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Effect of ?2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

ABSTRACT: The ?2-adrenergic system is an important regulator of human adipose tissue lipolysis. Polymorphisms that result in amino acid substitutions in the ?2-adrenergic receptor have been reported to alter lipolysis. We hypothesized that variations in the amino acid at position 16 of the ?2-adrenergic receptor would result in different lipolytic responses to intravenous epinephrine and exercise. 17 volunteers homozygous for glycine at position 16 (Gly/Gly, nine female) and 16 volunteers homozygous for arginine at position 16 (Arg/Arg, eight female) of the ?2-adrenergic receptor participated in this study. On one study day participants received infusions of epinephrine at submaximal (5 ng kg(-1) min(-1)) and maximal (40 ng kg(-1) min(-1)) lipolytic doses. The other study day volunteers bicycled for 90 min at 50-60% of maximum oxygen consumption (VO2max). [9,10-(3)H] Palmitate was infused both days to measure free fatty acid - palmitate kinetics. Oxygen consumption was measured using indirect calorimetry. Palmitate release rates in response to epinephrine and exercise were not different in the Gly/Gly and Arg/Arg participants. The only statistically significant difference we observed was a lesser ?VO2 in Arg/Arg volunteers in response to the submaximal epinephrine infusion. The polymorphisms resulting in Arg/Arg and Gly/Gly at position 16 of the ?2-adrenergic receptor do not result in clinically meaningful differences in lipolysis responses to epinephrine or submaximal exercise.

SUBMITTER: Du S

PROVIDER: S-EPMC4098745 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Effect of β2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

Du Shichun S Joyner Michael J MJ Curry Timothy B TB Eisenach John H JH Johnson Christopher P CP Schrage William G WG Jensen Michael D MD

Physiological reports 20140520 5

The β2-adrenergic system is an important regulator of human adipose tissue lipolysis. Polymorphisms that result in amino acid substitutions in the β2-adrenergic receptor have been reported to alter lipolysis. We hypothesized that variations in the amino acid at position 16 of the β2-adrenergic receptor would result in different lipolytic responses to intravenous epinephrine and exercise. 17 volunteers homozygous for glycine at position 16 (Gly/Gly, nine female) and 16 volunteers homozygous for a ...[more]

PMID: 24844639

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Project description:Evidence suggests that variation in the length of the poly-C repeat in the 3' untranslated region (3'UTR) of the ?2-adrenergic receptor gene (ADRB2) may contribute to interindividual variation in ?-agonist response. However, methodology in previous studies limited the assessment of the effect of sequence variation in the context of poly-C repeat length. The objectives of this study were to design a novel genotyping method to fully characterize sequence variation in the ADRB2 3'UTR poly-C repeat in asthma patients treated with inhaled corticosteroid and long-acting ?2-adrenergic agonist (ICS/LABA) combination therapy, and to analyze the effect of the poly-C repeat polymorphism on clinical response.In 2,250 asthma patients randomized to treatment with budesonide/formoterol or fluticasone/salmeterol in a six-month study (AstraZeneca study code: SD-039-0735), sequence diversity in the ADRB2 poly-C repeat region was determined using a novel sequencing-based genotyping method. The relationship between the poly-C repeat polymorphism and the incidence of severe asthma exacerbations, and changes in pulmonary function and asthma symptoms from baseline to the average during the treatment period, were analyzed.Poly-C repeat genotypes were assigned in 97% (2,192/2,250) of patients. Of the 13 different poly-C repeat alleles identified, six alleles occurred at a frequency of >5% in one or more population in this study. The repeat length of these six common alleles ranged from 10 to 14 nucleotides. Twelve poly-C repeat genotypes were observed at a frequency of >1%. No evidence of an association between poly-C repeat genotype and the incidence of severe asthma exacerbations was observed. Patients' pulmonary function measurements improved and asthma symptoms declined when treated with ICS/LABA combination therapy regardless of poly-C repeat genotype.The extensive sequence diversity present in the poly-C repeat region of the ADRB2 3'UTR did not predict therapeutic response to ICS/LABA therapy.

Project description:The regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer's disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multimeric protein complex that has multiple isoforms including α and α', which are seen as a doublet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/- mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypothalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life.

Dataset Information

Effect of ?2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

Publications

Effect of β2-adrenergic receptor polymorphisms on epinephrine and exercise-stimulated lipolysis in humans.

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