Helminth and Host Crosstalk: New Insight Into Treatment of Obesity and Its Associated Metabolic Syndromes.

Obesity and its associated Metabolic Syndromes (Mets) represent a global epidemic health problem. Metabolic inflammation, lipid accumulation and insulin resistance contribute to the progression of these diseases, thereby becoming targets for drug development. Epidemiological data have showed that the rate of helminth infection negatively correlates with the incidence of obesity and Mets. Correspondingly, numerous animal experiments and a few of clinic trials in human demonstrate that helminth infection or its derived molecules can mitigate obesity and Mets via induction of macrophage M2 polarization, inhibition of adipogenesis, promotion of fat browning, and improvement of glucose tolerance, insulin resistance and metabolic inflammation. Interestingly, sporadic studies also uncover that several helminth infections can reshape gut microbiota of hosts, which is intimately implicated in the pathogenesis of obesity and Mets. Overall, these findings indicate that the crosstalk between helminth and hosts may be a novel direction for obesity and Mets therapy. The present article reviews the molecular mechanism of how helminth masters immunity and metabolism in obesity.

Polyene Phosphatidylcholine Ameliorates High Fat Diet-Induced Non-alcoholic Fatty Liver Disease via Remodeling Metabolism and Inflammation.

Recent years have witnessed a rise in the morbidity of non-alcoholic fatty liver disease (NAFLD), in line with the global outbreak of obesity. However, effective intervention strategy against NAFLD is still unavailable. The present study sought to investigate the effect and mechanism of polyene phosphatidylcholine (PPC), a classic hepatoprotective drug, on NAFLD induced by high fat diet (HFD). We found that PPC intervention reduced the mass of liver, subcutaneous, epididymal, and brown fats in HFD mice. Furthermore, PPC supplementation significantly mitigated liver steatosis and improved glucose tolerance and insulin sensitivity in HFD mice, which was accompanied by declined levels of hepatic triglyceride, serum triglyceride, low density lipoprotein, aspartate aminotransferase, and alanine aminotransferase. Using transcriptome analysis, there were 1,789 differentially expressed genes (| fold change | ≥ 2, P < 0.05) including 893 upregulated genes and 896 downregulated genes in the HFD group compared to LC group. A total of 1,114 upregulated genes and 1,337 downregulated genes in HFD + PPC group were identified in comparison to HFD group. With the help of Gene Ontology (GO) analysis, these differentially expressed genes between HFD+PPC and HFD group were discovered related to "lipid metabolic process (GO: 0006629)," "lipid modification (GO: 0030258)," and "lipid homeostasis (GO: 0055088)". Though Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found pathways associated with hepatic homeostasis of metabolism and inflammation. Notably, the pathway "Non-alcoholic fatty liver disease (mmu04932)" (P-value = 0.00698) was authenticated in the study, which may inspire the potential mechanism of PPC to ameliorate NAFLD. The study also found that lipolysis, fatty acid oxidation, and lipid export associated genes were upregulated, while the genes in uptake of lipids and cholesterol synthesis were downregulated in the liver of HFD mice after PPC supplementation. Interestingly, PPC attenuated the metabolic inflammation via inhibiting pro-inflammatory macrophage in the livers of mice fed by HFD. In summary, this study demonstrates that PPC can ameliorate HFD-induced liver steatosis via reprogramming metabolic and inflammatory processes, which inspire clues for further clarifying the intervention mechanism of PPC against NAFLD.

Parasite-Derived Excretory-Secretory Products Alleviate Gut Microbiota Dysbiosis and Improve Cognitive Impairment Induced by a High-Fat Diet.

