leptin and Hypercholesterolemia

The effects of statins on insulin sensitivity, metabolic homeostasis and adipokines in humans are controversial. Several studies have investigated the impact of statin therapy on plasma leptin concentrations but the results have been inconsistent. The aim of the present study was to conduct a systematic review and meta-analysis of available evidence to calculate the effect size of statin therapy in changing serum leptin concentrations.. A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of statins on plasma leptin concentrations. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk-of-bias evaluation and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size.. Six trials, with a total of 425 subjects, met the eligibility criteria. Overall, statin therapy had no significant effect on leptin levels (weighted mean difference -0.32 ng ml. Unless more consistent evidence becomes available in the future, the hypothesis of a relationship between statin use and serum leptin concentrations seem to be unfounded.

Topics: Data Interpretation, Statistical; Dose-Response Relationship, Drug; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Leptin; Randomized Controlled Trials as Topic

It is well known that hypercholesterolemia can lead to atherosclerosis and coronary heart disease. Adipose tissue represents an active endocrine and metabolic site, which might be involved in the development of chronic disease. Because adipose tissue is a key site for cholesterol metabolism and the presence of hypercholesterolemia has been shown to induce adipocyte cholesterol overload, it is critical to investigate the role of hypercholesterolemia on normal adipose function. Studies in preadipocytes revealed that cholesterol accumulation can impair adipocyte differentiation and maturation by affecting multiple transcription factors. Hypercholesterolemia has been observed to cause adipocyte hypertrophy, adipose tissue inflammation, and disruption of endocrine function in animal studies. Moreover, these effects can also be observed in obesity-independent conditions as confirmed by clinical trials. In humans, hypercholesterolemia disrupts adipose hormone secretion of visfatin, leptin, and adiponectin, adipokines that play a central role in numerous metabolic pathways and regulate basic physiologic responses such as appetite and satiety. Remarkably, treatment with cholesterol-lowering drugs has been shown to restore adipose tissue endocrine function. In this review the role of hypercholesterolemia on adipose tissue differentiation and maturation, as well as on hormone secretion and physiologic outcomes, in obesity and non–obesity conditions is presented.

Topics: Adipocytes; Adiponectin; Adipose Tissue; Adiposity; Animals; Anticholesteremic Agents; Cell Differentiation; Clinical Trials as Topic; Disease Models, Animal; Humans; Hypercholesterolemia; Inflammation; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity

The dialogue between gut hormone, bile acids, and the brain plays an important role in energy homeostasis and the onset of Type 2 diabetes mellitus (T2DM). The present review focuses on: (i) bile acid metabolism and the role of bile acids in the regulation of both glucose homeostasis and the control of hypercholesterolemia; (ii) the role of gut hormones in energy homeostasis; and (iii) translation of the pathophysiology of bile acids and gut hormones into clinical practice. Although definitive mechanisms of action of gut hormones and bile acids have not been elucidated completely, these concepts allow us to understand several pharmacological interventions in the treatment of T2DM. Results from further clinical studies with related therapies will help us determine the role of these treatments in the management of energy homeostasis.

Topics: Bile Acids and Salts; Brain; Gastrointestinal Hormones; Ghrelin; Glucose; Homeostasis; Humans; Hypercholesterolemia; Incretins; Leptin; Receptors, Cytoplasmic and Nuclear; Satiety Response

This study aimed to investigate the possible relationships between adiponectin and leptin, blood lipids such as total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) as well as other clinical biomarkers in hyperlipidemia patients treated with red yeast rice.. 30 patients with primary hyperlipidemia were recruited, treated with red rice yeast capsules 600 mg twice a day for 8 weeks, and followed up for 4 weeks. The primary endpoint was the mean difference in LDL-C from baseline to week 8, while the secondary endpoints were the mean percentage changes from baseline of total cholesterol, TG, HDL-C, adiponectin, and leptin.. At week 8, the decrease in LDL-C and total cholesterol was -38.11 ± 30.90 mg/dl (p < 0.0001) and -44.54 ± 27.46 mg/dl (p < 0.0001), respectively, and the increase in adiponectin was 35.83 ± 67.85 μg/ml (p = 0.017) as compared to baseline. Adiponectin also correlated positively with HDL-C (r2 = 0.39; p = 0.001). Serum leptin correlated negatively with TG (r2 = 0.19; p = 0.035), and there was a trend of correlation between leptin and HDL-C, but this was not statistically significant (r2 = 0.16; p = 0.052).. Red yeast rice can significantly increase adiponectin and can significantly lower LDL-C and total cholesterol levels. Adiponectin correlates positively with HDL-C while serum leptin correlates negatively with TG. Red yeast rice has a potentially protective effect in obesity-related and cardiovascular diseases.

Topics: Adiponectin; Adult; Biological Products; Body Mass Index; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Supplements; Drug Combinations; Female; gamma-Aminobutyric Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Intention to Treat Analysis; Leptin; Lipids; Lovastatin; Male; Medicine, Chinese Traditional; Middle Aged; Treatment Outcome

Intake of dairy fat has long been considered as a risk factor for CVD. Pasture and dietary lipid supplementation have been reported to be reliable strategies in ruminant nutrition, in order to increase the content of α-linolenic acid (ALA), conjugated linoleic acid (CLA) and vaccenic acid (VA), and decrease SFA in milk fat. In the present study, we aimed at verifying whether consumption of a sheep cheese, naturally enriched in ALA, CLA and VA, would modify the plasma lipid and endocannabinoid profiles in mildly hypercholesterolaemic subjects. A total of forty-two adult volunteers (nineteen males and twenty-three females) with diagnosed mildly hypercholesterolaemia (total cholesterol 5·68-7·49 mmol/l) were randomly assigned to eat 90 g/d of a control or enriched cheese for 3 weeks, with a cross-over after 3 weeks of washout. Plasma lipids, endocannabinoids, adipokines and inflammatory markers were measured. The intake of enriched cheese significantly increased the plasma concentrations of CLA, VA, the n-3 fatty acids ALA and EPA, and more remarkably decreased that of the endocannabinoid anandamide. LDL-cholesterol decreased significantly (7%). No changes were detected in the levels of inflammatory markers; however, a significant correlation was found between the plasma levels of anandamide and leptin. The control cheese modified none of the parameters measured. The results obtained do not support the view that intake of dairy fat is detrimental to hypercholesterolaemic subjects. Indeed, they show that a naturally enriched cheese possesses beneficial properties, since it ameliorates the plasma lipid profile, and more remarkably reduces endocannabinoid biosynthesis.

Topics: Adult; Analysis of Variance; Cheese; Cholesterol, LDL; Dietary Fats; Endocannabinoids; Female; Food, Fortified; Humans; Hypercholesterolemia; Leptin; Linoleic Acids; Male; Middle Aged; Oleic Acids; Single-Blind Method

Apelin, a relatively newer adipokine with various actions in cardiovascular system, was recently reported to decrease in dyslipidemia. The present study addresses whether plasma apelin increases after hypolipidemic intervention either through therapeutic life style change (TLC) or statin treatment. A total of 134 patients were subjected to treatment with a TLC intervention for 12 weeks. Of these, 116 successfully completed the period, and LDL-cholesterol level decreased to target level (<160 mg/dL) in 54 (46.5%) individuals. The remaining 62 patients were treated with rosuvastatin for 12 weeks, and 56 of them finished the study. Circulating apelin, adiponectin, leptin, TNF-alpha, hsCRP and insulin levels were determined both at baseline and after TLC intervention and statin treatment. There was no significant change in plasma apelin concentration in patients unresponsive to TLC (p=0.110). LDL-cholesterol lowering either through TLC or statin treatment was accompanied by an increase in plasma apelin (p=0.000, p=0.020) and adiponectin (p=0.001, p=0.011). Serum leptin decreased after successful TLC (p=0.042/male, p=0.023/female) but not after statin treatment (p=0.959/male, p=0.134/female). Serum TNF-alpha (p=0.902) and plasma hsCRP (p=0.135) levels remained unchanged after TLC intervention but decreased after statin treatment (p=0.000, p=0.023, respectively). Plasma insulin and homeostasis model assessment scores decreased after TLC (p=0.000 for both) but not rosuvastatin treatment (p=0.865, p=0.722, respectively). In conclusion, independent of the type of treatment, reduction in LDL-cholesterol levels in otherwise healthy people with isolated dyslipidemia results in an increase in plasma apelin concentration. More experiments may show a substantial role for this peptide in the mechanism of atherosclerosis.

