- Email: [email protected]
Effect of statin therapy on leptin levels in patients with coronary heart disease
Peptides 31 (2010) 1205–1207
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Short communication
Effect of statin therapy on leptin levels in patients with coronary heart disease Yan-Ming Sun a,1 , Jia Li a,1 , Ying Luan b,1 , Lan-Feng Wang b,∗ a b
Department of Cardiac Care Unit, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin 150001, China Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
a r t i c l e
i n f o
Article history: Received 20 February 2010 Received in revised form 17 March 2010 Accepted 17 March 2010 Available online 23 March 2010 Keywords: HMG-COA reductase inhibitor Leptin Coronary heart disease
a b s t r a c t The goal of this study was to investigate the effects of simvastatin on the levels of plasma leptin and nitric oxide (NO) in patients with coronary heart disease (CHD). The study population consisted of 65 patients with CHD and 48 control individuals without signs or symptoms of CHD. The patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids, leptin and NO were determined before and after 12 weeks of treatment. Leptin levels were higher in patients with CHD than control (P < 0.05). Statin treatment significantly decreased plasma lipids and leptin levels and increased NO concentration in all CHD patients (P < 0.05). Serum leptin levels after treatment correlated negatively with the NO concentration (P < 0.05). Simvastatin may provide beneficial effects of reducing leptin levels, independent of its lipid-lowering action, which may play an important role in patients with CHD. © 2010 Elsevier Inc. All rights reserved.
1. Introduction Leptin, an adipocyte-derived satiety hormone, plays a crucial role in the regulation of food intake and energy expenditure through acting on its receptor expressed mainly in the hypothalamus [1,4]. There is a growing body of evidence indicating that leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity [3,7,15]. Recent studies demonstrated the leptin induces C-reactive protein production by human coronary endothelial cells, providing a local source of C-reactive protein that can play a direct role in promoting atherothrombosis in the coronary tree [6]. Previous studies in mice and humans suggested that leptin played a role in the regulation of HDL-C [11,18]. Leptin is suggested to be capable of influencing several apolipoprotein genes and the hepatic lipase gene expression [16]. The result prompted us to investigate the effects of simvastatin on circulating the levels of plasma leptin in patients with CHD.
coronary angiography. A stenosis estimated as >40% in at least one major coronary artery was considered to indicate CHD. The control population consisted of 48 (26 females, 22 males; age range 43–76 years) healthy subjects who attended a routine health check at the medical examination center. All CHD patients were asked to take low-fat diets and simvastatin 20 mg once daily at bedtime. Plasma leptin concentrations were measured in a single run using a commercially available RIA kit (Linco Research Inc., Missouri, MO, USA) according to the manufacturer’s instructions. The sensitivity of this assay is 0.5 ng/ml; the intraassay coefficient of variation being 4.98% and the interassay coefficient of variation being 4.5%. Fasting serum lipids, leptin and NO were determined before and after 12 weeks of treatment. All data were expressed as mean ± SD. Paired Student’s t-test was performed for the plasma lipid, leptin and NO concentrations before and after simvastatin treatment. Linear regression analysis was used for relationships between leptin and the metabolic characteristics studied. All statistical analyses were performed using the SPSS software package (SPSS 13.0).
2. Subjects and methods
3. Results
Sixty-five CHD patients were enrolled (38 females, 27 males; age range 45–72 years), unrelated to each other, who underwent
Demographic and metabolic characteristics of the control subjects and patients with CHD are shown in Table 1. Demographic characteristics of the two groups did not show a significant difference. Patients with CHD had a significantly higher leptin and lower NO level than those of control subjects (P < 0.05). Simvastatin treatment combined with low-fat diets significantly improved the lipid profiles, increased NO level and reduced leptin levels and body
∗ Corresponding author. Tel.: +86 451 85555260. E-mail address: [email protected] (L.-F. Wang). 1 All these authors contributed equally to this study. 0196-9781/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2010.03.023
1206
Y.-M. Sun et al. / Peptides 31 (2010) 1205–1207
Table 1 Comparison of the anthropometric and biochemical characteristics between controls and the CHD group.
