Brown Adipose Tissue PPARγ Is Required for the Insulin-Sensitizing Action of Thiazolidinediones

Brown adipose tissue (BAT) plays a critical role in metabolic homeostasis. BAT dysfunction is associated with the development of obesity through an imbalance between energy expenditure and energy intake. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is the master regulator of adipogenesis. However, the roles of PPARγ and thiazolidinediones (TZDs) in the regulation of BAT metabolism remain unclear. TZDs, which are selective PPARγ activators, improve systemic insulin resistance in animals and humans. In the present study, we generated brown adipocyte-specific PPARγ-deficient mice (BATγKO) to examine the in vivo roles of PPARγ and TZDs in BAT metabolism. In electron microscopic examinations, brown adipocyte-specific PPARγ deletion promoted severe whitening of brown fat and morphological alteration of mitochondria. Brown adipocyte-specific PPARγ deletion also reduced mRNA expression of BAT-selective genes. Although there was no difference in energy expenditure between control and BATγKO mice in calorimetry, norepinephrine-induced thermogenesis was impaired in BATγKO mice. Moreover, pioglitazone treatment improved diet-induced insulin resistance in the control mice but not in the BATγKO mice. These findings suggest that BAT PPARγ is necessary for the maintenance of brown adipocyte function and for the insulin-sensitizing action of TZDs

Roles of Transmembrane Protein 97 (TMEM97) in Adipose Tissue and Skeletal Muscle

The combination of sarcopenia and obesity (sarcopenic obesity) is associated with the development of metabolic syndrome and cardiovascular events. The molecular pathways that develop sarcopenic obesity have studied intensively. Transmembrane protein 97 (TMEM97) is 176 amino acids conserved integral membrane protein with four transmembrane domains that is expressed in several types of cancer. Its physiological significance in adipose tissue and skeletal muscle has been unclear. We studied TMEM97-transgenic mice and mice lacking TMEM97, and our findings indicate that TMEM97 expression is regulated in adipose tissue and skeletal muscle from obesity. TMEM97 represses adipogenesis and promotes myogenesis in vitro. Fat-specific TMEM97 transgenic mice showed systemic insulin resistance. Mice overexpressing TMEM97 in skeletal muscle exhibited systemic insulin resistance. Mice lacking TMEM97 were protected against diet-induced obesity and insulin resistance. These phenotypes are associated with the effects of TMEM97 on inflammation genes in adipose tissue and skeletal muscle. Our findings indicates that there is a link between TMEM97 and chronic inflammation in obesity

Role of glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 in hypertriglyceridemia and diabetes

In diabetes, the impairment of insulin secretion and insulin resistance contribute to hypertriglyceridemia, as the enzymatic activity of lipoprotein lipase (LPL) depends on insulin action. The transport of LPL to endothelial cells and its enzymatic activity are maintained by the formation of lipolytic complex depending on the multiple positive (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 [GPIHBP1], apolipoprotein C-II [APOC2], APOA5, heparan sulfate proteoglycan [HSPG], lipase maturation factor 1 [LFM1] and sel-1 suppressor of lin-12-like [SEL1L]) and negative regulators (APOC1, APOC3, angiopoietin-like proteins [ANGPTL]3, ANGPTL4 and ANGPTL8). Among the regulators, GPIHBP1 is a crucial molecule for the translocation of LPL from parenchymal cells to the luminal surface of capillary endothelial cells, and maintenance of lipolytic activity; that is, hydrolyzation of triglyceride into free fatty acids and monoglyceride, and conversion from chylomicron to chylomicron remnant in the exogenous pathway and from very low-density lipoprotein to low-density lipoprotein in the endogenous pathway. The null mutation of GPIHBP1 causes severe hypertriglyceridemia and pancreatitis, and GPIGBP1 autoantibody syndrome also causes severe hypertriglyceridemia and recurrent episodes of acute pancreatitis. In patients with type 2 diabetes, the elevated serum triglyceride levels negatively correlate with circulating LPL levels, and positively with circulating APOC1, APOC3, ANGPTL3, ANGPTL4 and ANGPTL8 levels. In contrast, circulating GPIHBP1 levels are not altered in type 2 diabetes patients with higher serum triglyceride levels, whereas they are elevated in type 2 diabetes patients with diabetic retinopathy and nephropathy. The circulating regulators of lipolytic complex might be new biomarkers for lipid and glucose metabolism, and diabetic vascular complications

