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Volume 118 (2001)
- Issue 6 Pages 363-
- Issue 5 Pages 303-
- Issue 4 Pages 251-
- Issue 3 Pages 147-
- Issue 2 Pages 81-
- Issue 1 Pages 5-
Volume 118, Issue 5
Displaying 1-8 of 8 articles from this issue
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Reviews: The Concept of Producing Anti-obesity Drugs: Its Past, Present and Future Prospects
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Koji FUKAGAWA, Toshiie SAKATAArticle type: Others
Subject area: Others
2001 Volume 118 Issue 5 Pages 303-308
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSCatecholamine, dopamine, serotonine (5HT) and neuronal histamine are anorectic monoamines and act as anorectic neurotransmitters. The anorectic agents as modulators of these monoamines inhibit appetite by activating release together with suppressing reuptake of those monoamines. The anorectic agents were classified in clinical use into either α1, β-adrenergic receptor agonists or 5HT-receptor agonist. Dexfenfluramine, a 5HT-receptor agonist, was inhibited in clinical use because of its cardiac complications including pulmonary hypertension and valvelar disease. Mazindol is an adrenergic agonist and the solitary antiobesity drug used clinically in Japan. Sibutramine shows the effects of both β-adrenergic and serotonergic receptor agonsists. Sibutramine induces not only appetite suppression but also acceleration of peripheral energy expenditure. No histaminergic anorectics have been employed in the clinical situation to date. L-Histizine, precursor amino acid of endogenous neuronal histamine, is useful for suppression of food intake, lipolytic acceleration of peripheral adipose tissues and enhanced energy expenditure in both animals and humans. L-Histizine thus inspires development of more effective and safer anorectics that can be used without suffering from the rebound phenomenon of body weight.View full abstractDownload PDF (898K) -
Shuji HIDAKA, Yoshihiro OGAWA, Kazuwa NAKAOSubject area: Others
2001 Volume 118 Issue 5 Pages 309-314
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThe discovery of the adipose-derived hormone leptin has generated interest in the interaction between peripheral signals and brain targets involved in the regulation of feedings and energy balance. Potential anti-obesity drugs can be based on any intervention between the neuropeptide and its receptor that would alter the biological responses mediated by the neuronal network, in particular, food intake, metabolism and energy expenditure. Modulation of neurons in the arcuate nucleus by leptin results in reduced expression of neuropeptide Y and agouti-related protein, and increased expression of pro-opiomelanocortin (the precursor of a-melanocyte-stimulating hormone) and cocaine- and amphetamine- regulated transcript. Whether leptin finds its way into general usage as an anti-obesity drug, the use of modern methods to identify and target the components of leptin signaling pathway will form the basis for new pharmacological approaches to the treatment of obesity.View full abstractDownload PDF (849K) -
Past, present and futureYasuto TAKAKURA, Toshihide YOSHIDASubject area: Others
2001 Volume 118 Issue 5 Pages 315-320
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSβ3-Adrenergic receptors (β3-AR) play an important role in the thermogenesis in brown adipose tissue and lipolysis in white adipose tissue. β3-AR agonists developed in the early stages produced marked weight reduction and an anti-diabetic effect in rats and mice, but did not in humans, because of the difference in the chemical structure of the β3-AR. In 1995, a naturally occurring variant (Trp64Arg) of the human β3-AR gene was shown to be correlated with obesity and insulin resistance in Pima Indians. Moreover, the fact that white adipocytes produce various hormones and cytokines that cause life-style-related disease was recently made clear. Because the reduction of the visceral fat is throught to be important to prevent these diseases, the expectations for the human β3-AR agonist having a novel anti-obesity effect are rising. Some interesting findings were recently reported with β3-AR agonists: the difference of the lipolysis was dependent on the existence of the Trp64Arg mutation and the up-regulation effect of the UCP1 and β3-ARs themselves in the adipose tissue and skeletal muscle. Therefore, we introduce informations (past, present and future) on β3-AR agonists in this paper.View full abstractDownload PDF (869K) -
Takashi KADOWAKISubject area: Others
2001 Volume 118 Issue 5 Pages 321-326