Sex (M:F) Age (years) Waist (cm) Height (cm) Weight (kg) Body mass index (kg/m2 ) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate Fasting glucose (mmol/L) Smoking Alcohol abuser
Controls
CHD group
26:22 49 ± 7.32 85.18 ± 5.37 169.75 ± 6.51 66.81 ± 8.90 23.15 ± 2.63 124 ± 16 62 ± 15 65 ± 13 4.74 ± 0.92 11 (22.91%) 8 (16.67%)
38:27 51 ± 6.39 83.09 ± 5.62 168.94 ± 6.83 69.27 ± 8.26 24.02 ± 2.34 127 ± 23 64 ± 16 67 ± 12 4.81 ± 1.03 16 (24.61%) 12 (18.46%)
Data are means ± SD. CHD, coronary heart disease.
Table 2 Comparison of the anthropometric and biochemical characteristics before and after treatment with simvastatin. Controls (n = 48)
Weight (kg) Body mass index (kg/m2 ) TG (mmol/L) TC (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) VLDL-C (mmol/L) Leptin (ng/ml) NO (mol/l)
66.81 ± 8.90 23.15 ± 2.63 1.59 4.15 1.35 2.13 0.84 8.29 69.05
± ± ± ± ± ± ±
0.39 0.43 0.21 0.73 0.12 3.39 10.44
CHD group (n = 65) Before treatment
After treatment
69.27 ± 8.26 24.02 ± 2.34
60.54 ± 7.35b 22.16 ± 2.09
2.04 4.52 1.21 2.19 0.88 20.36 47.65
± ± ± ± ± ± ±
0.65 0.57 0.17 0.81 0.14 6.21a 7.68a
1.67 4.36 1.25 2.18 0.86 11.67 60.32
± ± ± ± ± ± ±
0.61 0.59 0.18 0.79 0.15 5.26b 9.03b
Values are expressed as mean ± SD. CHD, coronary heart disease; TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; VLDL-C, very low density lipoprotein cholesterol; NO, nitric oxide. a P < 0.01 compared with control group. b P < 0.05 compared with before treatment.
weight (P < 0.01) (Table 2). To better investigate the statin therapy on leptin and NO levels, we performed linear regression analysis between leptin and the various parameters examined. Among the subjects with CHD, leptin showed a negative correlation with NO (r = −0.39, P < 0.05). Serum leptin concentration after treatment correlated negatively with the NO level (r = −0.31, P < 0.05). 4. Discussion The results of this study showed the following new findings: (1) compared with control subjects, patients with CHD show an higher leptin and lower NO; (2) leptin is inversely and strongly related to NO; (3) statin treatment significantly decreased plasma lipids and leptin levels and increased NO concentration in all CHD patients; (4) serum leptin concentrations after treatment correlated negatively with the NO level. Leptin, the product of the obese gene, is primarily secreted by the adipose tissue and it regulates body weight by its receptor mediated anorectic, thermogenic and antisteatotic effects [13]. Leptin has been shown to downregulate hepatic HMG-CoA reductase, while upregulate activities of both sterol 27-hydroxylase and cholesterol 7␣-hydroxylase, all together leading a substantial drop in VLDLC in plasma [17]. Furthermore, leptin has recently been shown to phosphorylate and activate AMP-activated protein kinase via central and peripheral mechanism [12]. In accordance with the notion that simvastatin mainly exerts its cholesterol lowering effect via inhibition of hepatic HMG-CoA reductase, it is tempting to spec-
ulate that impaired leptin receptor signaling could contribute, at least in part, to cholesterol dyshomeostasis and reduced response to statins through this metabolic pathway [8]. Leptin has been shown to increase NO release from endothelial cells in vitro [5]. The release of leptin by adipocytes may cause a local NO-mediated vasodilation in fatty tissue that enhances lipid metabolism [10]. Leptin was known to increase oxidative stress in endothelial cells and the long-term consequences of oxidative stress may include reductions in NO bioactivity and/or synthesis and an increase in the expression of adhesion molecules and chemokines that mediate vascular inflammation and atherogenesis [5]. Several reports indicated that hypertension, obesity, and dyslipidemia all may affect leptin levels [2,9,14]. As in our study, all subjects studied were normotensive and BMI was not shown to be directly related to endothelial dysfunction. Moreover, there was no relationship between these lipids and the percentage increase in leptin levels. Therefore, it is unlikely that blood pressure, BMI and the lipid parameters could account for the differences in leptin levels. To our knowledge, no previous study has assessed the effects of simvastatin on leptin and NO in patients with CHD, our results indicated that simvastatin may provide beneficial effects of reducing leptin levels, independent of its lipid-lowering action, which may play an important role in patients with CHD.