Topics: Adiponectin; Adult; Apelin; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Diet; Exercise; Female; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Middle Aged; Pyrimidines; Risk Reduction Behavior; Rosuvastatin Calcium; Sulfonamides; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Lipophilic and hydrophilic statins have different effects on adiponectin and insulin resistance in experimental studies and different effects on the rate of onset of new diabetes in large scale clinical studies. Therefore, we hypothesized that simvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients.. This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Forty-three patients were given placebo, simvastatin 20mg, or pravastatin 40 mg, respectively once daily for 2 months.. Simvastatin and pravastatin therapy significantly changed lipoprotein levels and improved flow-mediated dilation after 2 months when compared with baseline (P<0.001) or placebo treatment (P<0.001 by ANOVA). Simvastatin therapy significantly increased insulin levels (mean % changes; 127%, P=0.014) and decreased plasma adiponectin levels (10%, P=0.012) and insulin sensitivity as assessed by QUICKI (6%, P=0.007) when compared with baseline. By contrast, pravastatin therapy did not significantly change insulin levels (-3%, P=0.437) but significantly increased plasma adiponectin levels (9%, P=0.011) and insulin sensitivity (6%, P=0.008) when compared with baseline. In addition, these effects of simvastatin were significant when compared with pravastatin (P<0.001 for insulin levels by ANOVA on Ranks, P<0.001 for adiponectin and P=0.001 for QUICKI by ANOVA). When compared with baseline, simvastatin significantly increased plasma leptin levels (35%, P=0.028), but pravastatin did not (1%, P=0.822).. Despite causing comparable changes in lipoprotein and endothelium-dependent dilation, simvastatin and pravastatin therapy had differential metabolic effects in hypercholesterolemic patients that may be clinically relevant.

Topics: Adiponectin; C-Reactive Protein; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin; Insulin Resistance; Leptin; Lipoproteins; Male; Middle Aged; Pravastatin; Simvastatin; Treatment Outcome; Vasodilation

Adipokines are substances produced by the adipose tissue that may play significant roles in the mechanisms contributing to the development of atherosclerosis. Thiazolidinediones have been shown to improve endothelium-dependent vasodilation and to exert multiple antiatherosclerotic effects. This study tested the hypotheses that nondiabetic patients with cardiovascular risk factors have altered levels of adipokines that can be modified by pioglitazone treatment. Eighty patients with hypertension or hypercholesterolemia were in a double-blinded, placebo-controlled, crossover study. In each treatment phase, patients received pioglitazone 45 mg/day or placebo for 8 weeks. Endothelial function studies and biochemical assays were performed at the end of each 8-week treatment period. Twenty-two normal volunteers, matched with patients for age, gender, and body mass index, were recruited as a control group. Compared with controls, placebo-treated patients had lower adiponectin levels (11,160 +/- 763 vs 6,078 +/- 385 ng/ml, p <0.001) and similar plasma leptin levels (21.5 +/- 3.8 vs 16.2 +/- 1.5 ng/ml, p = 0.128) and resistin levels (5.1 +/- 0.4 vs 4.4 +/- 0.2 ng/ml, p = 0.250). In patients, pioglitazone treatment markedly increased adiponectin (+121%, p <0.001) and decreased resistin (-10.5%, p = 0.03). Leptin was not significantly decreased (-7.1%, p = 0.10). In multivariate analysis, pioglitazone-induced changes in endothelial reactivity to acetylcholine were the only significant predictor of increases in adiponectin. In conclusion, in nondiabetic patients with major cardiovascular risk factors, pioglitazone treatment beneficially influences circulating adipokine levels. The relation between the increase in adiponectin levels and the improvement in endothelial vasodilator activity suggests a mechanistic link between vascular effects and adiponectinemia.

Topics: Adipokines; Adiponectin; Adult; Aged; Case-Control Studies; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypercholesterolemia; Hypertension; Hypoglycemic Agents; Leptin; Male; Middle Aged; Pioglitazone; PPAR gamma; Resistin; Thiazolidinediones; Treatment Outcome

The investigation of serum leptin, ghrelin, insulin, seratonin hormones, NO, total oxidant/antioxidant status and brain cannaboid 1 receptor protein and apoptotic cell levels in atorvastatin and Lactobacillus acidophilus administrated experimental hypercholesterolemia was aimed in the project.. The addition of cholesterol to feeds increased the levels of serum cholesterol, insulin and leptin levels; on the other hand, reduced the levels of serotonin and ghrelin. In hypercholesterolemia, total oxidant and NO levels were increased, and total antioxidant levels were decreased.. The results showed that administrations of L. acidophilus and atorvastatin might be recommended for treatment of hypercholesterolemia.

Topics: Animals; Antioxidants; Atorvastatin; Cholesterol; Ghrelin; Hypercholesterolemia; Insulins; Lactobacillus acidophilus; Leptin; Oxidative Stress; Probiotics; Rats; Serotonin

The endoplasmic reticulum (ER) plays a pivotal role in maintaining cellular metabolic homeostasis. ER stress refers to the accumulation of misfolded proteins, which can trigger an unfolded protein response for survival or death in the cells. Diallyl disulfide (DADS), a major active compound in garlic, has many health benefits for patients with metabolic diseases, especially cardiovascular or fatty liver diseases. However, its role in attenuating hypercholesterolemia by suppressing ER stress remains unknown. Therefore, in this study, we determined whether DADS supplementation could reduce ER stress in apolipoprotein E-deficient (ApoE. ApoE. The metabolic parameters showed that increases in fat weight, leptin resistance, and hypercholesterolemia were reversed in DADS-supplemented mice (p < 0.05). In addition, DADS ameliorated not only the protein of ER stress markers, phospho-eukaryotic initiation factor 2 subunit alpha and C/EBP homologous protein in the liver (p < 0.05) but also glucose-related protein 78 localization in the aorta.. This indicates that DADS inhibits diet-induced hypercholesterolemia, at least in parts by regulating ER stress markers. DADS may be a good candidate for treating individuals with diet-induced hypercholesterolemia.

Topics: Animals; Apolipoproteins; Apolipoproteins E; Diet, Western; Endoplasmic Reticulum Stress; Hypercholesterolemia; Leptin; Mice

Topics: Adiponectin; Aged; Aged, 80 and over; Ankle Brachial Index; Aorta, Abdominal; Cardiovascular Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Case-Control Studies; Comorbidity; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Leptin; Male; Middle Aged; Overweight; Peripheral Arterial Disease; Polymyalgia Rheumatica; Resistin; Risk Factors; Smoking; Ultrasonography, Doppler, Color; Vascular Stiffness

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.

Topics: Animals; Cardiomegaly; Diet, High-Fat; Glucose Intolerance; Hypercholesterolemia; Insulin Resistance; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocytes, Cardiac; Obesity; Receptor, Angiotensin, Type 2

Stabilin-1 (STAB1) is a scavenger receptor expressed on alternatively activated macrophages and sinusoidal endothelial cells. Its ligands include oxidized low-density lipoprotein (LDL) and the extracellular matrix glycoprotein SPARC and it is present in both human and murine atherosclerotic lesions. We aimed to investigate the effect of specific deletion of STAB1 in bone marrow-derived cells, including macrophages on atherosclerotic lesion formation in mice.. Lethally irradiated hypercholesterolemic LDL receptor knockout mice received either wildtype (WT) or STAB1 knockout (STAB1 KO) bone marrow. Bone marrow transplanted mice were fed a Western-type diet for 9 weeks to induce atherosclerotic lesion formation.. Interestingly, LDL receptor knockout mice reconstituted with STAB1 KO bone marrow showed increased body weight gain (two-way ANOVA: p < 0.001) and larger white adipocyte cell sizes (43% increase in cell area; p < 0.05) as compared to WT bone marrow transplanted mice, which correlated positively (r = 0.82; p < 0.001). This was paralleled by a significant increase in white adipose tissue relative mRNA expression levels of the adipokine leptin (+94% p < 0.05). Despite these changes, no differences in serum lipid levels, the extent of in vivo macrophage foam cell formation or circulating leukocyte concentrations were observed. Moreover, the size and composition of atherosclerotic lesions was not different between the two experimental groups.. Bone marrow-specific Stabilin-1 deletion does not affect the susceptibility for atherosclerosis in mice. However, the increased body weight gain and adipocyte cell size highlight a potential role for leukocyte STAB1 in the development of metabolic disorders.