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSPeroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARγ by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARγ activity observed in heterozygous PPARγ-deficient mice or the Pro 12 Ala polymorphism in human PPARγ has been shown to prevent insulin resistance and obesity induced by a high-fat (HF) diet. We investigated whether functional antagonism toward PPARγ/RXR could be used to treat obesity and type 2 diabetes. We show herein that moderate reduction of PPARγ with an RXR antagonist or a PPARγ antagonist decreases triglyceride (TG) content in white adipose tissue, skeletal muscle and liver. These inhibitors potentiate leptin’s effects and stimulated adiponectin levels, which increases fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, severe reduction of PPARγ by treatment of heterozygous PPARγ-deficient mice with an RXR antagonist or a PPARγ antagonist depletes white adipose tissue and markedly decreases leptin and adiponectin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggest that appropriate functional antagonism of PPARγ/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.View full abstractDownload PDF (653K) -
Masayuki SAITO, Atsuko OHASHISubject area: Others
2001 Volume 118 Issue 5 Pages 327-333
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSUncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the β-adrenergic action of norepinephrine. Since the β3-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on β1-and β2-adrenoceptos. Therefore, β3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effactive anti-obesity tool.View full abstractDownload PDF (1128K) -
Tetsuya KAKUMA, Toshiie SAKATASubject area: Others
2001 Volume 118 Issue 5 Pages 334-339
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSRecent findings have shown that supplementation of leptin decreases body weight in leptin-deficient ob/ob mice through its suppressive effect on food intake and accelerating effect on energy expenditure, particularly on peripheral fat lipolysis. When endogenously hyperleptinemic obese rats were further induced to be hyperleptinemic exogeously using adenovirus vector, their body fat mass was reduced but not food intake. These findings implicate a direct lipolytic action of leptin on peripheral adipose tissues in obese rats because leptin transport capacity across the blood-brain barrier is almost saturated by the relative hyperleptinemia. Recovery from excessive body fat accumulation after adenovirus-induced hyperleptinemia is much slower than that after caloric restriction because there may be difference between those treatments in decreased lipogenic enzymes activities and/or increased activities of fatty acid oxidative enzymes and thermogenic uncoupling proteins. The fat melting effects of leptin may show its crucial pharmacologic potencies to design therapeutic strategies against morbid obesity. The studies on leptin provide a better understanding for creative approaches to anti-obesity drug that are efficient for reducing body fat mass without harmful side-effects.View full abstractDownload PDF (915K) -
Masatomi TSUJI, Nobuhiko SAITO, Shuji INOUESubject area: Others
2001 Volume 118 Issue 5 Pages 340-346
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSThere are two types of anti-obesity agents which are classified as inhibitors of absorption: inhibitors of lipid and carbohydrate absorption. Inhibitors of lipid absorption consist of lipase inhibitor (orlistat, Nomma Herb’s extract (CT-II) and fat substitute (olestra, sucrose polyester). Orlistat is now available as an anti-obesity drug in the USA and Europe. CT-II may be useful as a functional diet. Application of fat substitute is still limited in snack food. As for inhibitors of carbohydrate absorption, α-glucosidase inhibitors are now available as anti-diabetic drugs. To develop these agents for anti-obesity drug, solution of adverse effects on the gastrointestinal tract are necessary.View full abstractDownload PDF (872K) -
Hicomichi OKUDA, Li-Kun HANSubject area: Others
2001 Volume 118 Issue 5 Pages 347-351
Published: 2001
Released on J-STAGE: September 27, 2002
JOURNAL FREE ACCESSWe suggested a strategy for identifying anti-obesity drugs. The strategy aimed to prevent obesity through inhibiting intestinal absorption of dietary fat. Intestinal absorption of dietary fat was found to be reduced by tea saponin and chitosan through inhibiting pancreatic lipase activity, by chondroitin sulfate through inhibiting both pancreatic lipase activity and fatty acid absorption, and by lactosucrose through inhibiting β-monoglyceride absorption. All these functional substances reduced plasma triglyceride levels previously elevated by oral administration of a lipid emulsion containing corn oil. Furthermore, these substances were found to cause reduction in perimetrial adipose tissue weight, which had been elevated by oral administration of a high fat diet (containing 40% of beef tallow) to female mice. Based on these results, a strategy for identifying anti-obesity drugs was discussed.View full abstractDownload PDF (645K)
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