High-fat (HF) diet-induced neuroinflammation and cognitive decline in humans and animals have been associated with microbiota dysbiosis via the gut-brain axis. Our previous studies revealed that excretory-secretory products (ESPs) derived from the larval Echinococcus granulosus (E. granulosus) function as immunomodulators to reduce the inflammatory response, while the parasitic infection alleviates metabolic disorders in the host. However, whether ESPs can improve cognitive impairment under obese conditions remain unknown. This study aimed to investigate the effects of E. granulosus-derived ESPs on cognitive function and the microbiota-gut-brain axis in obese mice. We demonstrated that ESPs supplementation prevented HF diet-induced cognitive impairment, which was assessed behaviorally by nest building, object location, novel object recognition, temporal order memory, and Y-maze memory tests. In the hippocampus (HIP) and prefrontal cortex (PFC), ESPs suppressed neuroinflammation and HF diet-induced activation of the microglia and astrocytes. Moreover, ESPs supplementation improved the synaptic ultrastructural impairments and increased both pre- and postsynaptic protein levels in the HIP and PFC compared to the HF diet-treated group. In the colon, ESPs reversed the HF diet-induced gut barrier dysfunction, increased the thickness of colonic mucus, upregulated the expression of zonula occludens-1 (ZO-1), attenuated the translocation of bacterial endotoxins, and decreased the colon inflammation. Notably, ESPs supplementation alleviated the HF diet-induced microbiota dysbiosis. After clarifying the role of antibiotics in obese mice, we found that broad-spectrum antibiotic intervention abrogated the effects of ESPs on improving the gut microbiota dysbiosis and cognitive decline. Overall, the present study revealed for the first time that the parasite-derived ESPs alleviate gut microbiota dysbiosis and improve cognitive impairment induced by a high-fat diet. This finding suggests that parasite-derived molecules may be used to explore novel drug candidates against obesity-associated neurodegenerative diseases.

Microarray Analysis of lncRNA and mRNA Reveals Enhanced Lipolysis Along With Metabolic Remodeling in Mice Infected With Larval Echinococcus granulosus.

Parasitic infection improves metabolic homeostasis in "western diet"-induced obesity through the regulation of adipogenesis. However, the underlying mechanism is not yet fully understood. Using microarray analysis, this study investigated the long non-coding RNA (lncRNA) and messenger RNA (mRNA) profiles of subcutaneous adipose tissues from mice infected with Echinococcus granulosus protoscoleces. A total of 1052 mRNA (541 upregulated, 511 downregulated) and 220 lncRNA (126 upregulated, 94 downregulated) transcripts were differentially expressed (fold change ≥2, P < 0.05) in the infected subcutaneous adipose tissues. When compared with the control group, the infected mice showed a decrease in adipose tissue mass and a reduction in adipocyte size. Indirect calorimetry revealed the change in the energy metabolism after infection, characterized by a lower CO2 production and O2 consumption, a sharp decline in carbohydrate oxidation, and a slight increase in fat oxidation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the parasitic infection reprogrammed a complex metabolic network. Notably, "lipoxygenase" and "arginine and proline metabolism" pathways were significantly upregulated while "glycolysis," "tricarboxylic acid cycle," "de novo lipogenesis," and "lipid droplet" pathways were dramatically downregulated. In addition, several key lncRNAs were associated with insulin resistance and adipocyte differentiation. Overall, the present study suggested that E. granulosus infection could enhance lipolysis. Thus, our findings provide novel insights into parasite-mediated metabolic homeostasis, and into the mechanism of hypertrophic adipocytes in obesity.

Analyzing Dynamical Brain Functional Connectivity as Trajectories on Space of Covariance Matrices.

Human brain functional connectivity (FC) is often measured as the similarity of functional MRI responses across brain regions when a brain is either resting or performing a task. This paper aims to statistically analyze the dynamic nature of FC by representing the collective time-series data, over a set of brain regions, as a trajectory on the space of covariance matrices, or symmetric-positive definite matrices (SPDMs). We use a recently developed metric on the space of SPDMs for quantifying differences across FC observations, and for clustering and classification of FC trajectories. To facilitate large scale and high-dimensional data analysis, we propose a novel, metric-based dimensionality reduction technique to reduce data from large SPDMs to small SPDMs. We illustrate this comprehensive framework using data from the Human Connectome Project (HCP) database for multiple subjects and tasks, with task classification rates that match or outperform state-of-the-art techniques.

Discovering common change-point patterns in functional connectivity across subjects.

This paper studies change-points in human brain functional connectivity (FC) and seeks patterns that are common across multiple subjects under identical external stimulus. FC relates to the similarity of fMRI responses across different brain regions when the brain is simply resting or performing a task. While the dynamic nature of FC is well accepted, this paper develops a formal statistical test for finding change-points in times series associated with FC. It represents short-term connectivity by a symmetric positive-definite matrix, and uses a Riemannian metric on this space to develop a graphical method for detecting change-points in a time series of such matrices. It also provides a graphical representation of estimated FC for stationary subintervals in between the detected change-points. Furthermore, it uses a temporal alignment of the test statistic, viewed as a real-valued function over time, to remove inter-subject variability and to discover common change-point patterns across subjects. This method is illustrated using data from Human Connectome Project (HCP) database for multiple subjects and tasks.