Topics: Adipocytes, White; Adipose Tissue, White; Animals; Aortic Diseases; Atherosclerosis; Cell Adhesion Molecules, Neuronal; Diet, Western; Disease Models, Animal; Foam Cells; Hypercholesterolemia; Leptin; Male; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Receptors, LDL; Weight Gain

Olanzapine (OLZ) is efficacious whereas leads to adverse metabolic effects thus lead to higher risk of cardiovascular diseases (CVD) on schizophrenia. Cytokines have been found associated with metabolic disorders. Therefore, pretreatment prediction of OLZ-induced adverse metabolic effects is urgently needed. To investigate if baseline cytokine levels could become biomarkers for pathogenesis of schizophrenia or prediction for OLZ-induced adverse metabolic effects, we recruited 75 participants, including 23 schizophrenia inpatients, who were antipsychotic-free over the past 6 months or first episode and drug-naive and 52 matched health controls, in our prospective cohort study and cross-sectional study. We simultaneously examined 7 serum cytokine levels (IFN-γ, IL-1ra, IL-1β, IL-8, TNF-α, MCP-1, VEGF) before OLZ treatment by using liquid suspension array technique and obtained clinical correlates at 4-week intervals in total 8 weeks. The psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). The metabolic parameters were BMI, TG, total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein a, fasting glucose, HbA1c, insulin, and leptin. At baseline, IL-1ra and MCP-1 levels in schizophrenia were significantly higher than health controls (t = 4.55, P = 0.0001, t = 3.08 P = 0.003). BMI, fasting insulin, cholesterol, triglyceride, LDL, ApoB and leptin were significantly increased in patients with schizophrenia after 8 weeks of olanzapine treatment. Correlation analysis showed that the baseline IL-1ra level were significantly correlated with the increased levels of cholesterol (P = 0.004), LDL (P = 0.005), ApoB (P = 0.018) and leptin (P = 0.010), but not with the increased BMI, insulin or triglycerides. Further stepwise multiple linear regression analysis indicated that IL-1ra levels prior to treatment remained significantly associated with increased levels of cholesterol, LDL, ApoB and leptin. Above all, higher IL-1ra and MCP-1 levels may be biomarkers indicating pathogenesis of schizophrenia. Higher serum levels of IL-1ra may predict subsequent higher possibility of hypercholesterolemia and hyperleptinemia following OLZ treatment in schizophrenia patients.

Topics: Adult; Antipsychotic Agents; Biomarkers; Chemokine CCL2; Cross-Sectional Studies; Female; Hospitalization; Humans; Hypercholesterolemia; Interleukin 1 Receptor Antagonist Protein; Leptin; Male; Olanzapine; Prospective Studies; Schizophrenia

Non-digestible carbohydrates present in cereals such as fructans and arabinoxylans represent promising prebiotic nutrients to prevent the development of obesity and related metabolic disorders.. The aim of this study was to determine the corrective effects of wheat bran-derived arabinoxylan oligosaccharides in obese mice fed a western diet (WD). WD was given for 4 weeks before wheat bran extract (WBE) supplementation (5%) for an additional 4 weeks, whereas a control group received the standard diet.. Bifidogenic effect of WBE was evidenced by an induction of both Bifidobacterium animalis and Bifidobacterium pseudolongum in the caecal content. WBE supplementation normalised WD-induced fat-mass expansion, steatosis, hypercholesterolemia, hyperleptinemia, hyperglycemia and hyperinsulinemia reaching the values of control mice. The reduced glucose-dependent insulinotropic polypeptide (GIP) release observed in WD + WBE mice may be a protective mechanism in terms of reducing adipose tissue storage, hepatic steatosis and glucose homoeostasis.. We found that WBE completely abolished WD-induced metabolic disorders. Those results might be useful to take into account nutritional advices to treat obesity and related metabolic disorders such as type 2 diabetes, hypercholesterolaemia and fatty liver diseases when obesity was already established.

Topics: Adipose Tissue; Animals; Bifidobacterium; Blood Glucose; Cecum; Diabetes Mellitus, Type 2; Diet, Western; Dietary Fiber; Fatty Liver; Gastric Inhibitory Polypeptide; Hypercholesterolemia; Hyperglycemia; Hyperinsulinism; Leptin; Liver; Male; Metabolic Diseases; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligosaccharides; Prebiotics; Triticum; Xylans

A prevalent side-effect of simvastatin is attenuated glucose homeostasis. The underlying mechanism is unknown, but impaired lipid metabolism may provide the link. The aim of this study was to investigate whether simvastatin-treated patients had a lower capacity to oxidize lipids and reduced expression of the major proteins regulating lipid uptake, synthesis, lipolysis, and storage in skeletal muscle than matched controls.. Ten men were treated with simvastatin (HbA1c: 5.7 ± 0.1%), and 10 healthy men (HbA1c: 5.2 ± 0.1%) underwent an oral glucose tolerance test and a muscle biopsy was obtained. Fat oxidation rates were measured at rest and during exercise. Western blotting was used to assess protein content.. Patients treated with simvastatin had impaired glucose tolerance compared with control subjects, but fat oxidation at rest and during exercise was compatible. Skeletal muscle protein content of CD36, lipoprotein lipase (LPL), and diacylglycerol acyltransferase (DGAT) 1 were lower, and DGAT 2 tended to be lower in patients treated with simvastatin.. Patients treated with simvastatin had a reduced capacity to synthesize FA and diacylglycerol (DAG) into triacylglycerol in skeletal muscle compared to matched controls. Decreased lipid synthesis capacity may lead to accumulation of lipotoxic intermediates (FA and DAG) and hence impair glucose tolerance.

Topics: Adiponectin; Adult; Blood Glucose; Glucose Tolerance Test; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Insulin Resistance; Leptin; Lipid Metabolism; Male; Middle Aged; Muscle, Skeletal; Simvastatin

The present investigation was designed to examine the possible additive hypolipidemic effect of carvacrol (CARV) in combination with simvastatin (SIM) on poloxamer 407 (P407)-induced hyperlipidemia. Rats were injected with P407, (500 mg/ kg; i.p.), twice a week, for 30 days. Treatment was carried out by administration of SIM (20 mg/kg/day; p.o.) or CARV (50 mg/kg/day; p.o.) or combination of them. Treatment with CARV significantly decreased total cholesterol, triglycerides, low-density lipoprotein, atherogenic index, leptin, and increased high-density lipoprotein and adiponectin. Moreover, CARV potentiated the hypolipidemic effect of SIM. Both SIM and CARV alleviated the oxidative stress induced by P407. Interestingly, CARV, when combined with SIM, significantly ameliorated SIM-induced liver and muscle injury by reducing the level of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and myoglobin and restoring the normal histological picture of both liver and muscle as well as apoptosis.

Topics: Adiponectin; Animals; Anticholesteremic Agents; Caspase 3; Catalase; Cholesterol; Cymenes; Drug Combinations; Drug Evaluation, Preclinical; Drug Synergism; Glutathione; Hypercholesterolemia; Leptin; Liver; Male; Monoterpenes; Muscle, Skeletal; Organ Size; Rats, Sprague-Dawley; Simvastatin; Triglycerides

Cytochrome oxidase IV complex regulates energy production in mitochondria. Therefore, we determined the relation of COX genes with atherosclerosis in mice and pigs.. First, we compared atherosclerosis in the aortic arch of age-matched (24 weeks) C57BL/6J control (n = 10), LDL-receptor deficient (n = 8), leptin-deficient ob/ob (n = 10), and double knock-out (lacking LDL-receptor and leptin) mice (n = 12). Low aortic mitochondria-encoded cytochrome oxidase 1 in obese diabetic double knock-out mice was associated with a larger plaque area and higher propensity of M1 macrophages and oxidized LDL. Caloric restriction increased mitochondria-encoded cytochrome oxidase 1 and reduced plaque area and oxidized LDL. This was associated with a reduction of titer of anti-oxidized LDL antibodies, a proxy of systemic oxidative stress. Low of mitochondria-encoded cytochrome oxidase 1 was related to low expression of peroxisome proliferative activated receptors α, δ, and γ and of peroxisome proliferative activated receptor, gamma, co-activator 1 alpha reflecting mitochondrial dysfunction. Caloric restriction increased them. To investigate if there was a diabetic/obesity requirement for mitochondria-encoded cytochrome oxidase 1 to be down-regulated, we then studied atherosclerosis in LAD of hypercholesterolemic pigs (n = 37). Pigs at the end of the study were divided in three groups based on increasing LAD plaque complexity according to Stary (Stary I: n = 12; Stary II: n = 13; Stary III: n = 12). Low mitochondria-encoded cytochrome oxidase 1 in isolated plaque macrophages was associated with more complex coronary plaques and oxidized LDL. Nucleus-encoded cytochrome oxidase 4I1 and cytochrome oxidase 10 did not correlate with plaque complexity and oxidative stress. In mice and pigs, MT-COI was inversely related to insulin resistance.. Low MT-COI is related to mitochondrial dysfunction, oxidative stress and atherosclerosis and plaque complexity.

