JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice

AbstractType 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice.JTT-553 was repeatedly administered to DIO and KK-Ay mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-Ay mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-Ay mice.These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight

JTT-130, a novel intestinespecific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner,”

Microsomal triglyceride transfer protein (MTP) is involved in the assembly and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. JTT-130 is a novel intestine-specific MTP inhibitor, which has been shown to be useful in the prevention and treatment of dyslipidemia, obesity, and diabetes. JTT-130 has also been shown to suppress food intake in a dietary fat-dependent manner in rats. However, whether JTT-130 enables changes in food preference and nutrient consumption remains to be determined. Therefore, the aim of the present study was to investigate the effects of JTT-130 on food preference in rat under free access to two different diets containing 3.3% fat (low-fat diet, LF diet) and 35% fat (high-fat diet, HF diet). JTT-130 decreased HF diet intake and increased LF diet intake, resulting in a change in ratio of caloric intake from LF and HF diets to total caloric intake. In addition, macronutrient analysis revealed that JTT-130 did not affect carbohydrate consumption but significantly decreased fat consumption ( < 0.01). These findings suggest that JTT-130 not only inhibits fat absorption, but also suppresses food intake and specifically reduces food preference for fat. Therefore, JTT-130 is expected to provide a new option for the prevention and treatment of obesity and obesity-related metabolic disorders

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease

認知症を生じる遺伝性脳小血管病CADASILのiPS細胞モデルで病態を試験管内で再現することに成功. 京都大学プレスリリース. 2020-03-27.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). We have refined a differentiation protocol of endothelial cells to obtain mature mural cells (MCs) with their characteristic properties. iPSCs from three CADASIL patients with p.Arg182Cys, p.Arg141Cys and p.Cys106Arg mutations were differentiated into MCs and their functional and molecular profiles were compared. The differentiated CADASIL MCs recapitulated pathogenic changes reported previously: increased PDGFRβ and abnormal structure/distribution of filamentous actin network, as well as N3ECD/LTBP-1/HtrA1-immunopositive deposits. Migration rate of CADASIL MCs was enhanced but suppressed by knockdown of NOTCH3 or PDGFRB. CADASIL MCs showed altered reactivity to PDGF-BB. Patient-derived MCs can recapitulate CADASIL pathology and are therefore useful in understanding the pathogenesis and developing potential treatment strategies

Discovery of 6‑Phenylpyrimido[4,5‑<i>b</i>][1,4]oxazines as Potent and Selective Acyl CoA:Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents

The discovery and optimization of a series of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors based on a pyrimido­[4,5-<i>b</i>]­[1,4]­oxazine scaffold is described. The SAR of a moderately potent HTS hit was investigated resulting in the discovery of phenylcyclohexylacetic acid <b>1</b>, which displayed good DGAT1 inhibitory activity, selectivity, and PK properties. During preclinical toxicity studies a metabolite of <b>1</b> was observed that was responsible for elevating the levels of liver enzymes ALT and AST. Subsequently, analogues were synthesized to preclude the formation of the toxic metabolite. This effort resulted in the discovery of spiroindane <b>42</b>, which displayed significantly improved DGAT1 inhibition compared to <b>1</b>. Spiroindane <b>42</b> was well tolerated in rodents in vivo, demonstrated efficacy in an oral triglyceride uptake study in mice, and had an acceptable safety profile in preclinical toxicity studies