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Preface[Hot Topic: Medicinal Strategies in the Treatment of Obesity (Guest Editor: Akio Inui)]

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An insidious increase in features of the metabolic syndrome such as obesity, insulin resistance and dyslipidemia, has led to a worldwide epidemic of type 2 diabetes mellitus[1]. This heterogenous disorder accounts for 90-95% of all diabetes and afflicts an estimated 6% of the adult population in western society. The worldwide frequency of diabetes is expected to continue to grow by 6% annually, potentially reaching a total of 200-300 million cases in 2010. The main force driving this increasing incidence is a staggering increase in obesity, the single most important contributor to the pathogenesis of diabetes[1].

Several studies have shown that even a modest weight loss significantly improves the glycemic control of type 2 diabetic patients[2]. Thus, in the overweight diabetic patients, the initial aim is to achieve weight loss before considering the administration of specific antidiabetic agents. Unfortunately, advice for changing dietary habits (as well as for increasing physical activity) generally has a poor long-term success rate mainly because of hyperphagia, a classical manifestation of diabetes mellitus that remained incompletely understood.

Appetite and body weight are regulated in the central nervous system, particularly in the hypothalamus[3-7]. Sixty years ago, appetite is thought to be regulated through two hypothalamic areas : The lateral hypothalamus (LH, feeding center) and the ventromedial hypothalamus (VMH, satiety center), which was described as the dual center hypothesis. However, it is now apparent that networks comprising not only of LH and VMH, but also of the arcuate (ARC), paraventricular (PVN), dorsomedial (DMH), and suprachiasmatic (SCN) nuclei are important, with the ARC-PVN axis playing a major role[3-7]. Leptin, secreted from fat cells in response to body fat stores, is a key afferent signal providing metabolic information to the hypothalamus, particularly the ARC[4,6]. Leptin reduces food intake and increases energy expenditure via hypothalamic neuropeptide system, closing a negative feedback loop whereby an increase of food intake and excess fat depot lead to a compensatory reduction of appetite and body fat stores.

The ARC has an important population of neurons synthesizing a very potent orexigenic peptide and a key target for leptin, neuropeptide Y (NPY)[3-8]. NPY regulates body weight by stimulating food intake and by decreasing energy expenditure through sympathetic nervous system and favoring fat deposition. Obesity results if central NPY administration is continued for a few days, and this process is accompanied by insulin resistance in muscle[3,5,7]. Modest overexpression of NPY in transgenic mice also leads to the development of obesity and insulin resistance after high-sucrose feeding[9]. The resulting syndrome mimicks the energetic and metabolic features of the well-known rodent genetic models of obesity and diabetes, notably the ob / ob mouse and fa / fa Zucker rat which lack leptin and its receptor, respectively. Most obese and diabetic animal models or humans are well characterized by high leptin levels and thought to be a state of leptin resistance[3,4,6,7]. NPY expression in the ARC are down-regulated in such animal models. However, also known are an increased sensitivity to NPY action, aberrant NPY expression in the DMH and other hypothalamic sites, and altered NPY regulation that acts to protect the increased body weight[3,5,7]. Therefore, although the exact cause and nature of leptin resistance need to be fully examined, NPY can escape from the inhibitory influences of leptin and anorectic neuropeptides, thereby contributing to hyperphagia and unopposed weight gain. Hyperphagia and altered fuel metabolism are prominent features not only of type 2 diabetes but also of insulin-deficient type 1 diabetes mellitus[7,10]. The pathogenesis of this hyperphagia has also been a focus of investigation since it was first documented experimentally more than 30 years ago and many hypotheses have been forwarded to explain the phenomenon. Urinary loss of glucose, depletion of body fuel stores, and the inability to use glucose as an energy substrate were each proposed in early studies to explain the stimulatory effect of diabetes on food intake. However, recent studies indicate that this type of diabetic hyperphagia results from the direct effect of decreased signaling within the hypothalamus by leptin[10]. The fall of circulating leptin in insulin-dependent diabetes is mediated by decreased insulin-mediated glucose metabolism in fat tissue. NPY synthesis in the ARC and release in the PVN are markedly increased in uncontrolled insulin-deficient diabetic animals[7]. Therefore, it is likely that hyperphagia seen in both type 1 and type 2 diabetes mellitus is mediated, at least in part, by alterations in NPY function which may result from either relative leptin deficiency (type 1) or leptin resistance (type 2). The orexigenic effects of NPY are mediated through specific G-protein coupled receptors, namely Y1 and Y5, among the five Y receptor subtypes that have been cloned so far[8]. During the past decade, orally-active antagonists for Y1 and Y5 receptors have been developed. The chronic treatment by Y1 and Y5 receptor antagonists mostly successfully reduced food intake and body weight and improved glycemic control in rodent models of obesity and diabetes [8,11]. These antagonists are currently being explored as potential therapeutic agents in humans. Although some doubts are raised against the efficacy of the Y5 receptor antagonist[12], NPY drugs will have a useful place as part of the treatment program, as anorectic sibutramine, a noradrenaline and 5-hydroxytryptamine reuptake inhibitor, produces weight loss and improves glycemic control in obese diabetic patients[2,11]. Successful approaches to attenuating appetite will be beneficial in treating both type 1 and type 2 diabetes mellitus, especially when combined with behavioral modification techniques to increase the adherance of weight loss plans by patients.


[1] Moller, D.E. Nature, 2001, 414, 821. [2] Scheen, A.J.; Lefebvre, P.J. Diabetes Metab. Res. Rev. , 2000, 16, 114. [3] Inui, A. Pharmacol. Rev., 2000, 52, 35. [4] Schwartz, M.W.; Woods, S.C.; Porte, Jr D.; Seeley, R.J.; Baskin, D.J. Nature, 2000, 404, 661. [5] Williams, G.; Harrold, J.A.; Cutler, D.J. Proc. Nutr. Soc., 2000, 59, 385. [6] Friedman, J.M.; Halaas, J.L. Nature, 1998, 395, 763. [7] Kalra, S.P.; Dube, M.G.; Pu, S.; Xu, B.; Horvath, T.L.; Kalra, P.S. Endocr. Rev., 1999, 20, 68. [8] Inui, A. Trends Pharmacol. Sci., 1999, 20, 43. [9] Kaga, T.; Inui, A.; Okita, M.; Asakawa, A.; Ueno, N. Kasuga, M.; Fujimiya, M.; Nishimura, N.; Dobashi, R.; Morimoto, Y.; Liu, I.M.; Cheng, J.T. Diabetes, 2001, 50,1206. [10] Sindelar, D.K.; Havel, P.J.; Seeley, R.J.; Wilkinson, C.W.; Woods, S.C.; Schwartz, M.W. Diabetes, 1999, 48, 1275. [11] Bray, G.A.; Tartaglia, L.A. Nature, 2000, 404, 672. [12] Kirkpatrick, P. Nat. Rev. Drug Discov., 2002, 1, 932.

Document Type: Book Review


Affiliations: Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan

Publication date: September 1, 2003

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