Anti-obesity and anti-diabetic effects of CL 316, 243, a highly specific β3-adrenoceptor agonist, in yellow KK mice

Yoshida, Toshihide; Sakane, Naoki; Wakabayashi, Yasuo; Umekawa, Tsunekazu; Kondo, Motoharu

doi:10.1016/0024-3205(94)00408-0

Cited by 103 publications

(70 citation statements)

References 22 publications

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“…The CL-treatment also resulted in about 3-fold increase in plasma free fatty acid level , and significant reduction of the plasma levels of glucose,insulin and T3 in obese mice. These effects of CL were essentially the same as those reported previously [17,24].…”

Section: Effects Of Cl-treatment On Tissue Weights and Blood Parameterssupporting

confidence: 90%

“…UCP2 and UCP3 expression in skeletal muscle have been reported to increase in response to fasting [1,8] , which is a representative cue to elevate plasma free fatty acids. The present results showed that administration of CL produced a sustained elevation of plasma free fatty acids as a result of their potent lipomobilizing action on adipose tissues [19,24]. Moreover, Weigle et al [23] demonstrated that elevation of circulating free fatty acid levels induced by Intralipid plus heparin infusion mimicked the increased expression of muscle UCP3 seen after fasting.…”

Section: Discussionsupporting

confidence: 56%

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.BETA.3-Adrenergic Agonist Up-Regulates Uncoupling Proteins 2 and 3 in Skeletal Muscle of the Mouse.

Nakamura

Nagase

Asano

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. Chronic stimulation of the β3-adrenergic receptor (AR) in obese animals resulted in a reduced adiposity associated with an increased expression of thermogenic uncoupling protein (UCP)1 in adipose tissues. In this study, the mRNA expression of newly cloned UCP isoforms (UCP2 and UCP3) were examined in obese yellow KK and C57BL control mice. UCP2 mRNA was found in all tissues examined, with higher levels in adipose tissues and skeletal muscle of the obese mice. UCP3 mRNA was expressed in skeletal muscle, heart and brown adipose tissue similarly in the two mouse strains. Daily injection of a selective β3-adrenergic agonist, CL316,243 (0.1 mg/kg), for 10 days resulted in a marked reduction of white fat pad weight and 1.8~4.8-fold increase in the mRNA levels of UCP2 and UCP3 in skeletal muscle of obese mice. No noticeable change in the UCP2 and 3 mRNA levels was found in brown and white adipose tissues. It was also found that CL316,243 injection produced a marked and sustained elevation of the plasma free fatty acid level. These results, together with our previous findings of the fatty acid-induced UCP expression in a myocyte cell line in vitro, suggest that the β3-AR agonist-induced UCP expression in skeletal muscle may be mediated through the elevated plasma free fatty acids. It was also suggested that anti-obesity effect of β3-AR agonists is attributable to increased thermogenesis not only by UCP1 but also by UCP2 and UCP3.KEY WORDS: adipose tissue, β3-adrenergic agonist, fatty acid, obese mouse, uncoupling protein.

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Section: Effects Of Cl-treatment On Tissue Weights and Blood Parameterssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 56%

.BETA.3-Adrenergic Agonist Up-Regulates Uncoupling Proteins 2 and 3 in Skeletal Muscle of the Mouse.

Nakamura

Nagase

Asano

et al. 2001

The Journal of Veterinary Medical Science

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“…Sci. 60(4): 459-463, 1998 tolerance, and reduces adiposity [17,20]. Similar antiobesity and anti-diabetic effects of β3-AR agonists were also reported in other obese mouse and rat models [1,4,10].…”

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confidence: 54%

Anti-Obesity Effects of Selective Agonists to the .BETA.3-Adrenergic Receptor in Dogs. I. The Presence of Canine .BETA.3-Adrenergic Receptor and in vivo Lipomobilization by Its Agonists.

Sasaki

Uchida

Niiyama

et al. 1998

The Journal of Veterinary Medical Science

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ABSTRACT. It is known that in rodents and humans the β3-adrenergic receptor (β3-AR) is present primarily in adipocytes and plays a significant role in the adrenergic stimulation of lipolysis. We examined the expression of β3-AR mRNA in the dog and the lipomobilizing effects of β3-AR-selective agonists in vivo. Reverse transcription polymerase chain reaction of RNA extracted from dog adipose tissue produced a cDNA fragment, the nucleotide sequence of which was highly homologous to the corresponding regions of human (86.4%) and mouse (79.5%) β3-AR cDNA. The β3-AR mRNA was present at high levels in subcutaneous and visceral adipose tissues, but undetectable in other organs. When a selective β3-AR agonist, CL316,243, was infused intravenously into beagle 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 lower potency. β3-AR agonist infusion also increased the plasma insulin level. These results suggested that functional β3-AR is present in adipose tissues of the dog and that it is effective for in vivo lipomobilization. -KEY WORDS: adipose tissue, adrenergic agonist, β3-adrenergic receptor, canine, lipomobilization.J. Vet. Med. Sci. 60(4): 459-463, 1998 tolerance, and reduces adiposity [17,20]. Similar antiobesity and anti-diabetic effects of β3-AR agonists were also reported in other obese mouse and rat models [1,4,10]. In veterinary practice for companion animals, obesity is the most common nutritional disorder, as in humans [5,15]. However, in contrast to rodents and humans, there have been few reports about β3-AR and effects of its agonists in the canine and feline. As a series of experiments for possible application of β3-AR agonists to the pharmacological treatment of companion animal obesity, in this study, we confirmed the presence of canine β3-AR by analysis of its cDNA, and examined the acute lipomobilizing effects of two selective β3-AR agonists in non-obese healthy dogs. MATERIALS AND METHODS Animals:One male and six female adult beagle dogs weighing 10-13 kg were used several times each under various experimental conditions. Each experiment was carried out at least 7 days after the last one. The animal care and procedures were in accordance with the guidelines of the Animal Care and Use Committee of Hokkaido University. In mammals, there are two types of adipose tissues, white and brown adipose tissues. Although both tissues consist of a large number of adipocytes accumulating triglycerides, their physiological roles contrast: that is, white adipose tissue is the major site of energy storage and releases fatty acids into blood, while brown adipose tissue oxidizes fatty acids to produce heat and is the site of energy expenditure. Hydrolysis of triglycerides in adipocytes is largely dependent on the β-adrenergic action of catecholamines. Pharmacological and biochemical studies have demonstrated that three isoforms of the β-adrenergic receptor (AR), β1-, β...

