A Common Haplotype in the G-Protein–Coupled Receptor Gene GPR74 Is Associated with Leanness and Increased Lipolysis (original) (raw)
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The Arg 389 Gly β1-adrenergic receptor gene polymorphism and human fat cell lipolysis
2001
BACKGROUND: The b 1 -adrenoceptor is a candidate gene for obesity because of its role in catecholamine-induced energy homeostasis. A common Arg 389 Gly variant polymorphism has been shown in recombinant cells to influence its-coupling properties. OBJECTIVE: To investigate the effect of the Arg 389 Gly b 1 -adrenoceptor polymorphism on catecholamine-induced lipolysis in native human fat cells obtained by subcutaneous biopsy. SUBJECTS: Two-hundred and ninety-eight apparently healthy male and female subjects with a wide variation in body mass index (BMI, 18 -60 kg=m 2 ). MEASURES: The lipolytic sensitivities and maximum lipolytic action of noradrenaline and the selective adrenoceptor agonists dobutamine (b 1 ), terbutaline (b 2 ) and CGP 12177 (b 3 ) were determined in isolated subcutaneous adipocytes and related to badrenoceptor radioligand binding parameters. RESULTS: No differences in the sensitivity or maximum lipolytic capacity of the agonists were found between the genotypes. This was true both when all subjects were analyzed together and when subgroups (lean, obese, men, women) were analyzed separately. Radioligand binding to b 1 -or b 2 -adrenoceptors was also similar between genotypes. The polymorphism had no important influence on either BMI or the distribution of obese and non-obese subjects between the genotypes. CONCLUSION: The distribution of the Arg 389 Gly polymorphism is similar in lean and obese subjects and has no apparent effect on the lipolytic response to b-adrenergic stimulation in native human adipocytes. This suggests, despite the altered coupling properties reported in recombinant cells, that the Arg 386 Gly polymorphism has no important influence on human obesity.
G protein-coupled receptors (GPCRs) are expressed essentially on all cells, facilitating cellular responses to external stimuli, and are involved in nearly every biological process. Several members of this family play significant roles in the regulation of adipogenesis and adipose me-tabolism. However, the expression and functional significance of a vast number of GPCRs in adipose tissue are unknown. We used a high-throughput RT-PCR panel to determine the expres-sion of the entire repertoire of non-sensory GPCRs in mouse white, and brown adipose tissue and assess changes in their expression during adipogenic differentiation of murine adipocyte cell line, 3T3-L1. In addition, the expression of GPCRs in subcutaneous adipose tissues from lean, obese, and diabetic human subjects was evaluated by re-analyzing RNA-sequencing data. We detected a total of 292 and 271 GPCRs in mouse white and brown adipose tissue, respectively. There is a significant overlap in the expression of GPCRs betwee...
2012
SCFA are produced in the gut by bacterial fermentation of undigested carbohydrates. Activation of the Ga i-protein-coupled receptor GPR41 by SCFA in b-cells and sympathetic ganglia inhibits insulin secretion and increases sympathetic outflow, respectively. A possible role in stimulating leptin secretion by adipocytes is disputed. In the present study, we investigated energy balance and glucose homoeostasis in GPR41 knockout mice fed on a standard low-fat or a high-fat diet. When fed on the low-fat diet, body fat mass was raised and glucose tolerance was impaired in male but not female knockout mice compared to wild-type mice. Soleus muscle and heart weights were reduced in the male mice, but total body lean mass was unchanged. When fed on the high-fat diet, body fat mass was raised in male but not female GPR41 knockout mice, but by no more in the males than when they were fed on the low-fat diet. Body lean mass and energy expenditure were reduced in male mice but not in female knockout mice. These results suggest that the absence of GPR41 increases body fat content in male mice. Gut-derived SCFA may raise energy expenditure and help to protect against obesity by activating GPR41.
