Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma retinol-binding protein 4 (RBP4) may be a new adipokine linked to obesity-induced insulin resistance and type 2 diabetes. The impact of diabetic nephropathy on plasma RBP4 levels, however, is not known. We tested the hypothesis that microalbuminuria is associated with elevated plasma concentrations of RBP4 in type 2 diabetic subjects. Retinol, its binding protein and transthyretin (TTR) were measured in the plasma and urine of 62 type 2 diabetic subjects, 26 of whom had microalbuminuria. The results were compared to 35 healthy control subjects. Despite no differences in plasma retinol, concentrations of the RBP4 were significantly elevated in plasma of diabetic patients and significantly higher in those with microalbuminuria. The higher plasma levels of the binding protein in subjects with microalbuminuria were accompanied by both significantly elevated plasma TTR and increased urinary levels of RBP4. There were no correlations of plasma-binding protein levels and parameters of insulin resistance. Our study suggests that plasma RBP4 levels in type 2 diabetic patients are affected by incipient nephropathy. Therefore, further studies evaluating RBP4 as a regulator of systemic insulin resistance and type 2 diabetes will need to take renal function into consideration.
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PMID:Microalbuminuria is a major determinant of elevated plasma retinol-binding protein 4 in type 2 diabetic patients. 1756 82

We evaluated the effect of skeletal muscle mitochondrial uncoupling on energy and glucose metabolism under different diets. For 3 mo, transgenic HSA-mUCP1 mice with ectopic expression of uncoupling protein 1 in skeletal muscle and wild-type littermates were fed semisynthetic diets with varying macronutrient ratios (energy % carbohydrate-protein-fat): HCLF (41:42:17), HCHF (41:16:43); LCHF (11:45:44). Body composition, energy metabolism, and insulin resistance were assessed by NMR, indirect calorimetry, and insulin tolerance test, respectively. Gene expression in different organs was determined by real-time PCR. In wild type, both high-fat diets led to an increase in body weight and fat. HSA-mUCP1 mice considerably increased body fat on HCHF but stayed lean on the other diets. Irrespective of differences in body fat content, HSA-mUCP1 mice showed higher insulin sensitivity and decreased plasma insulin and liver triglycerides. Respiratory quotient and gene expression indicated overall increased carbohydrate oxidation of HSA-mUCP1 but a preferential channeling of fatty acids into muscle rather than liver with high-fat diets. Evidence for increased lipogenesis in white fat of HSA-mUCP1 mice suggests increased energy dissipating substrate cycling. Retinol binding protein 4 expression in white fat was increased in HSA-mUCP1 mice despite increased insulin sensitivity, excluding a causal role in the development of insulin resistance. We conclude that skeletal muscle mitochondrial uncoupling does not protect from the development of obesity in all circumstances. Rather it can lead to a "healthy" obese phenotype by preserving insulin sensitivity and a high metabolic flexibility, thus protecting from the development of obesity associated disturbances of glucose homeostasis.
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PMID:Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1. 1804 32

Retinol-binding protein-4 (RBP4), a 21-kDa protein synthesized in the liver and adipose tissue, has recently been described as a murine adipokine involved in the development of insulin resistance. The expression of the gene encoding RBP4 was increased in the adipose tissue, but not in the liver, of insulin-resistant adipose GLUT4(-/-) mice and five other mouse models of obesity and insulin resistance. In addition, intraperitoneal injection or transgenic overexpression of RBP4 in mice induced insulin resistance. While experimental clinical approaches (mostly applying clamp techniques) in humans confirmed correlations of RBP4 with insulin resistance, studies in larger groups out of clinical routine failed to demonstrate a connection with alternative measures of insulin sensitivity. Yet, significant associations of RBP4 with atherogenic lipids were found and a focus of future studies should be the influence on atherosclerosis and related complications. Based on current data, the function of RBP4 as an adipokine exerting metabolic effects in glucose metabolism in humans remains uncertain and might be restricted to rodent models.
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PMID:Retinol-binding protein-4 in experimental and clinical metabolic disease. 1859 8