Topics: Animals; Aorta, Thoracic; Atherosclerosis; Caloric Restriction; Coronary Vessels; Cytochrome-c Oxidase Deficiency; Diabetes Mellitus, Experimental; Electron Transport Complex IV; Energy Metabolism; Hypercholesterolemia; Insulin Resistance; Leptin; Lipoproteins, LDL; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mitochondria; Nuclear Receptor Coactivators; Oxidative Stress; Peroxisome Proliferator-Activated Receptors; Plaque, Atherosclerotic; Receptors, LDL; Receptors, Leptin; Swine; Swine, Miniature

Conflicting evidence concerning leptin in atherosclerosis has been published. Furthermore, dose-dependent effects of leptin on atherogenesis have not been studied.. Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR(-/-);ob/ob) mice were treated with saline, 0.1, 0.5, or 3.0mg/kg body weight (BW)/d recombinant leptin over 12weeks starting at 8weeks of age. Aortic root and brachiocephalic artery (BCA) atherosclerotic lesions were analyzed by oil red O staining. Furthermore, glucose homeostasis, lipid metabolism, and liver function including tissue studies were assessed in all animals.. Leptin treatment dose-dependently decreased BW in LDLR(-/-);ob/ob mice as compared to saline. Mice in the 0.1 and 0.5mg/kgBW/d groups remained heavier (i.e. subphysiological leptin dose) and in the 3.0mg/kgBW/d group had similar weight (i.e. physiological leptin dose) as compared to non-leptin-deficient LDLR(-/-) animals. Recombinant leptin dose-dependently reduced plaque area in the aortic root and the BCA by 36% and 58%, respectively. Leptin-mediated reductions of plasma total and LDL-cholesterol (Chol) remained independent predictors for aortic root plaque area. Chol content in liver, as well as hepatic expression of key lipid and proinflammatory genes, were dose-dependently regulated by leptin. Furthermore, leptin treatment increased circulating levels and adipose tissue mRNA expression of the adipokine adiponectin.. Leptin administration within the subphysiological to physiological range diminishes atherosclerotic lesions. Leptin appears to mediate its antiatherogenic effects indirectly through reduction of hypercholesterolemia and liver steatosis, as well as upregulation of insulin-sensitizing and atheroprotective adiponectin.

Topics: Adiponectin; Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol; Fatty Liver; Hypercholesterolemia; Insulin; Leptin; Lipid Metabolism; Male; Mice; Recombinant Proteins

To study the peripheral blood level of leptin and adiponectin and their possible effect on the functional status of the respiratory system in young asthmatic patients in relation to body mass index (BMI) for the optimization of asthma therapy.. Examinations were made in 133 people, including a study group of 93 patients with asthma who were divided into 2 groups according to BMI: 1) those with a BMI of less 25 kg/m2 and 2) those with a BMI of 30 kg/m2 or more, as well as a control group of 40 apparently healthy patients. The investigators studied external respiratory function (ERF), the peripheral blood levels of leptin and adiponectin, the biochemical composition of plasma, by determining total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides.. Lipid metabolic disorders as dyslipidemia and hypercholesterolemia, increased severity of disease, and decreased ERF were recorded in the concomitance of obesity and asthma. The peripheral blood level of leptin in young asthmatic patients with obesity was found to be associated with higher BMI.. A more severe course of disease presenting with decreased ERF, impaired lipid metabolism, and elevated peripheral blood leptin levels were noted in the concomitance of asthma and obesity at a young age.. Цель исследования. Изучить уровень лептина и адипонектина в периферической крови и их возможное влияние на функциональное состояние респираторной системы у больных бронхиальной астмой (БА) молодого возраста в зависимости от индекса массы тела (ИМТ) для оптимизации противоастматической терапии. Материалы и методы. Обследованы 133 человека: 93 больных БА, которых разделили на 2 группы с учетом ИМТ, и 40 практически здоровых добровольцев, составивших группу контроля. В 1-ю группу включили больных БА с ИМТ менее 25 кг/м2, во 2-ю группу - больные БА с ИМТ 30 кг/м2 и более. Изучали функцию внешнего дыхания (ФВД), уровни лептина и адипонектина в периферической крови, биохимический состав плазмы крови с определением общего холестерина (ХС), ХС липопротеидов высокой плотности, ХС липопротеидов низкой плотности, триглицеридов. Результаты. При сочетании ожирения и БА зарегистрированы нарушение липидного обмена по типу дислипидемии и гиперхолестеринемии, увеличение тяжести заболевания, снижения показателей ФВД. Установлено, что уровень лептина в периферической крови у больных БА молодого возраста с ожирением ассоциирован с повышением ИМТ. Заключение. При сочетании БА и ожирения в молодом возрасте отмечается более тяжелое течение заболевания, проявляющееся снижением показателей ФВД, нарушением липидного обмена и повышением уровня лептина в периферической крови.

Topics: Adiponectin; Adult; Asthma; Body Mass Index; Comorbidity; Dyslipidemias; Female; Humans; Hypercholesterolemia; Leptin; Male; Obesity; Young Adult

Testosterone deficiency causes fat deposition, particularly in visceral fat, and its replacement might reverse fat accumulation, however, the underlying mechanisms of such processes under diet-induced adiposity are largely unknown. To gain insights into the genome-wide role of androgen on visceral adipose tissue (VAT), RNA-Seq was used to investigate testosterone deficiency induced changes of VAT in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM), and castrated male pigs with testosterone replacement (CMT) treatments. The results showed that testosterone deficiency significantly increased VAT deposition and serum leptin concentrations. Moreover, a total of 1732 differentially expressed genes (DEGs) were identified between any two groups. Compared with gene expression profiles in IM and CMT pigs, upregulated genes in CM pigs, i.e.,

Topics: Adiposity; Animals; Castration; Cell Adhesion; Cell Differentiation; Cholesterol; Diet, High-Fat; Gene Expression Profiling; Hypercholesterolemia; Inflammation; Intra-Abdominal Fat; Leptin; Male; Obesity; Oxidation-Reduction; Swine; Swine, Miniature; Testosterone; Transcriptome

The female athlete triad (Triad), links low energy availability (EA), with menstrual dysfunction (MD), and impaired bone health. The aims of this study were to examine associations between EA/MD and energy metabolism and the prevalence of Triad-associated conditions in endurance athletes. Forty women [26.2 ± 5.5 years, body mass index (BMI) 20.6 ± 2.0 kg/m(2), body fat 20.0 ± 3.0%], exercising 11.4 ± 4.5 h/week, were recruited from national teams and competitive clubs. Protocol included gynecological examination; assessment of bone health; indirect respiratory calorimetry; diet and exercise measured 7 days to assess EA; eating disorder (ED) examination; blood analysis. Subjects with low/reduced EA (< 45 kcal/kg FFM/day), had lower resting metabolic rate (RMR) compared with those with optimal EA [28.4 ± 2.0 kcal/kg fat-free mass (FFM)/day vs 30.5 ± 2.2 kcal/kg FFM/day, P < 0.01], as did subjects with MD compared with eumenorrheic subjects (28.6 ± 2.4 kcal/kg FFM/day vs 30.2 ± 1.8 kcal/kg FFM/day, P < 0.05). 63% had low/reduced EA, 25% ED, 60% MD, 45% impaired bone health, and 23% had all three Triad conditions. 53% had low RMR, 25% hypercholesterolemia, and 38% hypoglycemia. Conclusively, athletes with low/reduced EA and/or MD had lowered RMR. Triad-associated conditions were common in this group of athletes, despite a normal BMI range. The high prevalence of ED, MD, and impaired bone health emphasizes the importance of prevention, early detection, and treatment of energy deficiency.

