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イヌの肥満に対する新しい予防・治療法の開発 : β3アドレナリン受容体を介する脂肪細胞の活性化

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Please use this identifier to cite or link to this item:https://doi.org/10.11501/3137176

Title: イヌの肥満に対する新しい予防・治療法の開発 : β3アドレナリン受容体を介する脂肪細胞の活性化
Other Titles: Anti-Obesity Effects of Selective Agonists to the β3-Adrenergic Receptor in Dog
Authors: 佐々木, 典康1 Browse this author
Authors(alt): Sasaki, Noriyasu1
Issue Date: 25-Mar-1998
Publisher: Hokkaido University
Abstract: Obesity is the most common nutritional disorder in small animal practices, as in humans. Current treatment of obesity in dogs mostly relies on reducing energy intake by low calorie diet or fasting and increasing energy expenditure by exercise. It is known that in rodents and humans that the β3-adrenergic receptor (β3-AR) is present primarily in adipocytes and plays a significant role in the adrenergic stimulation of lipolysis and heat production. The aim of this study was to evaluate the effectiveness of β3-adrenergic agonists for the treatment and prevention of obesity in the dog without any side effects. 1) The acute lipomobilizing effects of β3-AR-selective agonists were examined in the dog in vivo. When a selective β3-AR agonist, CL316, 243, was infused intravenously into dogs, the plasma level of free fatty acid increased in 30 min and persisted at higher levels for several hours. ICI D7114, another β3-AR agonist, also showed a similar lipomobilizing effect, but with two order of lower potency. β3-AR agonist infusion also increased the plasma insulin level, and heart rate. Thus, the lipomobilization effect of the β3-AR agonist may be due to a direct action on the β3-AR in adipocytes. These results suggested that functional β3-AR is present in adipose tissues of the dog and that it is effective for in vivo lipomobilization. 2) The chronic anti-obesity effects of CL316, 243 were examined, because CL316, 243 was more effective than ICI D711 when given acutely at the same dose. When a selective β3-adrenergic agonist, CL316, 243 (0.1mg/kg), was given orally to adult beagles every day for 5-7 weeks, body weight and girth were decreased compared with control placebo-treated dogs. The mean food intake of drug-treated dogs was reduced as compared to the placebo treated dogs, although the change was not statistically significant. There was no significant difference in blood biochemistry data before the experiment and at the end of the first or second phase of the experiment. In postmortem examinations, no apparent difference in gross appearance of individual organs, except fat pads, was found between the two groups. The fat pads of various sites of drug-treated dogs were small and the adipose tissue composed of multilocular cells containing smaller amounts of triglyceride. Immunohistochemical examination of this adipose tissue showed a remarkable increase in brown adipocytes expressing a thermogenic protein, uncoupling protein (UCP). The increased expression of UCP and its mRNA in drug-treated dogs was also confirmed by Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses. It was concluded that treatment with a β3-AR agonist stimulates UCP expression, which may lead to an increase in energy expenditure, and thereby is useful for the treatment and prevention of obesity in the dog. 3) To clarify the molecular structure of dog β3-AR, its cDNA was cloned by RT-PCR method and the nucleotide and deduced amino acid sequences were determined. A β3-AR cDNA fragment (650bp) was obtained by amplifying RT-PCR of RNA extracted from dog white adipose tissue. The nucleotide sequence of the fragment was 81.9-91.1% homologous to the corresponding region of β3-AR cDNA of other species so far reported. The deduced amino acid sequence (206 amino acid residues) was also highly homologous (87.4-89.8%) to other species, which it showed low sequence homologies (about 50%) compared to the β1- and β2-ARs. Thus, it is likely that the cDNA fragment obtained in this study was the dog β3-AR. The N-linked glycosylation sites and hydrophobic transmembrane regions were highly conserved in the dog β3-AR, but three amino acid residues (N-X-S) were inserted as compared to the rodent β3-AR. The tissue distribution of dog β3-AR mRNA was studied using RT-PCR. Abundant expression of β3-AR mRNA was found in subcutaneous and visceral adipose tissues. Unlike in rodents, a weak but apparent expression of β3-AR mRNA was found in lung, liver, kidney and spleen. Thus, the tissue distribution of β3-AR in the dog is a little different from these in rodents, and this may explain why the β3-AR agonists induce tachycardia as well as lipomobilization in the dogs.
Conffering University: 北海道大学
Degree Report Number: 甲第4460号
Degree Level: 博士
Degree Discipline: 獣医学
Type: theses (doctoral)
URI: http://hdl.handle.net/2115/51478
Appears in Collections:学位論文 (Theses) > 博士 (獣医学)

Submitter: 佐々木 典康

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