Fenofibrate alleviates insulin resistance by reducing tissue inflammation in obese ovariectomized mice.

BACKGROUND: Fenofibrate is a hypolipidemic peroxisome proliferator-activated receptor α (PPARα) agonist used clinically to reduce hypercholesterolemia and hypertriglyceridemia. OBJECTIVE: We investigated the effects of fenofibrate on insulin resistance and tissue inflammation in a high-fat diet (HFD)-fed ovariectomized (OVX) C57BL/6J mice, a mouse model of obese postmenopausal women. METHODS: Female OVX mice were randomly divided into 3 groups and received a low-fat diet, an HFD, or an HFD supplemented with 0.05% (w/w) fenofibrate for 9 weeks. Parameters of insulin resistance and tissue inflammation were measured using blood analysis, histological analysis, immunohistochemistry, and quantitative real-time polymerase chain reaction. RESULTS: When fenofibrate was administered to HFD-fed OVX mice for 9 weeks, we observed reductions in body weight gain, adipose tissue mass, and the size of visceral adipocytes without the change of food intake. Fenofibrate improved mild hyperglycemia, severe hyperinsulinemia, and glucose tolerance in these mice. It also reduced pancreatic islet size and insulin-positive ß-cell area to levels similar to those in OVX mice fed a low-fat diet. Concomitantly, administration of fenofibrate not only suppressed pancreatic lipid accumulation but also decreased CD68-positive macrophages in both the pancreas and visceral adipose tissue. Treatment with fenofibrate reduced tumor necrosis factor α (TNFα) mRNA levels in adipose tissue and lowered serum TNFα levels. CONCLUSION: These results suggest that fenofibrate treatment attenuates insulin resistance in part by reducing tissue inflammation and TNFα expression in HFD-fed OVX mice.

Ascorbic acid reduces insulin resistance and pancreatic steatosis by regulating adipocyte hypertrophy in obese ovariectomized mice.

Ascorbic acid has been suggested to regulate obesity in obese male rodents. Moreover, increased adipocyte size has been associated with metabolic disease. Thus, we investigated the effects of ascorbic acid on adipocyte hypertrophy and insulin resistance in high-fat diet (HFD)-induced obese ovariectomized (OVX) C57BL/6J mice, an animal model of obese postmenopausal women. Administration of ascorbic acid (5% w/w in diet for 18 weeks) reduced the size of visceral adipocytes without changes in body weight and adipose tissue mass in HFD-fed obese OVX mice compared with obese OVX mice that did not receive ascorbic acid. Ascorbic acid inhibited adipose tissue inflammation, as shown by the decreased number of crown-like structures and CD68-positive macrophages in visceral adipose tissues. Ascorbic acid-treated mice exhibited improved hyperglycemia, hyperinsulinemia, and glucose and insulin tolerance compared with nontreated obese mice. Pancreatic islet size and insulin-positive ß-cell area in ascorbic acid-treated obese OVX mice decreased to the levels observed in low-fat diet-fed lean mice. Ascorbic acid also suppressed pancreatic triglyceride accumulation in obese mice. These results suggest that ascorbic acid may reduce insulin resistance and pancreatic steatosis partly by suppressing visceral adipocyte hypertrophy and adipose tissue inflammation in obese OVX mice.

Efficient Multi-Scale Stereo-Matching Network Using Adaptive Cost Volume Filtering.

While recent deep learning-based stereo-matching networks have shown outstanding advances, there are still some unsolved challenges. First, most state-of-the-art stereo models employ 3D convolutions for 4D cost volume aggregation, which limit the deployment of networks for resource-limited mobile environments owing to heavy consumption of computation and memory. Although there are some efficient networks, most of them still require a heavy computational cost to incorporate them to mobile computing devices in real-time. Second, most stereo networks indirectly supervise cost volumes through disparity regression loss by using the softargmax function. This causes problems in ambiguous regions, such as the boundaries of objects, because there are many possibilities for unreasonable cost distributions which result in overfitting problem. A few works deal with this problem by generating artificial cost distribution using only the ground truth disparity value that is insufficient to fully regularize the cost volume. To address these problems, we first propose an efficient multi-scale sequential feature fusion network (MSFFNet). Specifically, we connect multi-scale SFF modules in parallel with a cross-scale fusion function to generate a set of cost volumes with different scales. These cost volumes are then effectively combined using the proposed interlaced concatenation method. Second, we propose an adaptive cost-volume-filtering (ACVF) loss function that directly supervises our estimated cost volume. The proposed ACVF loss directly adds constraints to the cost volume using the probability distribution generated from the ground truth disparity map and that estimated from the teacher network which achieves higher accuracy. Results of several experiments using representative datasets for stereo matching show that our proposed method is more efficient than previous methods. Our network architecture consumes fewer parameters and generates reasonable disparity maps with faster speed compared with the existing state-of-the art stereo models. Concretely, our network achieves 1.01 EPE with runtime of 42 ms, 2.92M parameters, and 97.96G FLOPs on the Scene Flow test set. Compared with PSMNet, our method is 89% faster and 7% more accurate with 45% fewer parameters.

