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Pediatric obesity is a chronic and growing problem for which new ideas about the biologic basis of obesity offer hope for effective solutions. Prevalence of pediatric and adult obesity is increasing despite a bewildering array of treatment programs and severe psychosocial and economic costs. The definition of obesity as an increase in fat mass, not just an increase in body weight, has profound influence on the understanding and treatment of obesity. In principle, body weight is determined by a balance between energy expenditure and energy intake, but this observation does not by itself explain obesity. There is surprisingly little evidence that the obese overeat and only some evidence that the obese are more sedentary. Understanding of the biologic basis of obesity has grown rapidly in the last few years, especially with the identification of a novel endocrine pathway involving the adipose tissue secreted hormone leptin and the leptin receptor that is expressed in the hypothalamus. Plasma leptin levels are strongly correlated with body fat mass and are regulated by feeding and fasting, insulin, glucocorticoids, and other factors, consistent with the hypothesis that leptin is involved in body weight regulation and may even be a satiety factor (Fig. 2, Table 1). Leptin injections have been shown to reduce body weight of primates, although human clinical trials will not be reported until summer 1997. So many peptides influencing feeding have been described that one or more may have therapeutic potential (Fig. 2, Table 1). Although the complexity of pathways regulating body weight homeostasis slowed the pace of understanding underlying mechanisms, these complexities now offer many possibilities for novel therapeutic interventions (Fig. 2). Obesity is a major risk factor for insulin resistance and diabetes, hypertension, cancer, gallbladder disease, and atherosclerosis. In particular, adults who were obese as children have increased mortality independent of adult weight. Thus, prevention programs for children and adolescents will have long-term benefits. Treatment programs focus on modification of energy intake and expenditure through decreased calorie intake and exercise programs. Behavior-modification programs have been developed to increase effectiveness of these intake and exercise programs. These programs can produce short-term weight loss. Long-term losses are more modest but achieved more successfully in children than in adults. Several drug therapies for obesity treatment recently have been approved for adults that produce sustained 5% to 10% weight losses but experience with their use in children is limited. Identification of the biochemical pathways causing obesity by genetic approaches could provide the theoretic foundation for novel, safe, and effective obesity treatments. The cloning of leptin in 1994 has already led to testing the efficacy of leptin in clinical trials that are now underway. Although novel treatments of obesity are being developed as a result of the new biology of obesity, prevention of obesity remains an important goal.
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PMID:Pediatric obesity. An overview of etiology and treatment. 913 Sep 24

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.
Atherosclerosis 1997 Jul 25
PMID:Serum leptin levels are independently correlated with two measures of HDL. 924 70

Hyperleptinemia is considered to be one of predictors of early atherosklerosis complications. This stimulated us to investigate differences between leptinemia in persons with accelerated atherosclerosis and leptinemia in probands without atherosclerosis complications. The study also verified whether leptinemia and its relationship to other anthropometric and biochemical parameters can differ in hypolipemic-treated probands and hypolipemic-untreated individuals. We examined 89 probands with accelerated atherosclerosis. The controls were 20 persons without any signs of accelerated atherosclerosis. Probands with accelerated atherosclerosis had a slight hyperglycemia and were slightly obese, but they did not meet criteria of metabolic cardiovascular syndrome. No significant differences between both groups under study were found in terms of anthropometric and biochemical parameters (BMI, % body fat, glycemia, insulin, C-peptide, intact proinsulin, total proinsulin cholesterol, HDL, triglycerides, LDL, homeostatic model of insulin secretion and resistance). Leptin concentration was not different as well. Stratification into males and females showed that women had a significantly higher leptinemia and fat tissue mass. Other biochemical parameters were similar in both groups. We suppose that in individuals without signs of metabolic syndrome, leptinemia does not belong among predictors of accelerated atherosclerosis. The accelerated atherosclerosis persons were then divided into subgroups according to medication (28 probands--pravastatin Lipostat 20, 15 probands--phenofibrate Lipanthyl 200M, 9 probands--simvastatin Zocor 20, 47 probands--no hypolipemic medication). No significant differences between the groups were found in terms of the analysed anthropometric and biochemical parameters, except leptinemia. The pravastatin-medicated probands had a significantly lower leptinemia (significant at 99% significance level) which was evidently sex-related than other patients. The pravastatin-administered persons showed no correlation between leptinemia and body fat mass (in contrast to other groups where such a correlation was highly statistically significant). These findings can be explained by a still unclear effect of pravastatin on insulin metabolism and on other factors involved in leptin synthesis and elimination. Thus, a new therapeutic effect of pravastatin can be supposed. This may account for a highly favourable effect of pravastatin on reduced manifestations of atherosclerosis complications event at a low LDL cholesterol decrease (particularly in persons with metabolic cardiovascular syndrome).
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PMID:[Serum leptin, early atherosclerosis and hypolipidemia (a new, previously undescribed effect of pravastatin, a hypolipemic agent)]. 1042 91

