Takahito Jomori

Inhibition of gastric inhibitory polypeptide signaling prevents obesity

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−/−, Lepob/Lepob) generated by crossbreeding Gipr−/− and obese ob/ob (Lepob/Lepob) mice gained less weight and had lower adiposity than Lepob/Lepob 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.

Long-term treatment with fidarestat suppresses the development of diabetic retinopathy in STZ-induced diabetic rats.

It is important to suppress retinal vascular changes for prevention of the onset and progression of diabetic retinopathy. In the present study, we investigated the dose-response effect of an aldose reductase (AR) inhibitor, fidarestat, on retinal vascular changes in the retinas of streptozotocin (STZ)-induced diabetic rats. Fidarestat (0.5, 1, and 2 mg/kg) was administered once a day, from 4 days after STZ injection, for 15 months. Microaneurysms and thickness of the basement membrane were frequently observed in the untreated diabetic group as compared to the nondiabetic control group. In addition, the number of pericytes decreased in the untreated diabetic group. Fidarestat diminished the prevalence rate of microaneurysms, basement membrane thickness and decrease in the number of pericytes, and complete suppression was observed at a dose of 2 mg/kg. Fidarestat also dose-dependently inhibited sorbitol accumulation in the retina. Furthermore, a close correlation was observed between the prevalence rate of microaneurysms and the decrease in the number of pericytes, which indicated that damage to pericytes triggers retinal vascular changes. These results suggest that fidarestat, by virtue of its long-term correction of the accelerated polyol pathway, has a potential role in preventing the progression of diabetic retinopathy.

Sorbitol dehydrogenase overexpression potentiates glucose toxicity to cultured retinal pericytes.

The polyol pathway consists of two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). There is a growing body of evidence to suggest that acceleration of the polyol pathway is implicated in the pathogenesis of diabetic vascular complications. However, a functional role remains to be elucidated for SDH in the development and progression of diabetic retinopathy. In this study, cultured bovine retinal capillary pericytes were used to investigate the effects of SDH overexpression on glucose toxicity. High glucose modestly increased reactive oxygen species (ROS) generation, decreased DNA synthesis, and up-regulated vascular endothelial growth factor (VEGF) mRNA levels in cultured pericytes. SDH overexpression was found to significantly stimulate ROS generation in high glucose-exposed pericytes and subsequently potentiate the cytopathic effects of glucose. Fidarestat, a newly developed AR inhibitor, and N-acetylcysteine, an antioxidant, completely prevented these deleterious effects of SDH overexpression on pericytes. Furthermore, fidarestat administration was found to significantly prevent vascular hyperpermeability, the characteristic changes of the early phase of diabetic retinopathy, in streptozotocin-induced diabetic rats. Our present results suggest that SDH-mediated conversion of sorbitol to fructose and the resultant ROS generation may play an active role in the pathogenesis of diabetic retinopathy. Blockage of sorbitol formation by fidarestat could be a promising therapeutic strategy for the treatment of early phase of diabetic retinopathy.

Low‐serum culture system improves the adipogenic ability of visceral adipose tissue‐derived stromal cells

In obese adipose tissue, infiltrating macrophages release proinflammatory cytokines that trigger insulin resistance. An adipocyte‐based platform from visceral fat would be useful to elucidate the pathology of adipose inflammation and to develop therapeutic drugs for insulin resistance. ADSCs (adipose tissue‐derived mesenchymal stromal cells) expanded from subcutaneous fat are intensively studied as sources for regenerative medicine. However, the adipocyte culture system from visceral fat tissue has not been utilized yet. We aimed to establish the bioactive adipocyte platform using ADSCs from visceral fat pad. Stromal vascular fractions were processed from epididymal fat pads of Sprague—Dawley rats and three human omental fat pads, and the ADSCs were expanded using a low‐serum culture method. The responses of ADSCs and ADSC‐adipocytes (their adipogenic lineages) to pioglitazone, a therapeutic drug for diabesity, were evaluated by gene expression and ELISA. ADSCs (1×108) were expanded from 10 g of rat epididymal fat pads or human omental fat pads over five passages. Cell surface marker expressions revealed that visceral ADSCs were equivalent to mesenchymal stem cells. ADSC‐adipocytes expanded in the low‐serum culture system significantly showed higher expression of adipogenic markers [PPAR (peroxisome proliferator‐activated receptor) γ, LPL (lipoprotein lipase) and FABP4 (fatty acid‐binding protein 4)] and adipocytokines [adiponectin, resistin, leptin, PAI‐1 (plasminogen‐activator inhibitor 1) and IL (interleukin)‐10] than those expanded in a high‐serum culture system. Pioglitazone accelerated the adipogenic induction and increased adiponectin expression in human ADSCs by 57.9±5.8‐fold (mean±S.E.M.) relative to control cells (P<0.001). Both in rat and human ADSC‐adipocytes, TNF‐α significantly induced proinflammatory cytokines [MCP‐1 (monocyte chemoattractant protein‐1) and IL‐6] and suppressed adiponectin expression, while pioglitazone antagonized these effects. The present findings suggest that visceral ADSC‐adipocytes expanded in low‐serum culture would be useful for adiposcience and pharmacological evaluations.

Bezafibrate induces myotoxicity in human rhabdomyosarcoma cells via peroxisome proliferator-activated receptor α signaling

Fibrates, the ligands of peroxisome proliferator-activated receptor alpha (PPARalpha), are used as a class of lipid-lowering drugs in clinical practice for the treatment of dyslipidemia. Fibrates are well tolerated in most cases concomitantly with occasional adverse reactions including muscular toxicity, which is enhanced by the combination with statins. This study was designed to investigate the effects of bezafibrate as a PPARalpha agonist on human embryo rhabdomyosarcoma (RD) cells and possible mechanisms responsible for bezafibrate-mediated myopathy. The results revealed that bezafibrate caused a dose-dependent decrease in cell viability, which was fortified in association with atorvastatin at a pharmacological dose. Bezafibrate at toxic doses of 300 and 1000microM upregulated PPARalpha at the mRNA level, counteracted by a PPARalpha antagonist (MK886). Bezafibrate at a toxic dose induced typical apoptotic characteristics related to the inhibition of phosphorylation of Akt which was blocked by PPARalpha antagonist. Toxic doses of bezafibrate initiated a significant increase in pyruvate dehydrogenase kinase 4 mRNA and protein levels, compromised by MK886. These results suggest the critical roles of PPARalpha signaling in bezafibrate-induced myotoxicity and the involvement of apoptosis through Akt pathway.