Obesity is currently considered as an epidemic in the western world, and it represents a major risk factor for life-threatening diseases such as heart attack, stroke, diabetes, and cancer. Taking advantage of DNA microarray technology, we tried to identify the molecules explaining the relationship between obesity and vascular disorders, comparing mRNA expression of about 12,000 genes in white adipose tissue between normal, high fat diet-induced obesity (DIO) and D-Trp 34 neuropeptide Yinduced obesity in mice. Expression of monocyte chemoattractant protein-1 (MCP-1) mRNA displayed a 7.2-fold increase in obese mice as compared with normal mice, leading to substantially elevated MCP-1 protein levels in adipocytes. MCP-1 levels in plasma were also increased in DIO mice, and a strong correlation between plasma MCP-1 levels and body weight was identified. We also showed that elevated MCP-1 protein levels in plasma increased the CD11b-positive monocyte/macrophage population in DIO mice. Furthermore, infusion of MCP-1 into lean mice increased the CD11b-positive monocyte population without inducing changes in body weight. Given the importance of MCP-1 in activation of monocytes and subsequent atherosclerotic development, these results suggest a novel role of adiposity in the development of vascular disorders.

Moriya R, Shirakura T, Ito J, Mashiko S, Seo T. Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice. Am J Physiol Endocrinol Metab 297: E1358 -E1365, 2009. First published October 6, 2009 doi:10.1152/ajpendo.00412.2009.-Glucose ingestion stimulates the secretion of the incretin hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Despite the critical role of incretins in glucose homeostasis, the mechanism of glucose-induced incretin secretion has not been established. We investigated the underlying mechanism of glucose-induced incretin secretion in vivo in mice. Injection of glucose at 1 g/kg in the upper intestine significantly increased plasma GIP and GLP-1 levels, whereas injection of glucose in the colon did not increase GIP or GLP-1 levels. This finding indicates that the glucose sensor for glucose-induced incretin secretion is in the upper intestine. Coadministration of a sodium-glucose cotransporter-1 (SGLT1) inhibitor, phloridzin, with glucose in the upper intestine blocked glucose absorption and glucose-induced incretin secretion. ␣-methyl-D-glucopyranoside (MDG), an SGLT1 substrate that is a nonmetabolizable sugar, significantly increased plasma GIP and GLP-1 levels, whereas phloridzin blocked these increases, indicating that concomitant transport of sodium ions and glucose (substrate) via SGLT1 itself triggers incretin secretion without the need for subsequent glucose metabolism. Interestingly, oral administration of MDG significantly increased plasma GIP, GLP-1, and insulin levels and reduced blood glucose levels during an intraperitoneal glucose tolerance test. Furthermore, chronic MDG treatment in drinking water (3%) for 13 days reduced blood glucose levels after a 2-h fast and in an oral glucose tolerance test in diabetic db/db mice. Our findings indicate that SGLT1 serves as the intestinal glucose sensor for glucose-induced incretin secretion and that a noncalorigenic SGLT1 substrate ameliorates hyperglycemia by stimulating incretin secretion.glucagon-like peptide-1; glucose-dependent insulinotropic peptide; ␣-methyl-D-glucopyranoside; insulin resistance GLUCOSE-DEPENDENT INSULINOTROPIC peptide (GIP) and glucagonlike peptide-1 (GLP-1) are insulinotropic gut hormones secreted from K cells, which are abundantly detected in the upper intestine, and L cells, which are abundantly detected in the lower intestine. GIP and GLP-1 play an important role in the regulation of blood glucose levels in humans and rodents via several mechanisms, including amplification of glucose-induced insulin secretion. Research has shown that incretinbased therapies, such as GLP-1 analogs and agents that inhibit GIP and GLP-1 degradation, have a therapeutic advantage over current therapies in the treatment of type 2 diabetes (1, 5). Because patients with type 2 diabetes have lower postprandial incretin levels (10, 18, 21), a therapeutic strategy that has been receiving increasing interest involves the use of oral drugs that i...

Melanin-concentrating hormone (MCH) is a cyclic amino acid neuropeptide localized in the lateral hypothalamus. Although MCH is thought to be an important regulator of feeding behavior, the involvement of this peptide in body weight control has been unclear. To examine the role of MCH in the development of obesity, we assessed the effect of chronic intracerebroventricular infusion of MCH in C57BL/6J mice that were fed with regular or moderately high-fat (MHF) diets. Intracerebroventricular infusion of MCH (10 microg/day for 14 days) caused a slight but significant increase in body weight in mice maintained on the regular diet. In the MHF diet-fed mice, MCH more clearly increased the body weight accompanied by a sustained hyperphagia and significant increase in fat and liver weights. Plasma glucose, insulin, and leptin levels were also increased in the MCH-treated mice fed the MHF diet. These results suggest that chronic stimulation of the brain MCH system causes obesity in mice and imply that MCH may have a major role in energy homeostasis.