Topics: Adult; Basal Metabolism; Bone Density; Calorimetry, Indirect; Diet Records; Energy Intake; Female; Female Athlete Triad Syndrome; Gynecological Examination; Humans; Hypercholesterolemia; Hypertension; Hypoglycemia; Leptin; Luteinizing Hormone; Menstruation Disturbances; Physical Endurance; Young Adult

In this study, two Lactobacillus strains (L. rhamnosus LA68 and L. plantarum WCFS1) were evaluated for their effects on high fat diet induced pathology in mice. The aim was to determine whether the administration of lactic acid bacteria had beneficial effects on ameliorating pathology. C57BL/6 mice fed a high fat diet were orally administered with the Lactobacillus strains. Both the metabolic and immunological parameters were analyzed. The administration of both of the strains had beneficial effects on mouse weight, serum cholesterol, TNF-α levels and liver histology. LA68 lowered the total cholesterol and HDL levels more prominently, whereas WCFS1 was more potent in lowering the TG and LDL levels. Leptin and adiponectin levels were increased in all experimental groups to different extents. The administration of L. plantarum WCFS1 led to a marked increase in leptin levels, as well as an increase in CD3+CD4+ and CD3+CD8+ cells, and a decrease of CD25+ cells, and had a lowering effect on IL-6 production and cell metabolic activity. In conclusion, active administration of both Lactobacillus strains had a positive effect on HFD-induced pathology. Although both of the tested strains had beneficial effects, oral administration of WCFS1 increased leptin levels and had a more prominent immunomodulatory effect, which should be taken into consideration in case of humane usage.

Topics: Adiponectin; Animals; Aspartate Aminotransferases; Body Weight; CD13 Antigens; Cholesterol, HDL; Cholesterol, LDL; Diet, High-Fat; Fatty Liver; Hypercholesterolemia; Interleukin-6; Lacticaseibacillus rhamnosus; Lactobacillus plantarum; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Probiotics; Triglycerides; Tumor Necrosis Factor-alpha

Leptin resistance oriented hyperleptinaemia is a common problem in obese subjects in association with hypercholesterolaemia. The most common target for hypercholesterolaemia is impaired low density lipoprotein receptor (LDLR). This study was carried out to investigate whether any alteration in LDLR expression could explain the occurrence of hypercholesterolaemia in the event of hyperleptinaemia.. Expression of LDLR and SREBP2 (sterol regulatory element binding protein 2) were examined in HepG2 cells by RT-PCR and Western blotting. JAK2 inhibitor II was used to verify the effect of JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway (common mediator for cytokine signaling). Co-localization of LDLR and insulin receptor (IR) was examined by confocal microscopy.. Leptin was found to reduce the expression of LDLR and its transcription factor SREBP2. On the other hand, a weak signal for stimulation of LDLR by leptin was noted to be mediated by JAK2 pathway. But the joint effect of the two signaling pathways kept LDLR only in depressed mode in presence of leptin. Confocal microscopy showed that LDLR made an intensively co-localized complex with insulin receptor in presence of leptin.. Our results show that though leptin stimulates LDLR expression very weakly through JAK-STAT signaling pathway, it mainly imposes inhibition on LDLR expression by inhibiting transcription factor SREBP2. The inter-association between LDLR and IR may be a reason to render LDLR functionally inactive in presence of leptin.

Topics: Diabetes Mellitus; Gene Expression Regulation; Hep G2 Cells; Humans; Hypercholesterolemia; Janus Kinase 2; Leptin; Obesity; Receptor, Insulin; Receptors, LDL; STAT Transcription Factors; Sterol Regulatory Element Binding Protein 2

The effects of maternal moderate-low physical training on postnatal development, glucose homeostasis and leptin concentration in adult offspring subjected to a low-protein diet during the perinatal period were investigated. Male Wistar rats (aged 150 d old) were divided into four groups according to maternal group: untrained (NTp, n 8); trained (Tp, n 8); untrained with a low-protein diet (NT+LPp, n 8); trained with a low-protein diet (T+LPp, n 8). The trained mothers were subjected to a protocol of moderate physical training over a period of 4 weeks (treadmill, 5 d/week, 60 min/d, at 65 % VO(2max)) before mating. At pregnancy, the intensity and duration of exercise was progressively reduced (50-20 min/d, at 65-30 % VO(2max)). The low-protein diet groups received an 8 % casein diet, and their peers received a 17 % casein diet during gestation and lactation. The pups' birth weight and somatic growth were recorded weekly up to the 150th day. Fasting blood glucose, cholesterol, serum leptin concentration, glucose and insulin tolerance tests were evaluated. The Tp animals showed no changes in somatic and biochemical parameters, while the NT+LPp group showed a greater abdominal circumference, hyperglycaemia, hypercholesterolaemia, glucose intolerance and lower plasma leptin. In the T+LPp animals, all of those alterations were reversed except for plasma leptin concentration. In conclusion, the effects of a perinatal low-protein diet on growth and development, glucose homeostasis and serum leptin concentration in the offspring were attenuated in pups from trained mothers.

Topics: Animals; Behavior, Animal; Birth Weight; Diet, Protein-Restricted; Female; Fetal Development; Fetal Growth Retardation; Hypercholesterolemia; Hyperglycemia; Insulin Resistance; Lactation; Leptin; Male; Maternal Behavior; Maternal Nutritional Physiological Phenomena; Motor Activity; Muscle, Skeletal; Pregnancy; Random Allocation; Rats; Rats, Wistar; Weight Gain

Obesity and diabetes are closely associated with hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D(2) synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.

Topics: Adrenocorticotropic Hormone; Animals; Corticosterone; Genotype; Hypercholesterolemia; Hyperglycemia; Hypothalamo-Hypophyseal System; Insulin Resistance; Intramolecular Oxidoreductases; Leptin; Lipocalins; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Pituitary-Adrenal System

Serum C-reactive protein (CRP) and leptin levels have been independently associated with the cardiovascular risk factors. The aim of the present study was to determine if their serum levels were associated with cardiovascular risk factors or metabolic syndrome as well as their correlation in the Taiwanese population.. This retrospective study included 999 subjects (> 18 y), who underwent a physical examination in Chang-Gung Memorial Hospital-Linkou and Chiayi in Taiwan. The associations between CRP and/or leptin levels and cardiovascular risk factors and metabolic syndrome were determined using independent two sample t-tests to detect gender differences and chi-square tests to evaluate differences in frequencies. To compare the means of the variables measured among the four groups (high and low leptin and high and low CRP), analysis of variance (ANOVA) was used.. Both CRP and leptin levels were independently associated with several cardiovascular risk factors, including diabetes, hypercholesterolemia and metabolic syndrome in both men and women (P < 0.05). In addition, a positive correlation between leptin and CRP levels was observed in both genders. Both high-CRP and high-leptin were associated with high blood glucose, waist circumference and serum triglyceride. Whereas increased metabolic syndrome incidence was observed in males with elevated leptin regardless of CRP levels, females with elevated CRP or leptin had increased incidence of metabolic syndrome.. Both leptin and CRP levels were associated with cardiovascular risk factors as well as metabolic syndrome score in both men and women although gender-specific differences were observed. Thus, CRP and leptin may represent useful biomarkers for predicting the onset of cardiovascular disease or metabolic syndrome in Taiwanese adults.. IRB/CGMH 100-3514B.

Topics: Adult; Age Factors; Analysis of Variance; Asian People; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Chi-Square Distribution; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Incidence; Leptin; Male; Metabolic Syndrome; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Sex Factors; Taiwan

An experiment was conducted to study the protective effect of feeding extruded and unextruded blueberry pomace (BBP) on selected metabolic parameters associated with metabolic syndrome in a model of high fructose (HF)-fed growing Sprague-Dawley rats. Treatments were as follows: (1) control (modified AIN-based diet); (2) HF diet (AIN diet with 58% fructose); (3) HF diet with 1.5% unextruded BBP; (4) HF diet with 1.5% extruded BBP; (5) HF diet with 3% unextruded BBP; and (6) HF diet with 3% extruded BBP. Compared with the control, HF feeding increased fasting plasma insulin and fasting and postprandial plasma triglycerides as well as homeostatic scores of insulin resistance and β-cell function, but not weight gain, diet intake and efficiency, abdominal fat, oral glucose tolerance, and fasting and postprandial plasma glucose, cholesterol, and leptin levels. Inclusion of unextruded or extruded BBP was effective in minimizing or ameliorating the fructose-induced metabolic anomalies, except postprandial plasma triglycerides, especially at 3% of the diet. In addition, unextruded or extruded BBP at 3% of the diet was also able to reduce plasma cholesterol and abdominal fat relative to the HF control, which may impart additional health benefits. Compared with the control, inclusion of unextruded or extruded BBP at both 1.5% and 3% resulted in lower total fat weight, and animals fed a diet supplemented with 3% unextruded BBP in fasting state or 3% unextruded BBP in fed state had lower leptin levels than the control. This is the first study demonstrating the beneficial effects of feeding blueberry pomace on health.