Quantification of the mRNA expression of G protein-coupled receptors in human adipose tissue 5
G protein-coupled receptors (GPCRs) are important regulators of human physiology and therefore the targets of a large number of modern therapeutics. Although GPCRs are important regulators of adipose tissue endocrine and energy storage functions, the expression and function of a majority of GPCRs in adipose tissue is poorly characterized. A first step in the functional characterization of adipose tissue GPCRs is to accurately quantify the expression of GPCRs in adipose tissue. In this methods chapter, a detailed, step-by-step protocol is presented for the isolation of adipose tissue total RNA, its conversion into cDNA and the real-time PCR quantification of human GPCR mRNA expression relative to the mRNA expression of the stable adipose tissue housekeeping gene peptidylprolyl isomerase A (PPIA). A comprehensive list of 377 manually validated, commercially available GPCR qPCR primers allows facilitated swift quantification of either the entire human GPCRome or individual GPCRs, thus providing a sensitive, flexible, and cost-effective means of determining the mRNA expression of GPCRs in adipose tissue.
Biotechnology & Biotechnological Equipment, 2020
Overweight and obesity are serious and an ever-growing problem in modern society. It is a major risk factors for a number of chronic diseases, including type 2 diabetes, cardiovascular diseases and cancer. Obesity is a complex condition resulting from the interaction of a range of genetic and environmental factors. The aim of this study was to identify genetic markers predisposing to, and molecular pathways associated with, obesity in Bulgarian healthy individuals. Whole-exome sequencing was performed on two DNA pools: one constructed of 32 Bulgarian centenarians and one of 61 young healthy individuals, both with normal BMI, and allele frequencies of detected variants were estimated for each pool. Centenarians were chosen as their exome could be considered 'golden standard' for health and longevity, including being free of genetic variants predisposing to obesity. The young individuals group was chosen so variants predisposing to obesity after adolescence can be evaluated when compared to the centenarians. Of all variants designated to be associated with obesity by the database DisGeNET, only 17% were discovered in the studied pools. Using the platform ToppGene, we identified three overrepresented pathways based on genes with variants showing significant prelevance in allele frequency in the young individuals group. These three pathways were all G-protein coupled receptor associated pathways: the GPCR ligand binding pathway, the G alpha (s) signalling events pathway and the Class A/1 (Rhodopsin-like receptors) pathway. Understanding the genetic etiology of obesity in different populations is instrumental in developing pharmacological targets for population-specific obesity therapies.
Effects of obesity/fatty acids on the expression of GPR120
Molecular Nutrition & Food Research, 2014
The effects that fatty acids (FAs) exert on G protein-coupled receptor-120 (GPR120) levels, a receptor for FAs, are still unknown. We analyzed the association between GPR120 and obesity, and the FA effects on its expression. Methods and results: GPR120 levels were analyzed in visceral adipose tissue (VAT) from nonobese and morbidly obese subject. VAT GPR120 mRNA and protein levels were lower in morbidly obese subjects (p = 0.004). After, these subjects underwent a high-fat meal. GPR120 mRNA expression in peripheral blood mononuclear cells in the fasting state was lower in morbidly obese subjects (p = 0.04), with a decrease 3 h after a high-fat meal only in morbidly obese subjects (p = 0.043). Also, incubations of visceral adipocytes from these subjects were made with different FAs. In nonobese subjects, palmitic, oleic, linoleic, and docosahexaenoic acids produced an increase in GPR120 mRNA and protein levels (p < 0.05). In morbidly obese subjects, only linoleic acid produced an increase in GPR120 mRNA and protein levels (p < 0.05). Conclusion: Morbidly obese subjects had lower GPR120 mRNA and protein levels in VAT and a lower mRNA expression after a high-fat meal in peripheral blood mononuclear cells. The FAs effect on GPR120 mRNA and protein levels in visceral adipocytes was lower in morbidly obese subjects.
Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82
PLoS ONE, 2011
G protein-coupled receptors (GPCR) are involved in the regulation of numerous physiological functions. Therefore, GPCR variants may have conferred important selective advantages during periods of human evolution. Indeed, several genomic loci with signatures of recent selection in humans contain GPCR genes among them the X-chromosomally located gene for GPR82. This gene encodes a so-called orphan GPCR with unknown function. To address the functional relevance of GPR82 gene-deficient mice were characterized. GPR82-deficient mice were viable, reproduced normally, and showed no gross anatomical abnormalities. However, GPR82-deficient mice have a reduced body weight and body fat content associated with a lower food intake. Moreover, GPR82-deficient mice showed decreased serum triacylglyceride levels, increased insulin sensitivity and glucose tolerance, most pronounced under Western diet. Because there were no differences in respiratory and metabolic rates between wild-type and GPR82-deficient mice our data suggest that GPR82 function influences food intake and, therefore, energy and body weight balance. GPR82 may represent a thrifty gene most probably representing an advantage during human expansion into new environments. Citation: Engel KMY, Schrö ck K, Teupser D, Holdt LM, Tö njes A, et al. (2011) Reduced Food Intake and Body Weight in Mice Deficient for the G Protein-Coupled Receptor GPR82. PLoS ONE 6(12): e29400.