Acknowledgement This work was supported by grants from the Foundation of the First Affiliated of Harbin Medical University (Q08-007).
References [1] Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 2008;22:1023–31. [2] Asferg C, Mogelvang R, Flyvbjerg A, Frystyk J, Jensen JS, Marott JL, et al. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. Am J Hypertens 2010;23:327–33. [3] Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R, et al. Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J Clin Endocrinol Metab 2004;89:2665–71. [4] Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 2008;149:2138–48. [5] Cooke JP, Oka RK. Does leptin cause vascular disease? Circulation 2002;106:1904–5. [6] De Rosa S, Cirillo P, Pacileo M, Di Palma V, Paglia A, Chiariello M. Leptin stimulated C-reactive protein production by human coronary artery endothelial cells. J Vasc Res 2009;46:609–17. [7] Gulturk S, Cetin A, Erdal S. Association of leptin with insulin resistance, body composition, and lipid parameters in postmenopausal women and men in type 2 diabetes mellitus. Saudi Med J 2008;29:813–20. [8] Jiao S, Matsuzawa Y, Matsubara K, Kubo M, Tokunaga K, Odaka H, et al. Abnormalities of plasma lipoproteins in a new genetically obese rat with non-insulin-dependent diabetes mellitus (Wistar fatty rat). Int J Obes 1991;15:487–95. [9] Koncsos P, Seres I, Harangi M, Illyes I, Jozsa L, Gonczi F, et al. Human paraoxonase-1 activity in childhood obesity and its relation to leptin and adiponectin levels. Pediatr Res 2010;67:309–13. [10] Mastronardi CA, Yu WH, McCann SM. Resting and circadian release of nitric oxide is controlled by leptin in male rats. Proc Natl Acad Sci U S A 2002;99:5721–6. [11] Mendez-Sanchez N, Gonzalez V, King-Martinez AC, Sanchez H, Uribe M. Plasma leptin and the cholesterol saturation of bile are correlated in obese women after weight loss. J Nutr 2002;132:2195–8. [12] Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339–43. [13] Morton NM, Emilsson V, de Groot P, Pallett AL, Cawthorne MA. Leptin signalling in pancreatic islets and clonal insulin-secreting cells. J Mol Endocrinol 1999;22:173–84. [14] Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and
Y.-M. Sun et al. / Peptides 31 (2010) 1205–1207 insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 2009;94:1137–44. [15] Nelson SM, Freeman DJ, Sattar N, Johnstone FD, Lindsay RS. IGF-1 and leptin associate with fetal HDL cholesterol at birth: examination in offspring of mothers with type 1 diabetes. Diabetes 2007;56:2705–9. [16] Soro A, Jauhiainen M, Ehnholm C, Taskinen MR. Determinants of low HDL levels in familial combined hyperlipidemia. J Lipid Res 2003;44:1536–44.
1207
[17] VanPatten S, Ranginani N, Shefer S, Nguyen LB, Rossetti L, Cohen DE. Impaired biliary lipid secretion in obese Zucker rats: leptin promotes hepatic cholesterol clearance. Am J Physiol Gastrointest Liver Physiol 2001;281:G393–404. [18] Wu ZH, Zhao SP, Ye HJ. The beneficial effects of high-density lipoprotein on adipocytes may relate to its anti-atherogenic properties. Med Hypotheses 2006;67:1195–9.