. Characterization of MCH-mediated obesity in mice. Am J Physiol Endocrinol Metab 284: E940-E945, 2003. First published January 28, 2003 10.1152 10. /ajpendo.00529.2002 hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus. Recently, we demonstrated that chronic intracerebroventricular infusion of MCH induced obesity accompanied by sustained hyperphagia in mice. Here, we analyzed the mechanism of MCH-induced obesity by comparing animals fed ad libitum with pair-fed and control animals. Chronic infusion of MCH significantly increased food intake, body weight, white adipose tissue (WAT) mass, and liver mass in ad libitum-fed mice on a moderately high-fat diet. In addition, a significant increase in lipogenic activity was observed in the WAT of the ad libitumfed group. Although body weight gain was marginal in the pair-fed group, MCH infusion clearly enhanced the lipogenic activity in liver and WAT. Plasma leptin levels were also increased in the pair-fed group. Furthermore, MCH infusion significantly reduced rectal temperatures in the pair-fed group. In support of these findings, mRNA expression of uncoupling protein-1, acyl-CoA oxidase, and carnitine palmitoyltransferase I, which are key molecules involved in thermogenesis and fatty acid oxidation, were reduced in the brown adipose tissue (BAT) of the pair-fed group, suggesting that MCH infusion might reduce BAT functions. We conclude that the activation of MCH neuronal pathways stimulated adiposity, in part resulting from increased lipogenesis in liver and WAT and reduced energy expenditure in BAT. These findings confirm that modulation of energy homeostasis by MCH may play a critical role in the development of obesity.melanin-concentrating hormone; body weight; liver weight; brown adipose tissue OBESITY IS CAUSED BY AN IMBALANCE between caloric intake and energy expenditure. The hypothalamus plays an important role in the integrated regulation of this homeostatic balance. In the past several years, a number of hypothalamic neuropeptides involved in feeding and energy homeostasis were discovered. Melanin-concentrating hormone (MCH), a cyclic neuropeptide originally isolated from salmon pituitaries (8), was recently identified as a mediator of energy homeostasis. In rodents, MCH is predominantly expressed in the lateral hypothalamic area, pivotal center of energy homeostasis (1,20). Qu et al. (15) found that MCH stimulated food intake after intracerebroventricular (ICV) administration. Furthermore, mRNA levels of MCH increased in genetic obesity models such as ob/ob, db/db, and A Y /a mice and Zucker fatty rats (5,14,15,21). These results suggest that MCH might play an important role in the regulation of energy homeostasis. In support of the potential role of MCH, prepro-MCH-deficient mice are lean and hypophagic and show a slight increase in their metabolic rate (18). Moreover, prepro-MCH overexpression in transgenic mice is marked by obesity and insulin resistance (11). However, these models do not rule out influence of the neur...

Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult to determine the relative importance of the Y1 receptor in feeding regulation. Herein we certified that the Y1 receptor is a major feeding receptor of NPY by using the potent and selective Y1 antagonist (-)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine (J-115814) and Y1 receptor-deficient (Y1-/-) mice. J-115814 displaced (125)I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y(1) receptors with K(i) values of 1.4, 1.8, and 1.9 nM, respectively, and inhibited NPY (10 nM)-induced increases in intracellular calcium levels via human Y1 receptors (IC(50) = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (K(i) > 10 microM), Y4 (K(i) = 640 nM) and Y5 receptors (K(i) = 6000 nM). Intracerebroventricular (ICV) (10-100 microg) and intravenous (IV) (0.3-30 mg/kg) administration of J-115814 significantly and dose-dependently suppressed feeding induced by ICV NPY (5 microg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) administration of J-115814 (3-30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by ICV NPY (5 microg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1-/- mice and was suppressed in wild-type and Y5-/- mice. These findings clearly suggest that J-115814 inhibits feeding behaviors through the inhibition of the typical Y1 receptor. We conclude that the Y1 receptor plays a key role in regulating food intake.

Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 microg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.antiobesity effect ͉ Y5R-deficient mice ͉ receptor occupancy N europeptide Y (NPY), a 36-aa peptide neurotransmitter, is one of the most potent orexigenic substances when injected into the brain. NPY expression is widely distributed in the CNS, including the hypothalamus, a region involved in energy homeostasis (1). NPY content and mRNA levels in the hypothalamus respond to feeding status, including food deprivation and refeeding (2, 3). Chronic central infusion of NPY in rodents results in a syndrome similar to that in some genetic obesity models, characterized by hyperphagia, insulin resistance, hyperinsulinemia, and reduced thermogenic activity in brown adipose tissue (4). NPY is, therefore, thought to have a major role in the physiological control of energy homeostasis, making it a target for the development of antiobesity agents.Five types of NPY receptors have been characterized (5). Pharmacological data suggest that the NPY Y5 receptor (Y5R) is involved in feeding regulation. For example, functional and binding activities of different peptide agonists at the Y5R in vitro correlated strongly with their efficacy in stimulating food intake (6). Administration of Y5R antagonists suppressed Y5R agonist-induced feeding (7), and mice lacking the Y5R showed a diminished response to exogenously administered Y5R agonists (8). The Y5R is also reported to regulate brown fat thermogenesis and energy expenditure (9). In addition, chronic intracerebroventricular administration of a Y5R-specific agonist, D-Trp-34NPY, produces obesity (10). These findings suggest that the Y5R is involved in the development of obesity. However, the physiological role of the Y5R in obesity models, rather than models that rely on exogenously added Y5R agonists, remains undefined.We reported that orally administered Y5R antagonist [2-(3,3-dimethyl-1-oxo-4H-1H-xanthen-9-yl)-5,5-dimethyl-cyclohexane-1,3-dione] reduced Y5R agonist-induced feeding and Y5R agonist-induced obesity (7, ...

In addition to the specific modulation of respective NPY receptor subtypes, recent investigations have revealed that modulation of multiple NPY receptor subtypes produces additive or even synergistic anti-obesity effects. Development of reliable small molecule Y1, Y2 and Y4 receptor ligands would greatly accelerate investigations and drug discovery.