Leptin, the satiety hormone expressed almost exclusively in adipose tissue, is a marker of body fat accumulation in humans. Recent studies have shown that plasminogen activator inhibitor-1 (PAI-1), a prothrombotic factor associated with atherosclerosis complications, is also produced in adipose tissue. The objective of the present study was to determine whether PAI-1 antigen plasma concentrations are associated with leptin plasma levels or the body fat mass (FM) independently of the variables known to influence PAI-1 production. Sixty-one nondiabetic women aged 18 to 45 years with a wide range of values for the body mass index ([BMI] 18.1 to 37.7 kg/m2) were evaluated for (1) body FM and fasting plasma levels of (2) PAI-1 antigen, (3) PAI-1 activity, (4) leptin, (5) insulin, (6) blood glucose, and (7) lipids (cholesterol, high-density lipoprotein [HDL]-cholesterol, and triglycerides [TG]). Body FM and fat-free mass (FFM) were estimated during fasting conditions by the bioimpedance analysis (BIA) method using a tetrapolar device. Body fat distribution was evaluated by the waist circumference and the waist to hip ratio (WHR). FM was directly associated with both PAI-1 antigen (r = .585, P < .001) and PAI-1 activity (r = .339, P < .001). Seemingly, leptin was positively related to both PAI-1 antigen (r = .630, P < .001) and PAI-1 activity (r = .497, P < .001). Moreover, both PAI-I antigen and PAI-1 activity were directly correlated with FFM (r = .285, P < .05, and r = .336, P < .01, respectively), BMI (r = .594, P < .001, and r = .458, P < .001, respectively), and WHR (r = .510, P < .001, and r = .391, P < .005, respectively). Insulin was directly related to PAI-1 antigen (r = .540, P < .001), PAI-1 activity (r = .259, P < .05), leptin (r = .447, P < .001), and FM (r = .435, P < .001). The association between PAI-1 antigen (dependent variable) and leptin or FM was tested by a stepwise regression model simultaneously including leptin, FM, BMI, WHR, age, FFM, and fasting insulin, blood glucose, TG, cholesterol, and HDL-cholesterol as independent variables. PAI-1 antigen maintained a significant positive independent relationship only with leptin (t = 2.923, P < .01), insulin (t = 3.489, P < .001), and fasting blood glucose (t = 2.092, P < .05), and a negative independent relationship with HDL-cholesterol (t = -2.634, P < .05). In conclusion, the strong relationship between PAI-1 antigen and leptin irrespective of other variables known to influence these factors seems to indicate that leptin per se may potentially increase PAI-1 plasma concentrations in obese subjects.
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PMID:Plasma plasminogen activator inhibitor-I is associated with plasma leptin irrespective of body mass index, body fat mass, and plasma insulin and metabolic parameters in premenopausal women. 1045 58

Leptin receptors are supposed to have signal effects and are located in most tissues in the organism but we failed to find literary data on concentration (measurement) of leptin receptors in the system circulation. We examined by the method of randomized selection the group of 20 patients with manifested atherosclerosis in whom BMI was calculated. Then we analyzed concentration of leptin receptor (double sandwich ELISA, standard recombinant human leptin), leptin, glucose, insulin, proinsulin, CRP and uric acid in the serum. The control group consisted of 103 probands without signs of atherosclerosis or other manifested diseases. The control group was subjected to determination of BMI, leptin and leptin receptor in the serum. Concentration of leptin receptor does not differ significantly between the patients with atherosclerosis and normal population. Probands with atherosclerosis showed a very close negative correlation between concentration of leptin receptor and leptinemia which is absent in normal population.
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PMID:Determination of leptin receptor in the serum and relations to laboratory and anthropological parameters in patients with atherosclerotic complications. 1074 33

Leptin values were investigated during four week treatment of obese children by weight reducing diet and dosed physical activity, controlled by sport-testers. Leptin values correlated significantly with BMI and HDL-cholesterol at the beginning of spa treatment and at the end of treatment. Values of leptin at the beginning of treatment correlated with fasting insulinaemia. There were no changes in leptin values during oral glucose tolerance test. Significant decrease of BMI, total cholesterol, LDL-cholesterol, triglycerides, systolic BP and leptin values appeared after four week treatment. Leptin values did not correlate with total or LDL-cholesterol at the beginning or at the end of the treatment and leptin values were not predictive for development of atherosclerosis.
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PMID:[Leptinemia in obese children during health spa therapy]. 1095 31