Contents lists available at ScienceDirect
Peptides journal homepage: www.elsevier.com/locate/peptides
Short communication
Effect of statin therapy on leptin levels in patients with coronary heart disease Yan-Ming Sun a,1 , Jia Li a,1 , Ying Luan b,1 , Lan-Feng Wang b,∗ a b
Department of Cardiac Care Unit, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin 150001, China Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
a r t i c l e
i n f o
Article history: Received 20 February 2010 Received in revised form 17 March 2010 Accepted 17 March 2010 Available online 23 March 2010 Keywords: HMG-COA reductase inhibitor Leptin Coronary heart disease
a b s t r a c t The goal of this study was to investigate the effects of simvastatin on the levels of plasma leptin and nitric oxide (NO) in patients with coronary heart disease (CHD). The study population consisted of 65 patients with CHD and 48 control individuals without signs or symptoms of CHD. The patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids, leptin and NO were determined before and after 12 weeks of treatment. Leptin levels were higher in patients with CHD than control (P < 0.05). Statin treatment significantly decreased plasma lipids and leptin levels and increased NO concentration in all CHD patients (P < 0.05). Serum leptin levels after treatment correlated negatively with the NO concentration (P < 0.05). Simvastatin may provide beneficial effects of reducing leptin levels, independent of its lipid-lowering action, which may play an important role in patients with CHD. © 2010 Elsevier Inc. All rights reserved.
1. Introduction Leptin, an adipocyte-derived satiety hormone, plays a crucial role in the regulation of food intake and energy expenditure through acting on its receptor expressed mainly in the hypothalamus [1,4]. There is a growing body of evidence indicating that leptin plays a role in fat metabolism and correlates with insulin resistance and other markers of the metabolic syndrome, independent of total adiposity [3,7,15]. Recent studies demonstrated the leptin induces C-reactive protein production by human coronary endothelial cells, providing a local source of C-reactive protein that can play a direct role in promoting atherothrombosis in the coronary tree [6]. Previous studies in mice and humans suggested that leptin played a role in the regulation of HDL-C [11,18]. Leptin is suggested to be capable of influencing several apolipoprotein genes and the hepatic lipase gene expression [16]. The result prompted us to investigate the effects of simvastatin on circulating the levels of plasma leptin in patients with CHD.
coronary angiography. A stenosis estimated as >40% in at least one major coronary artery was considered to indicate CHD. The control population consisted of 48 (26 females, 22 males; age range 43–76 years) healthy subjects who attended a routine health check at the medical examination center. All CHD patients were asked to take low-fat diets and simvastatin 20 mg once daily at bedtime. Plasma leptin concentrations were measured in a single run using a commercially available RIA kit (Linco Research Inc., Missouri, MO, USA) according to the manufacturer’s instructions. The sensitivity of this assay is 0.5 ng/ml; the intraassay coefficient of variation being 4.98% and the interassay coefficient of variation being 4.5%. Fasting serum lipids, leptin and NO were determined before and after 12 weeks of treatment. All data were expressed as mean ± SD. Paired Student’s t-test was performed for the plasma lipid, leptin and NO concentrations before and after simvastatin treatment. Linear regression analysis was used for relationships between leptin and the metabolic characteristics studied. All statistical analyses were performed using the SPSS software package (SPSS 13.0).
2. Subjects and methods
3. Results
Sixty-five CHD patients were enrolled (38 females, 27 males; age range 45–72 years), unrelated to each other, who underwent
Demographic and metabolic characteristics of the control subjects and patients with CHD are shown in Table 1. Demographic characteristics of the two groups did not show a significant difference. Patients with CHD had a significantly higher leptin and lower NO level than those of control subjects (P < 0.05). Simvastatin treatment combined with low-fat diets significantly improved the lipid profiles, increased NO level and reduced leptin levels and body
∗ Corresponding author. Tel.: +86 451 85555260. E-mail address: [email protected] (L.-F. Wang). 1 All these authors contributed equally to this study. 0196-9781/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2010.03.023
1206
Y.-M. Sun et al. / Peptides 31 (2010) 1205–1207
Table 1 Comparison of the anthropometric and biochemical characteristics between controls and the CHD group.