Topics: Abdominal Fat; Adiposity; Animals; Antioxidants; Blueberry Plants; Dietary Supplements; Food-Processing Industry; Fructose; Fruit; Hypercholesterolemia; Hyperinsulinism; Industrial Waste; Insulin Resistance; Leptin; Male; Metabolic Syndrome; Polyphenols; Random Allocation; Rats; Rats, Sprague-Dawley

Selenium (Se) is an essential trace element used for biosynthesis of selenoproteins and is acquired either through diet or cellular recycling mechanisms. Selenocysteine lyase (Scly) is the enzyme that supplies Se for selenoprotein biosynthesis via decomposition of the amino acid selenocysteine (Sec). Knockout (KO) of Scly in a mouse affected hepatic glucose and lipid homeostasis. Mice lacking Scly and raised on an Se-adequate diet exhibit hyperinsulinemia, hyperleptinemia, glucose intolerance, and hepatic steatosis, with increased hepatic oxidative stress, but maintain selenoprotein levels and circulating Se status. Insulin challenge of Scly KO mice results in attenuated Akt phosphorylation but does not decrease phosphorylation levels of AMP kinase alpha (AMPKα). Upon dietary Se restriction, Scly KO animals develop several characteristics of metabolic syndrome, such as obesity, fatty liver, and hypercholesterolemia, with aggravated hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hepatic glutathione peroxidase 1 (GPx1) and selenoprotein S (SelS) production and circulating selenoprotein P (Sepp1) levels are significantly diminished. Scly disruption increases the levels of insulin-signaling inhibitor PTP1B. Our results suggest a dependence of glucose and lipid homeostasis on Scly activity. These findings connect Se and energy metabolism and demonstrate for the first time a unique physiological role of Scly in an animal model.

Topics: AMP-Activated Protein Kinases; Animals; Fatty Liver; Glucose Intolerance; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Hypercholesterolemia; Hyperinsulinism; Leptin; Lyases; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Oxidative Stress; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Proto-Oncogene Proteins c-akt; Selenium; Selenoproteins

The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D.. The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficiency by ~92% compared with nondiabetic Ins2(+/+):apoE(-/-) mice. From 13 weeks to 25 weeks of age, diabetic Ins2(+/Akita):apoE(-/-) mice were treated with low-dose leptin (at 0.4 μg/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ~41%, especially in LDL fractions, in diabetic Ins2(+/Akita):apoE(-/-) mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ~62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling.. The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D.

Topics: Adaptor Proteins, Vesicular Transport; Animals; Apolipoproteins E; Atherosclerosis; Cholesterol; Diabetes Mellitus, Type 1; Disease Models, Animal; Disease Progression; Eating; Gene Expression Regulation; Hypercholesterolemia; Injections, Intraperitoneal; Insulin; Insulin Receptor Substrate Proteins; Leptin; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Recombinant Proteins; RNA, Messenger; Time Factors

The adverse effects of metabolic disorders in obesity have been extensively studied; however, the pathologic effects of hyperphosphatemia or phosphate toxicity in obesity have not been studied in similar depth and detail, chiefly because such an association is thought to be uncommon. Studies have established that the incidence of obesity-associated nephropathy is increasing. Because hyperphosphatemia is a major consequence of renal impairment, this study determines the in vivo effects of hyperphosphatemia in obesity.. We genetically induced hyperphosphatemia in leptin-deficient obese (ob/ob) mice by generating ob/ob and klotho double knockout [ob/ob-klotho(-/-)] mice. As a control, we made ob/ob mice with hypophosphatemia by generating ob/ob and 1-alpha hydroxylase double knockout [ob/ob-1α(OH)ase(-/-)] mice. Compared to the wild-type mice, all three obese background mice, namely ob/ob, ob/ob-klotho(-/-), and ob/ob-1α(OH)ase(-/-) mice developed hypercholesterolemia. In addition, the hyperphosphatemic, ob/ob-klotho(-/-) genetic background induced generalized tissue atrophy and widespread soft-tissue and vascular calcifications, which led to a shorter lifespan; no such changes were observed in the hypophosphatemic, ob/ob-1α(OH)ase(-/-) mice. Significantly, in contrast to the reduced survival of the ob/ob-klotho(-/-) mice, lowering serum phosphate levels in ob/ob-1α(OH)ase(-/-) mice showed no such compromised survival, despite both mice being hypercholesterolemic.. These genetic manipulation studies suggest phosphate toxicity is an important risk factor in obesity that can adversely affect survival.

Topics: Animals; Calcitriol; Calcium; Cholesterol; Glucuronidase; Hypercholesterolemia; Hyperphosphatemia; Klotho Proteins; Leptin; Mice; Mice, Knockout; Obesity; Phosphates

Oxidative stress accelerates adipocyte differentiation and lipid accumulation, leading to endoplasmic reticulum (ER) stress, which causes insulin resistance. Because metallothionein (MT) has a role in prevention of oxidative and ER stress, we examined the effects of MT on the development of obesity induced by 27 wk of a high-fat diet (HFD) in female MT-I- and MT-II-null (MT(-/-)) and wild-type (MT(+/+)) mice. Body weight, fat mass, and plasma cholesterol increased at a greater rate in MT(-/-) mice fed an HFD than in MT(-/-) mice fed a control diet (CD) and MT(+/+) mice fed an HFD, indicating that MT(-/-) mice fed an HFD became obese and hypercholesterolemic and that MT could prevent HFD-induced obesity. The observed increases in the levels of plasma leptin and leptin mRNA in the white adipose tissue of MT(-/-) mice fed the HFD suggested a leptin-resistant state. Enhanced expression of a mesoderm-specific transcript, which regulates the enlargement of fat cells, was accompanied by enlarged adipocytes in the white adipose tissue of young MT(-/-) mice before obesity developed after 3 and 8 wk of feeding the HFD. Thus, MT may have a preventive role against HFD-induced obesity by regulating adipocyte enlargement and leptin signaling.

Topics: Adipocytes; Animals; Cell Size; Dietary Fats; Female; Hypercholesterolemia; Leptin; Metallothionein; Mice; Mice, Knockout; Obesity; RNA, Messenger

Topics: Adult; Chemokines; Chronic Disease; Cyclosporine; Dermatitis; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Intercellular Signaling Peptides and Proteins; Leptin; Male; Metabolic Syndrome; Psoriasis; Skin; Up-Regulation

Resistin in serum is associated with high risk in patients with atherosclerosis. This clinical study aimed to investigate whether pitavastatin can regulate the serum level of resistin, together with levels of other inflammatory cytokines and adipocytokines.. Forty two outpatients (mean age 65.2 +/- 12.6 yr, M/F: 21/21) with hypercholesterolemia were administered 2 mg of pitavastatin and serum levels of resistin, together with serum levels of adiponectin, leptin, TNF-alpha and hsCRP, were measured before, and 12 weeks after enrollment.. There was no significant gender-related difference in initial serum resistin levels. Pitavastatin significantly decreased LDL-cholesterol after 12 weeks. Initial levels of resistin showed a significant correlation with those of hsCRP (r=0.38, p=0.013), but not TNF-alpha or HOMA-R. Serum resistin, but not adiponectin and leptin, levels were significantly decreased, dropping from 17.1 +/- 9.9 ng/ dL to 15.2+/-10.0 (p=0.001) after 12 weeks of administration. The patient group with a baseline hsCRP > or = 0.1 at enrollment (n=17) had decreased levels of both resistin and hsCRP (p=0.011 and p=0.022, respectively).. This study showed the pleiotropic effect of pitavastatin on the serum resistin concentration, suggesting that it may assist in the prevention of atherosclerosis.

Topics: Adiponectin; Aged; C-Reactive Protein; Female; Humans; Hypercholesterolemia; Leptin; Male; Middle Aged; Quinolines; Resistin; Tumor Necrosis Factor-alpha

The role of leptin in the pathomechanism of atherosclerosis, through its free radical generating ability is established. Its effect however, on the regulation of intracellular cholesterol synthesis has not been studied. The aim of the present study was to elucidate whether leptin influences endogenous cholesterol synthesis in monocytes. Furthermore, leptin signaling to HMG CoA reductase in control and hypercholesterolemic monocytes were compared. The in vitro effect of leptin was studied on freshly isolated human monocytes obtained from healthy control volunteers and patients with hypercholesterolemia. Our results can be summarized as follows: (1) Leptin is able to increase endogenous cholesterol synthesis in human monocytes in vitro. (2) The cholesterol synthesis increasing effect of the hormone is more pronounced in hypercholesterolemic monocytes with high basal cholesterol biosynthesis. (3) The leptin-induced Ca(2+) signal was involved in the enhancement of HMG CoA reductase activation in monocytes from both controls and hypercholesterolemic patients. (4) In control monocytes the Ca(2+) signal originated from intracellular pools, whereas in patients, Ca(2+)-influx and protein kinase C activation were found to be responsible for the leptin-effect. Mevalonate cycle inhibiting fluvastatin and 25-hydroxycholesterol decreased cholesterol production in leptin-stimulated monocytes. Our present study provides the first proof of the cholesterol synthesis enhancing effect of leptin through a statin-sensitive pathway in circulating monocytes. Furthermore our results suggest that leptin can be involved in the pathomechanism of atherosclerotic plaque formation also through its effect on cholesterol biosynthesis in monocytes.