Leptin is produced in adipose tissue and acts in the hypothalamus to regulate food intake. However, recent evidence also indicates a potential for direct roles for leptin in peripheral tissues, including those of the immune system. In this study, we provide direct evidence that macrophages are a target tissue for leptin. We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin. Leptin also stimulates both phosphoinositide 3-kinase (PI 3-kinase) activity and tyrosine phosphorylation of JAK2 and STAT3 in these cells. We investigated the effects of leptin on hormone-sensitive lipase (HSL), which acts as a neutral cholesterol esterase in macrophages and is a rate-limiting step in cholesterol ester breakdown. Leptin significantly increased HSL activity in J774.2 macrophages, and these effects were additive with the effects of cAMP and were blocked by PI 3-kinase inhibitors. Conversely, insulin inhibited HSL in macrophages, but unlike adipocytes, this effect did not require PI 3-kinase. These results indicate that leptin and insulin regulate cholesterol-ester homeostasis in macrophages and, therefore, defects in this process caused by leptin and/or insulin resistance could contribute to the increased incidence of atherosclerosis found associated with obesity and type 2 diabetes.
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PMID:Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways. 1133 38

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
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PMID:Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. 1134 29

Leptin-deficient mice (ob/ob) are an excellent murine model for obesity, insulin resistance, and diabetes, all of which are components of a multiple risk factor syndrome that, along with hypercholesterolemia, precipitates a potential high risk for atherosclerosis. In the current study, we show an unexpectedly severe hyperlipidemia in ob/ob mice on a background of low density lipoprotein receptor (LDLR) deficiency (-/-). Doubly mutant mice (LDLR-/-;ob/ob) exhibited striking elevations in both total plasma cholesterol (TC) and triglyceride (TG) levels (1715 +/- 87 and 1016 +/- 172 mg/dl, respectively), at age 3-4 months, resulting in extensive atherosclerotic lesions throughout the aorta by 6 months. Lipoprotein analyses revealed the elevated TC and TG levels to be due to a large increase in an apoB-containing broad-beta remnant lipoprotein fraction. While fasting, diet restriction, and low level leptin treatment significantly lowered TG levels, they caused only slight changes in TC levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggest that leptin deficiency increased hepatic triglyceride production but did not change cholesterol production in ob/ob mice regardless of their LDLR genotype. These data provide evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice are caused by distinct mechanisms and point to the possibility that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. This model will be an excellent tool for future studies on the relationship between impaired fuel metabolism, increased plasma remnant lipoproteins, diabetes, and atherosclerosis.
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PMID:Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor. 1144 60

Leptin, the product of ob gene, is an endocrine hormone that regulates adipose tissue mass. Recently, leptin has been found to generate a growth signal involving a tyrosine kinase-dependent intracellular pathway and promote angiogenic processes via activation of leptin receptor (Ob-R) in endothelial cells. However, it is not clear how leptin functions to promote multi-step processes involved in the neovascularization at the atherosclerotic plaque. We have examined the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) and Ob-R in human atherosclerotic lesions, leptin-mediated angiogenesis in vivo and in vitro. Immunohistochemical analysis of human atherosclerotic aorta revealed an increased expression of Ob-R in the intima of neorevascularized regions and of both MMPs and TIMPs predominantly in the endothelial lining of intimal neovessels and macrophages/foam cells. In the rat corneal angiogenesis assay, leptin elicited a comparable sensitivity of angiogenic activity to those of vascular endothelial growth factor (VEGF). The immunohistological analysis of the leptin-treated rat cornea showed definitive rises in Ob-R, MMPs and TIMPs expression as well as those of VEGF receptor (VEGFR-1). Leptin (10-40 ng/ml) induced proliferation of the human umbilical vein endothelial cells (HUVECs) and elevation of MMP-2, MMP-9, TIMP-1, and TIMP-2 expression in a dose-dependent manner. Leptin also induced increases of MMP-2, MMP-9, TIMP-1, and Up-regulated the human coronary artery smooth muscle cells (HCASMCs). These findings suggest that leptin, a hormone with pluralistic properties including a mitogenic activity on vascular endothelial cells, plays a role in matrix remodeling by regulating the expression of MMPs and TIMPs. Taken together, our findings further provide evidences for leptin's role as an angiogenesis inducer in the normal organ (rat cornea) and in aberrant vasculature under duress like atherosclerosis.
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PMID:Potential role of leptin in angiogenesis: leptin induces endothelial cell proliferation and expression of matrix metalloproteinases in vivo and in vitro. 1146 Aug 88


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