Potentiometric Glucose Detection by Paper-based Electrochemical Sensor on CMOS Chip

This paper presents a low cost portable medical device for biochemical sensor using CMOS chip and paper-based fluidic channel. We measured a potential produced by enzyme activity of glucose between the working and reference electrode on CMOS chip. A liquid sample is transported by paper-based fluidic channel, which is made of chromatography paper and silicone resin, and consists of the area for filtering a sample (filter layer) and that for reacting enzyme (enyzme layer). The paper-based fluidic channel is used by combining CMOS chip, and the solution with glucose is dropped from top of the paper-based fluidic channel. The concentrations of glucose are detected by potentiometry (open circuit potential time). The experimental results show that the glucose concentration is measured by CMOS chip and paper-based fluidic channel

Simultaneous Electrochemical Measurement using Paper Fluidic Channel on CMOS Chip

This paper described the new system of biosensing using CMOS chip. The system was expected to be used in various circumstances because it was suitable for miniaturization compared to the conventional system. To conduct electrochemical measurements, the new system used paper fluidic channel set on the CMOS chip to transport solution to the on-chip electrodes. The materials of paper fluidic channel were only paper and silicone resin, and these were biocompatible. In experiment, we carried out simultaneous detection of glucose and ethanol in liquid sample solutions on the 5mm square CMOS chip and paper fluidic channel. Furthermore, this system can detect various target molecules in addition to glucose and ethanol, and increase number of simultaneous measurement by adding some more process to the paper and CMOS chip.

Four-Dimensional N=1 Supersymmetric Yang-Mills Theory on the Lattice without Fine-Tuning

We propose a method to formulate four-dimensional N=1 super Yang-Mills theory on the lattice without fine-tuning. We first show that four-dimensional Weyl fermion in a real representation, which is equivalent to Majorana fermion, can be formulated using the domain wall approach with an addition of a Majorana mass term only for the unwanted mirror fermion. This formalism has manifest gauge invariance. Fermion number conservation is violated only by the additional Majorana mass term for the mirror fermion and the violation is propagated to the physical fermion sector through anomalous currents. Due to this feature, the formalism, when applied to the gluino in the present case, ensures the restoration of supersymmetry in the continuum limit without fine-tuning, unlike the proposal by Curci and Veneziano.Comment: 7 pages, TeX, no figure, final version accepted by Physics Letters B.; explanation for exact chiral symmetry in L_5->\infty limit adde

Unitary IIB Matrix Model and the Dynamical Generation of the Space Time

We propose a unitary matrix model as a regularization of the IIB matrix model of Ishibashi-Kawai-Kitazawa-Tsuchiya (IKKT). The fermionic part is incorporated using the overlap formalism in order to avoid unwanted ``doublers'' while preserving the global gauge invariance. This regularization, unlike the one adopted by IKKT, has manifest U(1)^10 symmetry, which corresponds to the ten-dimensional translational invariance of the space time. We calculate one-loop effective action around some typical BPS-saturated configurations in the weak coupling limit. We also discuss a possible scenario for the dynamical generation of the four-dimensional space time through spontaneous breakdown of the U(1)^10 symmetry in the double scaling limit.Comment: 30 pages, 1 Postscript figure, The final version accepted by NP

A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin-/- obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD

Measuring cosmogenic Li9 background in a reactor neutrino experiment

Cosmogenic isotopes 9Li and 8He produced in the detector are the most problematic background in the reactor neutrino experiments designed to determine precisely the neutrino mixing angle theta13. The average time interval of cosmic-ray muons in the detector is often on the order of the lifetimes of the 9Li and 8He isotopes. We have developed a method for determining this kind of background from the distribution of time since last muon for muon rate up to about 20 Hz when the background-to-signal ratio is small, on the order of a few percents.Comment: 9 pages, 3 figures. To appear in NIM