[Show abstract][Hide abstract] ABSTRACT: Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr(-/-)) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr(-/-), Lep(ob)/Lep(ob)) generated by crossbreeding Gipr(-/-) and obese ob/ob (Lep(ob)/Lep(ob)) mice gained less weight and had lower adiposity than Lep(ob)/Lep(ob) mice. The Gipr(-/-) mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.
Nature Medicine 08/2002; 8(7):738-42. DOI:10.1038/nm727 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In an attempt to explore a novel therapeutic approach, a new synthetic sulfatide derivative (SKK60037) was evaluated in an acute rat model of P-selectin and leukocyte-dependent thrombotic glomerulonephritis (TG). In vitro, SKK60037 inhibits the function of P- and L-selectin more effectively than sialyl Lewis X (sLe(x)), a well-established selectin blocker. TG was induced by the intravenous administration of nephrotoxic globulin (NTG) to rats pretreated with a subclinical dose of lipopolysaccharide. In this model, platelet accumulation was remarkable within 10 minutes after induction of disease, followed by the infiltration of leukocytes, mainly neutrophils and macrophages. Thrombus formation and fibrinogen deposition in the glomeruli were observed within 1 hour, and they proceeded until 6 hours. P-selectin was highly expressed in glomeruli, whereas E-selectin and L-selectin ligands were not detected. We tested the effects of SKK60037 in this model in comparison with sLe(x) and antirat P-selectin monoclonal antibody (ARP2-4). SKK60037 blocked platelet accumulation in glomerular capillaries at 10 minutes after NTG injection. At 6 hours, leukocyte infiltration and thrombosis were significantly suppressed. Protective effects of SKK60037 were similar to those of ARP2-4, whereas sLe(x) showed minimum effect. The superior effects and more favorable characteristics of SKK60037 to sLe(x) suggest the potential of SKK60037 for clinical application.
American Journal of Kidney Diseases 09/2001; 38(2):265-73. DOI:10.1053/ajkd.2001.26085 · 5.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A newly developed selectin ligand inhibitor (SKK-60060) has been shown to block P- and L-selectins in vitro. We examined its inhibition of leukocyte–endothelial interactions in vivo against retinal ischemia-reperfusion injury and protective effects on ischemia-induced retinal damage.Retinal ischemia was induced by temporary ligation of the optic sheath for 60 min in anesthetized pigmented rats. SKK-60060 was administered 5 min before reperfusion and 4, 12, 24 and 48 hr thereafter, and leukocyte dynamics in the retinal microcirculation were evaluated using acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was also assessed histologically.SKK-60060 treatment suppressed leukocyte rolling during the reperfusion period; their numbers in the SKK-60060-treated rats were reduced by 67.0% (P < 0.01) and 53.2% (P < 0.01) at 12 and 24 hr, respectively. The subsequent leukocyte accumulation was also inhibited in SKK-60060-treated rats; accumulated leukocytes in the SKK-60060-treated rats were reduced by 72.8% (P < 0.01) and 53.4% (P < 0.01) at 12 and 24 hr, respectively. Retinal venous vasodilation in SKK-60060-treated rats were significantly suppressed at each time point (P < 0.05). Histological examination demonstrated protective effects of SKK-60060 on ischemia-induced retinal damage, which were more substantial in the inner retina (P < 0.01).SKK-60060 significantly inhibits the leukocyte rolling along the major retinal veins and their accumulation during the reperfusion period. These results suggest therapeutic potential of SKK-60060 for ischemia-reperfusion injury.
Experimental Eye Research 10/2000; 71(3-71):283-293. DOI:10.1006/exer.2000.0880 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. Sarpogrelate and its active metabolite (M-1) are potent inhibitors of human platelet aggregation, and selectively inhibit 5-HT2-serotonergic receptors on human platelets. However, the plasma concentrations of these inhibitors do not correlate to the inhibitory effect on platelet aggregation after administration. Sarpogrelate disappears from the plasma more rapidly in comparison to the duration of its pharmacological effect, and the plasma concentration of M-1 is very low (< 1/10 of sarpogrelate). In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effects of sarpogrelate and M-1, by considering both the competitive reversible inhibition and the association/dissociation process of these drugs at the 5-HT2 receptors on platelets (Most data used for analysis were obtained from the literatures, except for the serum protein binding rate of M-1). The developed model was well fitted to the actual data, and suggested that M-1 was more effective for the inhibition of platelet aggregation than sarpogrelate. On the basis of these findings, a new method was developed for predicting inhibitory effects on platelet aggregation after oral administration of sarpogrelate hydrochloride. This method is useful for planning a rational dosage regimen of sarpogrelate hydrochloride and predicting the duration of antiplatelet activity after the discontinuance of the drug.
Yakugaku zasshi journal of the Pharmaceutical Society of Japan 12/1999; 119(11):850-60. · 0.26 Impact Factor