Topics: Acetates; Area Under Curve; Atherosclerosis; Calcium; Calcium Signaling; Carbon Radioisotopes; Case-Control Studies; Cholesterol; Demography; Female; Humans; Hypercholesterolemia; Inositol 1,4,5-Trisphosphate; Leptin; Male; Middle Aged; Monocytes

Maternal hypercholesterolaemia during pregnancy increases lipid peroxidation in mothers and fetuses and programs increased susceptibility to atherosclerosis later in life. The objective of this study was to elucidate the role of the placenta in mediating oxidative stress from mother to offspring.. Comparison between normo- and hypercholesterolaemic mothers (n = 36 each) and their children.. Obstetric wards, hospitals of the University of Naples and Regione Campania.. Healthy primiparas delivering by caesarean section.. Biochemical measurements of oxidative stress and serum leptin in cord plasma and placenta, immunochemistry of placenta microvessels, and vasoreactivity studies were performed.. Oxidative status (i.e. lipid composition and content of oxidised fatty acids, activity of pro- and antioxidant enzymes, immunohistochemical presence of oxidation-specific epitopes) in maternal and cord blood and in placental tissue, as well as vascular reactivity in omental arteries.. Hypercholesterolaemia during pregnancy was associated with extensive changes in fatty acid composition of both maternal and cord blood lipids, sufficient to alter vasoreactivity of omental vessels. Results also indicated that the placenta is not only subject to substantial oxidative stress, but that it may further increase fetal oxidative stress through changes of pro- and antioxidant enzyme activities.. The placenta plays an important role in both transmitting and enhancing pathogenic effects of gestational hypercholesterolaemia.

Topics: Adult; Arteries; Fatty Acids; Female; Fetal Blood; Gestational Age; Humans; Hypercholesterolemia; Immunohistochemistry; Leptin; Lipid Peroxidation; Lipids; Muscle Contraction; Muscle, Smooth, Vascular; Omentum; Oxidation-Reduction; Oxidative Stress; Placenta; Pregnancy; Pregnancy Complications; Vasoconstrictor Agents; Vasomotor System

Fenofibrate, a selective (1)PPAR-alpha activator, is prescribed to treat human dyslipidemia. The aim of this study was to delineate the mechanism of fenofibrate-mediated reductions in adiposity, improvements in insulin sensitivity, and lowering of triglycerides (TG) and free fatty acids (FFA) and to investigate if these favorable changes are related to the inhibition of lipid deposition in the aorta. To test this hypothesis we used male LDLr deficient mice that exhibit the clinical features of metabolic syndrome X when fed a high fat high cholesterol (HF) diet. LDLr deficient mice fed HF diet and simultaneously treated with fenofibrate (100 mg/kg body weight) prevented development of obesity, lowered serum triglycerides and cholesterol, improved insulin sensitivity, and prevented accumulation of lipids in the aorta. Lowering of circulating lipids occurred via down-regulation of lipogenic genes, including fatty acid synthase, acetyl CoA carboxylase and diacyl glycerol acyl transferase-2, concomitant with decreased liver TG and cholesterol, and TG output rate. Fenofibrate also suppressed liver apoCIII mRNA levels and markedly increased lipoprotein lipase mRNA levels, known to enhance serum TG catabolism. In addition, fenofibrate profoundly reduced epididymal fat and mesenteric fat mass to the levels seen in lean mice. The reductions in body weight were associated with elevation of hepatic uncoupling protein 2 (UCP2) mRNA, a concomitant increase in the ketone body formation, and improved insulin sensitivity associated with tumor necrosis factor-alpha reductions and phosphoenol pyruvate carboxykinase down-regulation. These results demonstrate that fenofibrate improves lipid abnormalities partly via inhibition of TG production and partly via clearance of TG-rich apoB particles by elevating LPL and reduced apoCIII. The prevention of obesity development occurred via energy expenditure. Fenofibrate-mediated hypolipidemic effects together with improved insulin sensitivity and loss of adiposity led to the reductions in the aortic lipid deposition by inhibiting early stages of atherosclerosis possibly via vascular cell adhesion molecule-1 (VCAM-1) modulation. These results suggest that potent PPAR-alpha activators may be useful in the treatment of syndrome X.

Topics: Adiposity; Animals; Aorta; Coronary Artery Disease; Diet, Atherogenic; Energy Metabolism; Fenofibrate; Gluconeogenesis; Hypercholesterolemia; Hypertriglyceridemia; Insulin; Insulin Resistance; Leptin; Ligands; Lipid Metabolism; Lipids; Lipogenesis; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; PPAR alpha; Receptors, LDL; Triglycerides; Weight Gain

Limited data are available on the association of insulin resistance, adipokines, and in vivo lipid peroxidation. We investigated the relationships between insulin resistance, adipokines (leptin, adiponectin, and resistin), and oxidative stress in nondiabetic, hypercholesterolemic patients. Seventy-six nondiabetic patients with hypercholesterolemia participated in this cross-sectional study. Fasting glucose and insulin concentrations were analyzed. Serum leptin, adiponectin, and resistin concentrations and urinary excretion of 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)) were determined using enzyme-linked immunosorbent assay. We divided all subjects into 3 groups, classified by the tertiles of homeostasis model assessment of insulin resistance (HOMA-IR) values, and clinical parameter comparisons were made among the 3 groups. The results showed that serum leptin (P < .001) and adiponectin levels (P < .05) were significantly different among the groups, although serum resistin was not different. Furthermore, the group with the highest HOMA-IR had a significantly higher urinary 8-epi-PGF(2alpha) excretion than the group with the lowest HOMA-IR (P = .017). Circulating leptin was positively correlated with urinary 8-epi-PGF(2alpha) (r = 0.323, P < .01) and HOMA-IR (r = 0.524, P < .001). Circulating adiponectin was negatively correlated with body mass index (r = -0.252, P < .05) and HOMA-IR (r = -0.228, P < .05). We could not find a relationship between circulating adiponectin or resistin and urinary 8-epi-PGF(2alpha) excretion. Stepwise multiple linear regression analysis showed that leptin was associated with the urinary 8-epi-PGF(2alpha) excretion after adjusting for age, sex, body mass index, blood lipids, and HOMA-IR (P = .002). In conclusion, our results show that more insulin-resistant state of nondiabetic, hypercholesterolemic patients is associated with decreased adiponectin and increased leptin and urinary 8-epi-PGF(2alpha) levels, although no relationship with resistin was observed. Furthermore, serum leptin independently contributed to urinary 8-epi-PGF(2alpha) excretion.

Topics: Adiponectin; Adult; Aged; Body Mass Index; Dinoprost; Female; Humans; Hypercholesterolemia; Insulin Resistance; Leptin; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Regression Analysis

To determine effects of obesity and diet in dogs on plasma lipid and lipoprotein concentrations by assaying plasma leptin and ghrelin concentrations and determining total plasma cholesterol and triglyceride concentrations as well as the concentrations of cholesterol and triglycerides in various lipoprotein classes (ie, very-low-density, low-density, and high-density lipoproteins).. 24 Beagles; 12 lean (mean [+/- SEM] body weight, 12.7 +/- 0.7 kg) and 12 chronically obese (21.9 +/- 0.8 kg) dogs of both sexes, between 1 and 9 years old.. Total plasma cholesterol and triglyceride concentrations; lipoprotein cholesterol and triglyceride concentrations; and plasma ghrelin, leptin, free fatty acids, insulin, and glucose concentrations were measured and compared between lean and obese dogs, both of which were fed a complete and balanced maintenance diet. Chronically obese dogs were subsequently fed a high-protein low-energy diet to evaluate effects of diet composition on plasma lipid and lipoprotein measurements.. Chronic obesity resulted in a significant decrease in plasma ghrelin concentration and a significant increase in plasma leptin, cholesterol, and triglyceride concentrations in dogs. High total plasma cholesterol and triglyceride concentrations resulted from increased cholesterol and triglyceride concentrations in all lipoprotein fractions. In obese dogs, modification of diet composition resulted in beneficial effects on plasma lipid and leptin concentrations, even before weight loss was observed.. Correlations exist between obesity and plasma measurements (ie, lipoproteins, leptin, insulin, and ghrelin) commonly associated with obesity. Modification of diet composition to control energy intake improves plasma lipid and leptin concentrations in obese dogs.

