Human Metabolic Diseases Research Articles

Advances in pig models of human diseases.

Animal models of human diseases play a critical role in medical research. Pigs are anatomically and physiologically more like humans than are small rodents such as mice, making pigs an attractive option for modeling human diseases. Advances in recent years in genetic engineering have facilitated the rapid rise of pig models for use in studies of human disease. In the present review, we summarize the current status of pig models for human cardiovascular, metabolic, neurodegenerative, and various genetic diseases. We also discuss areas that need to be improved. Animal models of human diseases play a critical role in medical research. Advances in recent years in genetic engineering have facilitated the rapid rise of pig models for use in studies of human disease. In the present review, we summarize the current status of pig models for human cardiovascular, metabolic, neurodegenerative, various genetic diseases and xenotransplantation.

Roles of miR-124-3p/Scd1 in urolithin A-induced brown adipocyte differentiation and succinate-dependent regulation of mitochondrial complex II

Brown adipocytes have been linked to managing human obesity and related metabolic diseases. A large number of natural products have emerged that can activate brown adipocytes tissue (BAT) to active thermogenesis, but the epigenetic mechanisms have not been fully resolved. In this study, we identified the induction of miR-124-3p by urolithin A (UA) as a means to increase the thermogenic activity of brown adipocytes. Overexpression of miR-124-3p enhances thermogenesis by increasing mitochondrial content in brown adipocytes. Mechanistically, to clarify that miR-124-3p affects fatty acid synthesis using bioinformatics methods, it is clear that miR-124 affects the synthesis of fatty acids through the enrichment analysis of the KEGG pathway, and using dual luci.ferase to determine the target gene as stearoyl-CoA desaturase 1 (SCD1) while controlling rates of fatty acids synthesis and de novo brown fat biogenesis. Finally, in the overexpression of miR-124-3p and UA-treated BAT, succinate accumulation was enhanced in cells and fueled mitochondrial complex II activities. This study highlights a miR-124-3p/SCD1/succinate pathway that stimulates thermogenesis of BAT via the modulatory roles of UA.

Roles of Insect Oenocytes in Physiology and Their Relevance to Human Metabolic Diseases.

Oenocytes are large secretory cells present in the abdomen of insects known to synthesize very-long-chain fatty acids to produce hydrocarbons and pheromones that mediate courtship behavior in adult flies. In recent years, oenocytes have been implicated in the regulation of energy metabolism. These hepatocyte-like cells accumulate lipid droplets under starvation and can non-autonomously regulate tracheal waterproofing and adipocyte lipid composition. Here, we summarize evidence, mostly from Drosophila, establishing that oenocytes perform liver-like functions. We also compare the functional differences in oenocytes and the fat body, another lipid storage tissue which also performs liver-like functions. Lastly, we examine signaling pathways that regulate oenocyte metabolism derived from other metabolic tissues, as well as oenocyte-derived signals that regulate energy homeostasis.

An integrated bioinformatic investigation of mitochondrial solute carrier family 25 (SLC25) in colon cancer followed by preliminary validation of member 5 (SLC25A5) in tumorigenesis

Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25.

Drosophila melanogaster as a low-cost and valuable model for studying type 2 diabetes.

Drosophila melanogaster has been used as the most successful invertebrate model for studying metabolic diseases such as type 2 diabetes (T2D). We induced T2D by feeding Drosophila larvae on a high-sugar diet (HSD). The glucose and trehalose, glycogen, lipid, triglyceride, and protein levels were determined in HSD-fed larvae. Moreover, larval food intake, water content, size, and weight in addition to the development until pupation were observed. Levels of Drosophila insulin-like peptides (DILPs 2, 3, and 5), as well as adipokinetic hormone (AKH), were also determined in HSD-fed larvae by quantitative real-time polymerase chain reaction. The results demonstrated that HSD could induce elevated levels of glucose, trehalose, glycogen, and proteins in larvae. The larvae consumed less food intake and were smaller, lighter, and less developed on HSD than those on the control diet. Moreover, the water content of larvae fed HSD was similar to that fed the control diet.HSD induced higher expression of DILP3 and AKH, confirming hyperglycemia with insulin resistance. In sum, Drosophila offers an appropriate model for quick and inexpensive in vivo experimentation on human metabolic diseases.

Posttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases.