Sex (M:F) Age (years) Waist (cm) Height (cm) Weight (kg) Body mass index (kg/m2 ) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate Fasting glucose (mmol/L) Smoking Alcohol abuser
Controls
CHD group
26:22 49 ± 7.32 85.18 ± 5.37 169.75 ± 6.51 66.81 ± 8.90 23.15 ± 2.63 124 ± 16 62 ± 15 65 ± 13 4.74 ± 0.92 11 (22.91%) 8 (16.67%)
38:27 51 ± 6.39 83.09 ± 5.62 168.94 ± 6.83 69.27 ± 8.26 24.02 ± 2.34 127 ± 23 64 ± 16 67 ± 12 4.81 ± 1.03 16 (24.61%) 12 (18.46%)
Data are means ± SD. CHD, coronary heart disease.
Table 2 Comparison of the anthropometric and biochemical characteristics before and after treatment with simvastatin. Controls (n = 48)
Weight (kg) Body mass index (kg/m2 ) TG (mmol/L) TC (mmol/L) HDL-C (mmol/L) LDL-C (mmol/L) VLDL-C (mmol/L) Leptin (ng/ml) NO (mol/l)
66.81 ± 8.90 23.15 ± 2.63 1.59 4.15 1.35 2.13 0.84 8.29 69.05
± ± ± ± ± ± ±
0.39 0.43 0.21 0.73 0.12 3.39 10.44
CHD group (n = 65) Before treatment
After treatment
69.27 ± 8.26 24.02 ± 2.34
60.54 ± 7.35b 22.16 ± 2.09
2.04 4.52 1.21 2.19 0.88 20.36 47.65
± ± ± ± ± ± ±
0.65 0.57 0.17 0.81 0.14 6.21a 7.68a
1.67 4.36 1.25 2.18 0.86 11.67 60.32
± ± ± ± ± ± ±
0.61 0.59 0.18 0.79 0.15 5.26b 9.03b
Values are expressed as mean ± SD. CHD, coronary heart disease; TC, total cholesterol; TG, triglyceride; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; VLDL-C, very low density lipoprotein cholesterol; NO, nitric oxide. a P < 0.01 compared with control group. b P < 0.05 compared with before treatment.
weight (P < 0.01) (Table 2). To better investigate the statin therapy on leptin and NO levels, we performed linear regression analysis between leptin and the various parameters examined. Among the subjects with CHD, leptin showed a negative correlation with NO (r = −0.39, P < 0.05). Serum leptin concentration after treatment correlated negatively with the NO level (r = −0.31, P < 0.05). 4. Discussion The results of this study showed the following new findings: (1) compared with control subjects, patients with CHD show an higher leptin and lower NO; (2) leptin is inversely and strongly related to NO; (3) statin treatment significantly decreased plasma lipids and leptin levels and increased NO concentration in all CHD patients; (4) serum leptin concentrations after treatment correlated negatively with the NO level. Leptin, the product of the obese gene, is primarily secreted by the adipose tissue and it regulates body weight by its receptor mediated anorectic, thermogenic and antisteatotic effects [13]. Leptin has been shown to downregulate hepatic HMG-CoA reductase, while upregulate activities of both sterol 27-hydroxylase and cholesterol 7␣-hydroxylase, all together leading a substantial drop in VLDLC in plasma [17]. Furthermore, leptin has recently been shown to phosphorylate and activate AMP-activated protein kinase via central and peripheral mechanism [12]. In accordance with the notion that simvastatin mainly exerts its cholesterol lowering effect via inhibition of hepatic HMG-CoA reductase, it is tempting to spec-
ulate that impaired leptin receptor signaling could contribute, at least in part, to cholesterol dyshomeostasis and reduced response to statins through this metabolic pathway [8]. Leptin has been shown to increase NO release from endothelial cells in vitro [5]. The release of leptin by adipocytes may cause a local NO-mediated vasodilation in fatty tissue that enhances lipid metabolism [10]. Leptin was known to increase oxidative stress in endothelial cells and the long-term consequences of oxidative stress may include reductions in NO bioactivity and/or synthesis and an increase in the expression of adhesion molecules and chemokines that mediate vascular inflammation and atherogenesis [5]. Several reports indicated that hypertension, obesity, and dyslipidemia all may affect leptin levels [2,9,14]. As in our study, all subjects studied were normotensive and BMI was not shown to be directly related to endothelial dysfunction. Moreover, there was no relationship between these lipids and the percentage increase in leptin levels. Therefore, it is unlikely that blood pressure, BMI and the lipid parameters could account for the differences in leptin levels. To our knowledge, no previous study has assessed the effects of simvastatin on leptin and NO in patients with CHD, our results indicated that simvastatin may provide beneficial effects of reducing leptin levels, independent of its lipid-lowering action, which may play an important role in patients with CHD.
