, but their pathogeneses are unclear. AIMS Our aim was to determine in obesity interrelationships among serum levels of leptin, the mineral-regulating hormones, bone turnover markers, and sclerostin. METHODS This case-control study was performed in 20 women having bariatric surgery and 20 control women matched for race and age. Anthropometrics and fasting serum biochemistries were measured in controls and in bariatric patients the morning of surgery. RESULTS Body mass index (48.9 vs. 25.4 kg/m(2)), weight (128.6 vs. 71.9 kg), serum leptin (74.6 vs. 25.2 ng/ml), PTH (44.5 vs. 28.8 pg/ml), fibroblast growth factor 23 (FGF23) (42.4 vs. 25.9 pg/ml), and bone alkaline phosphatase (BAP) (25.8 vs. 17.5 U/liter) were higher, but height (162.3 vs. 167.7 cm) and 1,25-dihydroxyvitamin D (1,25D) (39.2 vs. 48.7 pg/ml) were lower in bariatric surgery patients than controls. There was no difference in serum sclerostin, amino-terminal collagen cross-links, 25-hydroxyvitamin D (25D), calcium, phosphate, and creatinine between groups. In the combined sample, leptin was positively related to PTH, FGF23, and BAP but not to 1,25D or sclerostin. Multiple regression analysis demonstrated that PTH was predicted by leptin and Ca (R(2) = 0.39); 1,25D by 25D, FGF23, and phosphate (R(2) = 0.43); FGF23 by leptin and 1,25D (R(2) = 0.27); BAP by leptin, PTH, and Ca (R(2) = 0.39); and sclerostin by leptin and PTH (R(2) = 0.20). CONCLUSIONS Women having bariatric surgery had higher leptin, PTH, FGF23, and BAP and lower 1,25D than controls. Leptin predicted the serum levels of PTH, 1,25D, and FGF23, the mineral-regulating hormones, and BAP, a bone formation marker, in women with body mass index ranging from 13.9-65.8 kg/m(2). The results suggest that leptin has an endocrine or paracrine effect on PTH and FGF23 production and that PTH may be one of the signals in obesity that leads to increased bone mass.

Vitamin D and hyperparathyroidism in obesity

BACKGROUND Low vitamin D status and hyperparathyroidism occur in obesity and may be involved in pathogenesis of obesity-associated comorbid conditions. AIMS Our aims were to determine in obesity whether there was vitamin D insufficiency, assessed by serum 25-hydroxyvitamin D (s25D) and serum PTH (sPTH) and whether it related to comorbid conditions. METHODS We conducted a case-control study of 48 women having bariatric surgery and 50 healthy women frequency matched for race, age, year, and season of study. Height, weight, s25D, sPTH, serum 1,25-dihydroxyvitamin D (s1,25D), serum bone alkaline phosphatase, serum cross-linked N-telopeptides of type 1 collagen, and serum calcium, phosphate, creatinine, glucose, and insulin were measured, and comorbid conditions were documented from patient files. RESULTS Weight (140 vs. 76 kg, P < 0.001), sPTH (44.4 vs. 25.6 pg/ml, P < 0.001), s1,25D (39 vs. 24 pg/ml, P < 0.001), serum bone alkaline phosphatase (19 vs. 12 ng/ml, P < 0.001), serum cross-linked N-telopeptides of type 1 collagen (9.6 vs. 7.9 nm bone collagen equivalents, P = 0.007), serum phosphate (3.45 vs. 3.24 mg/dl, P = 0.043), and serum creatinine (1.05 vs. 0.87 mg/dl, P < 0.001) were higher, and s25D (16 vs. 23 ng/ml, P <.001) was lower in bariatric-surgery women than control women. s25D was lower in bariatric-surgery women than controls in summer (17 vs. 26 ng/ml, P < 0.0001) but not winter (15 vs. 18 ng/ml, P > 0.2). Multiple regression analysis demonstrated that weight predicted s25D (P < 0.001) and sPTH (P = 0.001), but s25D did not predict sPTH or the presence of comorbid conditions except for osteoarthritis. CONCLUSION Women having bariatric surgery had lower s25D and higher sPTH. The major determinant of s25D and sPTH was weight. Hyperparathyroidism in obesity did not indicate vitamin D insufficiency. Low s25D was not associated with comorbid conditions, apart from osteoarthritis.

Ethanol impairs differentiation of human adipocyte stromal cells in culture.

BACKGROUND Bioinformatic resources suggest that adipose tissue expresses mRNAs for alcohol dehydrogenases (ADHs) and ALDH2, and epidemiological studies indicate that heavy alcohol use reduces adipose tissue mass. We therefore characterized the expression of alcohol metabolizing enzymes in human, rat and mouse adipose tissue, preadipocytes, and adipocytes, the ability of adipocytes to metabolize ethanol, and the effects of ethanol on differentiation of human adipose stromal cells (hASCs). METHODS Adipose tissue, preadipocytes, and adipocytes were collected from rodents or from humans undergoing bariatric surgery. hASCs were differentiated in vitro using standard methods. Gene expression and cellular differentiation were analyzed by Western blotting, RT-PCR, and microscopy. RESULTS Class I ADH was expressed in human > mouse > rat adipose tissue, whereas ALDH2 was high in all samples. ADH, catalase, and ALDH2 were induced during differentiation of hASCs. The presence of 50 mM ethanol markedly reduced the differentiation of hASCs; this effect was associated with inhibition of expression of transcription factors required for differentiation, but did not depend on the ability of the cells to metabolize ethanol. CONCLUSIONS Human adipose tissue expresses alcohol oxidizing enzymes. The presence of ethanol at physiologically relevant concentrations inhibits differentiation of hASCs. Ethanol could alter adipose tissue biology, inducing a form of acquired lipodystrophy, which is consistent with epidemiological studies.