Insulin resistance defines an impairment in the biologic response to insulin action in target tissues, primarily the liver, muscle, adipose tissue, and brain. Insulin resistance affects physiology in many ways, causing hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperinsulinemia, elevated inflammatory markers, and endothelial dysfunction, and its persistence leads to the development metabolic disease, including diabetes, obesity, cardiovascular disease, or nonalcoholic fatty liver disease (NAFLD), as well as neurological disorders such as Alzheimer’s disease. In addition to classical transcriptional factors, posttranscriptional control of gene expression exerted by microRNAs and RNA-binding proteins constitutes a new level of regulation with important implications in metabolic homeostasis. In this review, we describe miRNAs and RBPs that control key genes involved in the insulin signaling pathway and related regulatory networks, and their impact on human metabolic diseases at the molecular level, as well as their potential use for diagnosis and future therapeutics.

Regulation of the NLRP3 Inflammasome by Posttranslational Modifications.

Inflammasomes are important in human health and disease, whereby they control the secretion of IL-1β and IL-18, two potent proinflammatory cytokines that play a key role in inflammatory responses to pathogens and danger signals. Several inflammasomes have been discovered over the past two decades. NLRP3 inflammasome is the best characterized and can be activated by a wide variety of inducers. It is composed of a sensor, NLRP3, an adapter protein, ASC, and an effector enzyme, caspase-1. After activation, caspase-1 mediates the cleavage and secretion of bioactive IL-1β and IL-18 via gasdermin-D pores in the plasma membrane. Aberrant activation of NLRP3 inflammasomes has been implicated in a multitude of human diseases, including inflammatory, autoimmune, and metabolic diseases. Therefore, several mechanisms have evolved to control their activity. In this review, we describe the posttranslational modifications that regulate NLRP3 inflammasome components, including ubiquitination, phosphorylation, and other forms of posttranslational modifications.

Role of GALNT2 on Insulin Sensitivity, Lipid Metabolism and Fat Homeostasis.

O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society.

Changing lanes: seasonal differences in cellular metabolism of adipocytes in grizzly bears (Ursus arctos horribilis).

Obesity is among the most prevalent of health conditions in humans leading to a multitude of metabolic pathologies such as type 2 diabetes and hyperglycemia. However, there are many wild animals that have large seasonal cycles of fat accumulation and loss that do not result in the health consequences observed in obese humans. One example is the grizzly bear (Ursus arctos horribilis) that can have body fat content > 40% that is then used as the energy source for hibernation. Previous in vitro studies found that hibernation season adipocytes exhibit insulin resistance and increased lipolysis. Yet, other aspects of cellular metabolism were not addressed, leaving this in vitro model incomplete. Thus, the current studies were performed to determine if the cellular energetic phenotype-measured via metabolic flux-of hibernating bears was retained in cultured adipocytes and to what extent that was due to serum or intrinsic cellular factors. Extracellular acidification rate and oxygen consumption rate were used to calculate proton efflux rate and total ATP defined as both ATP from glycolysis and from mitochondrial respiration. Hibernation adipocytes treated with hibernation serum produced less ATP and exhibited lower maximal respiration and glycolysis ratesthan active season adipocytes. These effects were reversed with serum from the opposite season. Insulin had little influence on total ATP production and lipolysis in both hibernation and active serum-treated adipocytes. Together, these results suggest that the metabolic suppression occurring in hibernation adipocytes are downstream of insulin signaling and likely due to a combined reduction in mitochondria number and/or function and glycolytic processes. Future elucidation of the serum components and the cellular mechanisms that enable alterations in mitochondrial function could provide a novel avenue for the development of treatments for human metabolic diseases.

Timing of High-glucose Diet in the C. elegans Lifecycle Impacts Fertility Phenotypes.

Human metabolic diseases and high-sugar diets have been associated with infertility. Previous studies show that high-glucose diet also affects fertility in C. elegans, leading to decreased offspring production and delayed reproductive timing. We tested whether the timing of glucose exposure affects these fertility defects or the embryo to larval transition. We found that decreased offspring production was strictly a response to high-glucose exposure in adulthood, whereas the delayed reproductive profile was influenced by both developmental and adult diets. We found no effect of high-glucose diet on the number of embryos that develop to the first larval stage. Together, these results suggest that the decreased offspring production and delayed reproductive profile may be separable phenotypes, and that a high-glucose diet reduces the number of offspring by interfering with processes regulated during adulthood.

Emerging effects of tryptophan pathway metabolites and intestinal microbiota on metabolism and intestinal function.