Expression of uncharacterized male germ cell-specific genes and discovery of novel sperm-tail proteins in mice.

The identification and characterization of germ cell-specific genes are essential if we hope to comprehensively understand the mechanisms of spermatogenesis and fertilization. Here, we searched the mouse UniGene databases and identified 13 novel genes as being putatively testis-specific or -predominant. Our in silico and in vitro analyses revealed that the expressions of these genes are testis- and germ cell-specific, and that they are regulated in a stage-specific manner during spermatogenesis. We generated antibodies against the proteins encoded by seven of the genes to facilitate their characterization in male germ cells. Immunoblotting and immunofluorescence analyses revealed that one of these proteins was expressed only in testicular germ cells, three were expressed in both testicular germ cells and testicular sperm, and the remaining three were expressed in sperm of the testicular stages and in mature sperm from the epididymis. Further analysis of the latter three proteins showed that they were all associated with cytoskeletal structures in the sperm flagellum. Among them, MORN5, which is predicted to contain three MORN motifs, is conserved between mouse and human sperm. In conclusion, we herein identify 13 authentic genes with male germ cell-specific expression, and provide comprehensive information about these genes and their encoded products. Our finding will facilitate future investigations into the functional roles of these novel genes in spermatogenesis and sperm functions.

Characterization of Mammalian ADAM2 and Its Absence from Human Sperm.

The members of the ADAM (a disintegrin and metalloprotease) family are membrane-anchored multi-domain proteins that play prominent roles in male reproduction. ADAM2, which was one of the first identified ADAMs, is the best studied ADAM in reproduction. In the male germ cells of mice, ADAM2 and other ADAMs form complexes that contribute to sperm-sperm adhesion, sperm-egg interactions, and the migration of sperm in the female reproductive tract. Here, we generated specific antibodies against mouse and human ADAM2, and investigated various features of ADAM2 in mice, monkeys and humans. We found that the cytoplasmic domain of ADAM2 might enable the differential association of this protein with other ADAMs in mice. Western blot analysis with the anti-human ADAM2 antibodies showed that ADAM2 is present in the testis and sperm of monkeys. Monkey ADAM2 was found to associate with chaperone proteins in testis. In humans, we identified ADAM2 as a 100-kDa protein in the testis, but failed to detect it in sperm. This is surprising given the results in mice and monkeys, but it is consistent with the failure of ADAM2 identification in the previous proteomic analyses of human sperm. These findings suggest that the reproductive functions of ADAM2 differ between humans and mice. Our protein analysis showed the presence of potential ADAM2 complexes involving yet-unknown proteins in human testis. Taken together, our results provide new information regarding the characteristics of ADAM2 in mammalian species, including humans.

Reduced Fertility and Altered Epididymal and Sperm Integrity in Mice Lacking ADAM7.

The mammalian epididymis is a highly convoluted tubule that connects the testis to the vas deferens. Its proper functions in sperm transport, storage, and maturation are essential for male reproduction. One of the genes predominantly expressed in the epididymis is ADAM7 (a disintegrin and metalloprotease 7). Previous studies have shown that ADAM7 synthesized in the epididymis is secreted into the epididymal lumen and is then transferred to sperm membranes, where it forms a chaperone complex that is potentially involved in sperm fertility. In this study, we generated and analyzed mice with a targeted disruption in the Adam7 gene. We found that the fertility of male mice was modestly but significantly reduced by knockout of Adam7. Histological analyses revealed that the cell heights of the epithelium were dramatically decreased in the caput of the epididymis of Adam7-null mice, suggesting a requirement for ADAM7 in maintaining the integrity of the epididymal epithelium. We found that sperm from Adam7-null mice exhibit decreased motility, tail deformation, and altered tyrosine phosphorylation, indicating that the absence of ADAM7 leads to abnormal sperm functions and morphology. Western blot analyses revealed reduced levels of integral membrane protein 2B (ITM2B) and ADAM2 in sperm from Adam7-null mice, suggesting a requirement for ADAM7 in normal expression of sperm membrane proteins involved in sperm functions. Collectively, our study demonstrates for the first time that ADAM7 is required for normal fertility and is important for the maintenance of epididymal integrity and for sperm morphology, motility, and membrane proteins.