Acknowledgement This work was supported by grants from the Foundation of the First Affiliated of Harbin Medical University (Q08-007).
References [1] Ahima RS, Lazar MA. Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 2008;22:1023–31. [2] Asferg C, Mogelvang R, Flyvbjerg A, Frystyk J, Jensen JS, Marott JL, et al. Leptin, not adiponectin, predicts hypertension in the Copenhagen City Heart Study. Am J Hypertens 2010;23:327–33. [3] Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R, et al. Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J Clin Endocrinol Metab 2004;89:2665–71. [4] Bingham NC, Anderson KK, Reuter AL, Stallings NR, Parker KL. Selective loss of leptin receptors in the ventromedial hypothalamic nucleus results in increased adiposity and a metabolic syndrome. Endocrinology 2008;149:2138–48. [5] Cooke JP, Oka RK. Does leptin cause vascular disease? Circulation 2002;106:1904–5. [6] De Rosa S, Cirillo P, Pacileo M, Di Palma V, Paglia A, Chiariello M. Leptin stimulated C-reactive protein production by human coronary artery endothelial cells. J Vasc Res 2009;46:609–17. [7] Gulturk S, Cetin A, Erdal S. Association of leptin with insulin resistance, body composition, and lipid parameters in postmenopausal women and men in type 2 diabetes mellitus. Saudi Med J 2008;29:813–20. [8] Jiao S, Matsuzawa Y, Matsubara K, Kubo M, Tokunaga K, Odaka H, et al. Abnormalities of plasma lipoproteins in a new genetically obese rat with non-insulin-dependent diabetes mellitus (Wistar fatty rat). Int J Obes 1991;15:487–95. [9] Koncsos P, Seres I, Harangi M, Illyes I, Jozsa L, Gonczi F, et al. Human paraoxonase-1 activity in childhood obesity and its relation to leptin and adiponectin levels. Pediatr Res 2010;67:309–13. [10] Mastronardi CA, Yu WH, McCann SM. Resting and circadian release of nitric oxide is controlled by leptin in male rats. Proc Natl Acad Sci U S A 2002;99:5721–6. [11] Mendez-Sanchez N, Gonzalez V, King-Martinez AC, Sanchez H, Uribe M. Plasma leptin and the cholesterol saturation of bile are correlated in obese women after weight loss. J Nutr 2002;132:2195–8. [12] Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339–43. [13] Morton NM, Emilsson V, de Groot P, Pallett AL, Cawthorne MA. Leptin signalling in pancreatic islets and clonal insulin-secreting cells. J Mol Endocrinol 1999;22:173–84. [14] Mulligan K, Khatami H, Schwarz JM, Sakkas GK, DePaoli AM, Tai VW, et al. The effects of recombinant human leptin on visceral fat, dyslipidemia, and
Y.-M. Sun et al. / Peptides 31 (2010) 1205–1207 insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 2009;94:1137–44. [15] Nelson SM, Freeman DJ, Sattar N, Johnstone FD, Lindsay RS. IGF-1 and leptin associate with fetal HDL cholesterol at birth: examination in offspring of mothers with type 1 diabetes. Diabetes 2007;56:2705–9. [16] Soro A, Jauhiainen M, Ehnholm C, Taskinen MR. Determinants of low HDL levels in familial combined hyperlipidemia. J Lipid Res 2003;44:1536–44.
1207
[17] VanPatten S, Ranginani N, Shefer S, Nguyen LB, Rossetti L, Cohen DE. Impaired biliary lipid secretion in obese Zucker rats: leptin promotes hepatic cholesterol clearance. Am J Physiol Gastrointest Liver Physiol 2001;281:G393–404. [18] Wu ZH, Zhao SP, Ye HJ. The beneficial effects of high-density lipoprotein on adipocytes may relate to its anti-atherogenic properties. Med Hypotheses 2006;67:1195–9.