Elevated serum retinol-binding protein (RBP) concentration has been associated with obesity and insulin resistance, but accompanying retinol values have not been reported. Assessment of retinol is required to discriminate between apo-RBP, which may act as an adipokine, and holo-RBP, which transports vitamin A. The relations between serum RBP, retinol, retinyl esters, BMI, and measures of insulin resistance were determined in obese adults. Fasting blood (> or =8 h) was collected from obese men and women (n = 76) and blood chemistries were obtained. Retinol and retinyl esters were quantified by HPLC and RBP by ELISA. RBP and retinol were determined in age and sex-matched, nonobese individuals (n = 41) for comparison. Serum apo-RBP was two-fold higher in obese (0.90 +/- 0.62 microM) than nonobese subjects (0.44 +/- 0.56 microM) (P < 0.001). The retinol to RBP ratio (retinol:RBP) was significantly lower in obese (0.73 +/- 0.13) than nonobese subjects (0.90 +/- 0.22) (P < 0.001) and RBP was strongly associated with retinol in both groups (r = 0.71 and 0.90, respectively, P < 0.0001). In obese subjects, RBP was associated with insulin (r = 0.26, P < 0.05), homeostatic model assessment of insulin resistance (r = 0.29, P < 0.05), and quantitative insulin sensitivity check index (r = -0.27, P < 0.05). RBP was associated with BMI only when obese and nonobese subjects were combined (r = 0.25, P < 0.01). Elevated serum RBP, derived in part from apo-RBP, was more strongly associated with retinol than with BMI or measures of insulin resistance in obese adults. Investigations into the role of RBP in obesity and insulin resistance should include retinol to facilitate the measurement of apo-RBP and retinol:RBP. When evaluating the therapeutic potential of lowering serum RBP, consideration of the consequences of vitamin A metabolism is paramount.
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PMID:Retinol to retinol-binding protein (RBP) is low in obese adults due to elevated apo-RBP. 1882 Jan 76

The study objective was to evaluate the realization of the reducing diet recommended in the treatment of overweight or obesity (1500 kcal) with regard to the caloric value and the content of basic nutrients, vitamins and bioelements. The study was conducted on a group of 48 women. Daily food rations were evaluated based on a week's dietary register. Results were averaged in each patient and compared to the norms worked out by the Institute of Food and Feeding in Warsaw for subjects with low physical activity. The mean energetic value of the diets was found to meet the requirements. Approximately 50% of the obese women consumed high-protein, low-fat and low-carbohydrate food rations. The analysis of vitamin content in daily food rations showed insufficient intake of vitamin E (in 89.6% of women), thiamin (83.3%), riboflavin (93.7%), niacin (60.4%), vitamin B6 (87.5%), folic acid (89.6%) and vitamin C (72.9%). Vitamin A intake was higher than the recommended norm in 47.9% of women. The lowest realization was noted in the case of potassium (64.6% of rations below the norm), calcium (100% below the norm), magnesium (64.6% below the norm). However, dietary sodium and phosphate content in most obese women exceeded the norms. The intake was too low in the case of iron (in 91.7%), zinc (in 97.9%) and copper (in 100%). It seems that long-term compliance with such a diet requires additional individual supplementation.
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PMID:[Assessment of realization of a reducing diet by obese women during treatment of excessive body mass]. 1914 32

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.
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PMID:Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans. 1919 Feb 63

Retinol-binding protein-4 (RBP4) is an emerging candidate drug target for type 2 diabetes and lipofuscin-mediated macular degeneration. The retinoic acid derivative fenretinide (N-(4-hydroxyphenyl) retinamide; HPR) exerts therapeutic effects in mouse models of obesity, diabetes, and Stargardt's disease by targeting RBP4. Fenretinide competes with retinoids for RBP4 binding, disrupts RBP4-transthyretin (TTR) complexes, and results in urinary secretion of RBP4 and systemic depletion of retinol. To enable the search for nonretinoid molecules with fenretinide-like activities we developed a HTS-compatible homogeneous TR-FRET assay monitoring the displacement of retinoic acid derivatives from RBP4 in high-density 384-well and 1536-well microtiter plate formats. The retinoid displacement assay proved to be highly sensitive and robust after miniaturization with IC(50)s for fenretinide and retinol ranging around 50 and 100 nM, respectively, and Z'-factors around 0.7. In addition, a surface plasmon resonance (SPR)-based secondary assay was developed to interrogate small molecule RBP4 binders for their ability to modulate the RBP4-TTR interaction. Finally, a 1.6 x 10(6) compound library was screened against the retinoid displacement assay. Several potent retinoid competitors were identified that also appeared to disrupt RBP4-TTR complexes. Some of these compounds could potentially serve as valuable tools to further probe RBP4 biology in the future.
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PMID:Time-resolved fluorescence resonance energy transfer and surface plasmon resonance-based assays for retinoid and transthyretin binding to retinol-binding protein 4. 1948 4