Journal of Biological Chemistry, 2000
Catecholamines play an important role in controlling white adipose tissue function and development. and ␣2-adrenergic receptors (ARs) couple positively and negatively, respectively, to adenylyl cyclase and are coexpressed in human adipocytes. Previous studies have demonstrated increased adipocyte ␣2/-AR balance in obesity, and it has been proposed that increased ␣2-ARs in adipose tissue with or without decreased -ARs may contribute mechanistically to the development of increased fat mass. To critically test this hypothesis, adipocyte ␣2/-AR balance was genetically manipulated in mice. Human ␣2A-ARs were transgenically expressed in the adipose tissue of mice that were either homozygous (؊/؊) or heterozygous (؉/؊) for a disrupted 3-AR allele. Mice expressing ␣2-ARs in fat, in the absence of 3-ARs (3-AR ؊/؊ background), developed high fat diet-induced obesity. Strikingly, this effect was due entirely to adipocyte hyperplasia and required the presence of ␣2-ARs, the absence of 3-ARs, and a high fat diet. Of note, obese ␣2-transgenic, 3 ؊/؊ mice failed to develop insulin resistance, which may reflect the fact that expanded fat mass was due to adipocyte hyperplasia and not adipocyte hypertrophy. In summary, we have demonstrated that increased ␣2/-AR balance in adipocytes promotes obesity by stimulating adipocyte hyperplasia. This study also demonstrates one way in which two genes (␣2 and 3-AR) and diet interact to influence fat mass.
Diabetes, 2001
Several adrenoceptor subtypes are expressed in adipocytes, which together exert their influence on adipocyte metabolism. Therefore, we specifically examined the interactive effect of Trp64Arg ( 3) and Glu 12 /Glu 9 (␣ 2b) adrenoceptor (AR) polymorphisms on energy metabolism and body composition in healthy women with a wide range of body habitus. We genotyped 909 unrelated women (age 55 ± 12 [mean ± SD] years, range 19-87; body weight 88 ± 22 kg, range 40-167; and BMI 33 ± 8 kg/m 2 , range 16-64) for Trp64Arg 3AR and Glu 12 /Glu 9 ␣2bAR variants. We examined the independent effect of the Glu 12 /Glu 9 ␣2bAR variant on body composition and energy balance, in a large cohort of Caucasian women (n = 909). A second goal was to examine the interaction effect of Glu 12 /Glu 9 ␣2bAR and Trp64Arg 3AR on the same phenotypes. The obesity-related phenotypes studied were as follows: body weight, BMI, fat mass, visceral fat, fat-free mass, resting metabolic rate (RMR), VO 2max , leisure time physical activity, and daily energy intake. Body composition and body fat distribution were measured by dual-energy X-ray absorptiometry and radiographic imagery, VO 2max by a treadmill test to exhaustion, and RMR by indirect calorimetry. An analysis of covariance indicated that in the entire cohort, there was no significant difference between Glu 12 /Glu 9 ␣2bAR carriers and control subjects for any of the obesity-related phenotypes that were examined. However, we observed a significant interaction effect of the Trp64Arg and Glu 12 /Glu 9 variants on fat mass (P = 0.009) and percent fat (P = 0.016). Age, height, body weight, BMI, fat-free mass, visceral fat, energy expenditure, respiratory quotient, physical fitness, and energy intake were not different among groups. Collectively, these findings support an interaction effect of the two adrenoceptor variants on body fatness in Caucasian women, although the physiological mechanism by which they exert this effect remains to be determined. Diabetes 50:91-95, 2001