Topics: Animals; Dog Diseases; Dogs; Energy Intake; Female; Ghrelin; Hypercholesterolemia; Hypertriglyceridemia; Leptin; Lipoproteins; Male; Obesity; Peptide Hormones

Human obesity is associated with abnormal hepatic cholesterol homeostasis and resistance to leptin action. Because leptin administration to rodents promotes the biliary elimination of plasma cholesterol, this study was designed to elucidate a pathophysiological role for leptin during the development of obesity. We fed mice diets containing high or low saturated fat contents. Before and after the onset of obesity, we measured downstream targets of leptin action and evaluated plasma, hepatic, and biliary cholesterol metabolism. Although not obese at 28 days, mice fed a high fat diet became hyperleptinemic. Sensitivity to leptin was evidenced by downregulation of both hepatic stearoyl CoA desaturase-1 and fatty acid synthase. Due principally to upregulation of adenosine triphosphate-binding cassette proteins A1 and G5, plasma high density lipoprotein (HDL) cholesterol concentrations increased, as did relative secretion rates of biliary cholesterol. A smaller, more hydrophilic bile salt pool decreased intestinal cholesterol absorption. In this setting, hepatic cholesterol synthesis was downregulated, indicative of increased uptake of plasma cholesterol. After 56 days of high fat feeding, obesity was associated with leptin resistance, as evidenced by marked hyperleptinemia without downregulation of stearoyl CoA desaturase-1 or fatty acid synthase and by upregulation of hepatic cholesterol and bile salt synthesis. Hypercholesterolemia was attributable to overproduction and decreased clearance of large HDL(1) particles. In conclusion, before the onset of obesity, preserved leptin sensitivity promotes biliary elimination of endogenous cholesterol in response to dietary fat. Leptin resistance due to obesity leads to a maladaptive response whereby newly synthesized cholesterol in the liver is eliminated via bile.

Topics: Animals; Bile; Bile Acids and Salts; Cholesterol; Cholesterol, HDL; Diet; Dietary Fats; Down-Regulation; Drug Resistance; Fatty Acid Synthases; Hypercholesterolemia; Isoenzymes; Leptin; Liver; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Obesity; Stearoyl-CoA Desaturase

Both environmental and genetic factors play important roles in the development of the metabolic syndrome. To elucidate how these factors interact under normal conditions, C57Bl/6 (B6) and 129S6/SvEvTac (129) mice were placed on a low-fat or high-fat diet. Over 18 weeks, the 129 strain developed features of the metabolic syndrome, notably obesity, hyperinsulinemia, and glucose intolerance only on the high-fat diet; the B6 strain on the other hand developed these features on both diets. High-fat feeding of both strains led to decreased serum triglycerides, hepatic steatosis, and hypercholesterolemia; however, B6 mice developed worse steatosis and a larger increase in LDL cholesterol. Both B6 background and high-fat feeding increased sterol regulatory element-binding protein-1c (SREBP-1c), a key regulator of lipogenic gene transcription, and its downstream targets. Stearoyl-CoA desaturase 1 (SCD1), an enzyme that regulates monounsaturated fatty acid (MUFA) synthesis, was also increased at the mRNA and enzyme activity levels by both high-fat feeding and B6 background. Furthermore, lipid analysis revealed increased hepatic triglycerides and MUFAs in B6 and high-fat-fed mice. Thus, dietary fat and genetic background act through SREBP-1c and SCD1 to affect hepatic lipid metabolism contributing to the development of the metabolic syndrome.

Topics: Animals; Blood Glucose; Body Weight; CCAAT-Enhancer-Binding Proteins; Diet, Fat-Restricted; Dietary Fats; DNA-Binding Proteins; Hypercholesterolemia; Insulin; Leptin; Liver; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Stearoyl-CoA Desaturase; Sterol Regulatory Element Binding Protein 1; Transcription Factors

Leptin may play an important role in the development of atherosclerosis. We evaluated the effect of atorvastatin on leptin secretion in vivo and in vitro.. Sixteen rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into 2 groups: (1) high cholesterol diet for 6 weeks (n=8), and (2) the same cholesterol diet plus atorvastatin (2.5 mg/kg/day) for 6 weeks (n=8). A control group (n=5) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for RNA analysis. The direct effect of atorvastatin on leptin release was assayed in primary rabbit adipocytes. Leptin levels in serum and adipocytes culture supernatant were measured by ELISA. RT-PCR was used to evaluate leptin mRNA expressions in adipose and adipocytes.. Compared with control group, rabbits fed with high cholesterol diet showed higher levels of serum total cholesterol, LDL cholesterol and leptin, all of which were significantly reduced by atorvastatin treatment. Leptin mRNA expression of adipose was significant lower in rabbits treated with atorvastatin than those fed with high cholesterol diet continuously (0.81+/-0.31 vs. 1.23+/-0.36, P<0.05). Atorvastatin dose-dependently inhibited leptin secretion and mRNA expression in cultured adipocytes.. Atorvastatin can inhibit leptin release and mRNA expression, and reduces serum leptin level in hypercholesterolemic rabbits.

Topics: Adipocytes; Adipose Tissue; Animals; Atorvastatin; Cholesterol; Drug Evaluation, Preclinical; Heptanoic Acids; Hypercholesterolemia; Leptin; Pyrroles; Rabbits; RNA, Messenger

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

Topics: Body Mass Index; Coronary Disease; Female; Humans; Hypercholesterolemia; Leptin; Lipid Metabolism; Lipids; Male; Nutritional Physiological Phenomena; Obesity; Risk Factors

Neuropeptide Y (NPY) is a 36 amino acid peptide well known for its role in regulating food intake and energy homeostasis. It has previously been shown that the NPY Y2 receptor is required for a full biological response to leptin in the central nervous system. We have examined the impact of this receptor on plasma levels of lipid and cholesterol in wild type and obese (ob/ob) mice. The results show that an absence of Y2 in female mice has no effect on cholesterol level in normal lean mice but profoundly decreases serum cholesterol and glucose levels in ob/ob mice. We conclude that NPY, interacting with the Y2 receptor, participates in cholesterol and glucose homeostasis of obese mice.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Crosses, Genetic; Female; Hypercholesterolemia; Hyperglycemia; Leptin; Lipids; Lipoproteins; Mice; Mice, Inbred BALB C; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Receptors, Neuropeptide Y; Temperature; Time Factors

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.

Topics: Animals; Arteriosclerosis; Diet; Disease Models, Animal; Hypercholesterolemia; Hypertriglyceridemia; Leptin; Lipoproteins; Mice; Mice, Inbred C57BL; Receptors, LDL; Receptors, Leptin

Leptin is a protein hormone produced by adipocytes that reflects the body fat content. The aim of our study was to compare serum leptin levels in randomly selected untreated males and females with hypercholesterolemia and combined hyperlipidemia and in healthy control subjects matched for age and body mass index and to study the relations between leptin and serum lipids and lipoproteins. No statistically significant differences in serum leptin levels were found between the male control group (5.26 +/- 2.81 ng/mL(-1)) and the male group with hypercholesterolemia (8.16 +/- 3.85 ng/mL(-1)) or combined hyperlipidemia (7.51 +/- 4.83 ng/mL(-1)) and between the female control group (13.0 +/- 8.12 ng/mL(-1)) and the female group with hypercholesterolemia (15.36 +/- 8.89 ng/mL(-1)) or combined hyperlipidemia (18.63 +/- 10.15 ng/mL(-1)). Leptin concentration in male group with hypercholesterolemia did not differ significantly from the female control group; in the other male groups, leptin levels were significantly lower than those of the other female groups. Serum leptin levels in all studied groups except for the male group with hypercholesterolemia positively correlated with body mass index. Serum leptin levels correlated negatively with high-density lipoprotein cholesterol in the female group with hypercholesterolemia (r = -0.67, P < 0.01) and the male group with combined hyperlipidemia (r = -0.56, P < 0.01). A positive correlation between serum leptin and high-density lipoprotein cholesterol (r = 0.67, P < 0.01) and between leptin and lipoprotein (a) (r = 0.71, P < 005) was found in female group with combined hyperlipidemia. No other significant relationships between leptin and serum lipids or lipoproteins were found. We conclude that serum leptin levels in patients with hyperlipidemias do not significantly differ from those healthy control subjects matched by age and body mass index.

Topics: Adult; Apolipoproteins E; Body Mass Index; Cholesterol, HDL; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Leptin; Male; Middle Aged; Regression Analysis