Retinol binding protein 4 (RBP4) is an adipokine involved in the pathogenesis of insulin resistance in obese adults and children. Since insulin resistance occurs during puberty, independently of adiposity, a role for RBP4 in the onset of this phenomenon may be hypothesized. In order to verify our hypothesis, we studied 90 subjects (45 obese and 45 lean controls). A complete physical examination was assessed, the z-score body mass index (BMI) was calculated, fat mass was assessed by bioelectric impedance analysis, and pubertal stage was assessed according to Tanner. Serum insulin and serum RBP4 levels were assayed. Obese and lean children differed for z-score BMI, fat mass, homeostasis model assessment of insulin resistance (HOMA-IR) and RBP4 levels. z-score BMI and HOMA-IR showed a direct correlation with RBP4 in the total population. When the subjects were divided in lean and obese, this correlation was evident only in obese (r2: 0.2; p=0.009 and r2: 0.2; p=0.01), but not in lean subjects (r2: 0.09; p=0.1 and r2: 0.03; p=0.4). Both in obese and lean HOMA-IR values were higher in pubertal subjects than in pre-pubertal (p<0.001), while serum RBP4 levels were similar in pubertal and in pre-pubertal subjects (>0.1). We conclude that RBP4 is correlated with adiposity and insulin resistance in obese children, but it is not involved in the insulin resistance occurring during puberty.
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PMID:Variations of retinol binding protein 4 levels are not associated with changes in insulin resistance during puberty. 1979 89

The synthetic retinoid Fenretinide (FEN) increases insulin sensitivity in obese rodents and is in early clinical trials for treatment of insulin resistance in obese humans with hepatic steatosis (46). We aimed to determine the physiological mechanisms for the insulin-sensitizing effects of FEN. Wild-type mice were fed a high-fat diet (HFD) with or without FEN from 4-5 wk to 36-37 wk of age (preventive study) or following 22 wk of HF diet-induced obesity (12 wk intervention study). Retinol-binding protein-4 (RBP4) knockout mice were also fed the HFD with or without FEN in a preventive study. FEN had minimal effects on HFD-induced body weight gain but markedly reduced HFD-induced adiposity and hyperleptinemia in both studies. FEN-HFD mice gained epididymal fat but not subcutaneous or visceral fat mass in contrast to HFD mice without FEN. FEN did not have a measurable effect on energy expenditure, food intake, physical activity, or stool lipid content. Glucose infusion rate during hyperinsulinemic-euglycemic clamp was reduced 86% in HFD mice compared with controls and was improved 3.6-fold in FEN-HFD compared with HFD mice. FEN improved insulin action on glucose uptake and glycogen levels in muscle, insulin-stimulated suppression of hepatic glucose production, and suppression of serum FFA levels in HFD mice. Remarkably, FEN also reduced hepatic steatosis. In RBP4 knockout mice, FEN reduced the HFD-induced increase in adiposity and hyperleptinemia. In conclusion, long-term therapy with FEN partially prevents or reverses obesity, insulin resistance, and hepatic steatosis in mice on HFD. The anti-adiposity effects are independent of the RBP4 lowering effect.
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PMID:Long-term Fenretinide treatment prevents high-fat diet-induced obesity, insulin resistance, and hepatic steatosis. 1982 3

Resveratrol is a naturally occurring polyphenol known to affect energy metabolism and insulin sensitivity in mice and lipogenic gene expression in adipocytes. Here, we sought to get further insight into the impact of resveratrol on adipocyte biology by studying its effects on oxidative metabolism and the expression of the insulin resistance-related adipokines resistin and Retinol-Binding Protein 4 (RBP4) in mature adipocytes. Effects were assessed in 3T3-L1 adipocytes and in adipocytes derived from primary mouse embryonic fibroblasts (MEF). Besides reducing triacylglycerol content and the mRNA levels of lipogenic genes, resveratrol treatment resulted in both models in increased mRNA levels of carnitine palmitoyltransferase 1 (a rate-limiting enzyme in mitochondrial fatty acid oxidation), reduced mRNA levels of receptor interacting protein 140 (a suppressor of oxidative metabolism), and signs of enhanced flux through the fatty acid beta-oxidation pathway. In primary MEF-derived adipocytes, the treatment also increased mitochondrial DNA content and the mRNA levels of subunit II of cytochrome oxidase (a component of the mitochondrial respiratory chain) and of uncoupling protein 1. Expression of resistin and RBP4 was reduced in both adipocyte models following resveratrol treatment. The results indicate that resveratrol directly acts in mature white adipocytes to favor a remodeling toward increased oxidative capacity and reduced lipogenesis, while down-regulating two putative insulin resistance factors. These results constitute novel insights into resveratrol action in adipocytes that add to the potential of this food phytochemical and its synthetic analogues for the control of obesity and related metabolic disorders.
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PMID:Resveratrol enhances fatty acid oxidation capacity and reduces resistin and Retinol-Binding Protein 4 expression in white adipocytes. 2110 18


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