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“…Chronic ␤ 3 -agonist treatment causes increased insulin sensitivity in various models (9,(32)(33)(34). However, chronic CL316243 administration had no effect on the diabetes phenotype of A-ZIP/F-1 mice, which suggests that the antidiabetic effects of this ␤ 3 agonist require adipose tissue.…”

Section: Discussionmentioning

confidence: 99%

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

Гаврилова

Marcus‐Samuels²,

Reitman³

2000

Diabetes

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Stimulation of ␤ 3 -adrenergic receptors increases metabolic rate via lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Other acute effects include decreased gastrointestinal motility and food intake and increased insulin secretion. Chronic treatment with a ␤ 3 agonist ameliorates diabetes and obesity in rodents. We studied the effects of ␤ 3 stimulation in A-ZIP/F-1 mice, which have virtually no WAT, a reduced amount of BAT, severe insulin resistance, and diabetes. In contrast with wild-type mice, treatment of A-ZIP/F-1 mice with CL316243, a ␤ 3 -adrenergic agonist, did not increase O 2 consumption. A single dose of CL316243 produced a 2-fold increase in serum free fatty acids, a 53-fold increase in insulin, and a 2.4-fold decrease in glucose levels in wild-type mice but no change in A-ZIP/F-1 animals. The A-ZIP/F-1 mice also did not show reduced gastrointestinal motility or 24-h food intake during ␤ 3 stimulation. Chronic administration of CL316243 to the A-ZIP/F-1 mice did not improve their thermogenesis, hyperglycemia, or hyperinsulinemia. Thus, all of the ␤ 3 effects studied were absent in the lipoatrophic A-ZIP/F-1 mice, including the effects on nonadipose tissues. From these results, we suggest that all of the effects of ␤ 3 agonists are initiated at the adipocyte with the nonadipose effects being secondary events presumably mediated by signals from adipose tissue. Diabetes 49: [1910][1911][1912][1913][1914][1915][1916] 2000 T he ␤ 3 -adrenergic receptor is a G protein-coupled receptor found predominantly on adipocytes (1-3). ␤ 3 -Adrenergic receptor activity and mRNA have also been reported in the smooth muscle of the gastrointestinal tract and in other sites (2,4,5). ␤ 3 -Adrenergic stimulation causes lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Chronic administration of a ␤ 3 -adrenergic agonist leads to decreased fat mass and improvement of diabetes in rodent obesity models (6,7). Human ␤ 3 research has been hampered by the lack of a sufficiently selective drug (8), but in one study, ␤ 3 -agonist treatment increased nonoxidative glucose disposal and fractional fat oxidation (9). In rodents, acute ␤ 3 -agonist treatment has effects besides stimulating lipolysis and thermogenesis, such as inhibiting gastrointestinal motility and food intake and stimulating insulin secretion. The mechanisms underlying these effects are not well understood.Several transgenic mouse lines with reduced amounts of adipose tissue have been developed (10-13). In the A-ZIP/F-1 mouse, adipose tissue ablation was achieved by adiposeselective expression of a dominant negative protein to certain B-ZIP transcription factors. The A-ZIP/F-1 mice have virtually no WAT, a reduced amount of BAT, leptin deficiency, severe insulin resistance and diabetes, and an accelerated adaptation to fasting (12,14). Surgical transplantation of adipose tissue into A-ZIP/F-1 mice reverses their metabolic syndrome, which demonstrates that the lack of fat is the cause of ...

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Anti-obesity and anti-diabetic effects of CL 316, 243, a highly specific β3-adrenoceptor agonist, in yellow KK mice

Cited by 103 publications

References 22 publications

.BETA.3-Adrenergic Agonist Up-Regulates Uncoupling Proteins 2 and 3 in Skeletal Muscle of the Mouse.

.BETA.3-Adrenergic Agonist Up-Regulates Uncoupling Proteins 2 and 3 in Skeletal Muscle of the Mouse.

Anti-Obesity Effects of Selective Agonists to the .BETA.3-Adrenergic Receptor in Dogs. I. The Presence of Canine .BETA.3-Adrenergic Receptor and in vivo Lipomobilization by Its Agonists.

Lack of responses to a beta3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice.

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