The metabolism of dietary tryptophan occurs locally in the gut primarily via host enzymes, with ~ 5% metabolized by gut microbes. Three major tryptophan metabolic pathways are serotonin (beyond the scope of this review), indole, kynurenine and related derivatives. We introduce the gut microbiome, dietary tryptophan and the potential interplay of host and bacterial enzymes in tryptophan metabolism. Examples of bacterial transformation to indole and its derivative indole-3 propionic acid demonstrate associations with human metabolic disease and gut permeability, although causality remains to be determined. This review will focus on less well-known data, suggestive of local generation and functional significance in the gut, where kynurenine is converted to kynurenic acid and xanthurenic acid via enzymatic action present in both host and bacteria. Our functional data demonstrate alimited effect on intestinal epithelial cell monolayer permeability and on healthy mouse ileum. Other data suggest a modulatory effect on the microbiome, potentially in pathophysiology. Supportive of this, we found that the expression of mRNA for three kynurenine pathway enzymes were increased in colon from high-fat-fed mice, suggesting that this host pathway is perturbed in metabolic disease. These data, along with that frombacterial genomic analysis and germ-free mice, confirms expression and functional machinery of enzymes in this pathway. Therefore, the host and microbiota mayplay a significant dual role in either the production or regulation of these kynurenine metabolites which, in turn, can influence both host and microbiome, especially in the context of obesity and intestinal permeability.

Potential roles of gut microbiota and microbial metabolites in chronic inflammatory pain and the mechanisms of therapy drugs.

Observational findings achieved that gut microbes mediate human metabolic health and disease risk. The types of intestinal microorganisms depend on the intake of food and drugs and are also related to their metabolic level and genetic factors. Recent studies have shown that chronic inflammatory pain is closely related to intestinal microbial homeostasis. Compared with the normal intestinal flora, the composition of intestinal flora in patients with chronic inflammatory pain had significant changes in Actinomycetes, Firmicutes, Bacteroidetes, etc. At the same time, short-chain fatty acids and amino acids, the metabolites of intestinal microorganisms, can regulate neural signal molecules and signaling pathways, thus affecting the development trend of chronic inflammatory pain. Glucocorticoids and non-steroidal anti-inflammatory drugs in the treatment of chronic inflammatory pain, the main mechanism is to affect the secretion of inflammatory factors and the abundance of intestinal bacteria. This article reviews the relationship between intestinal microorganisms and their metabolites on chronic inflammatory pain and the possible mechanism.

Hypothalamic miR-1983 Targets Insulin Receptor β and the Insulin-mediated miR-1983 Increase Is Blocked by Metformin.

MicroRNAs (miRNAs) expressed in the hypothalamus are capable of regulating energy balance and peripheral metabolism by inhibiting translation of target messenger RNAs (mRNAs). Hypothalamic insulin resistance is known to precede that in the periphery, thus a critical unanswered question is whether central insulin resistance creates a specific hypothalamic miRNA signature that can be identified and targeted. Here we show that miR-1983, a unique miRNA, is upregulated in vitro in 2 insulin-resistant immortalized hypothalamic neuronal neuropeptide Y-expressing models, and in vivo in hyperinsulinemic mice, with a concomitant decrease of insulin receptor β subunit protein, a target of miR-1983. Importantly, we demonstrate that miR-1983 is detectable in human blood serum and that its levels significantly correlate with blood insulin and the homeostatic model assessment of insulin resistance. Levels of miR-1983 are normalized with metformin exposure in mouse hypothalamic neuronal cell culture. Our findings provide evidence for miR-1983 as a unique biomarker of cellular insulin resistance, and a potential therapeutic target for prevention of human metabolic disease.

Fluoride exposure cause colon microbiota dysbiosis by destroyed microenvironment and disturbed antimicrobial peptides expression in colon

Colon microenvironment and microbiota dysbiosis are closely related to various human metabolic diseases. In this study, a total of 72 healthy female mice were exposed to fluoride (F) (0, 25, 50 and 100 mg/L F−) in drinking water for 70 days. The effect of F on intestinal barrier and the diversity and composition in colon microbiota have been evaluated. Meanwhile, the relationship among F-induced colon microbiota alterations and antimicrobial peptides (AMPs) expression and short-chain fatty acids (SCFAs) level also been assessed. The results suggested that F decreased the goblet cells number and glycoprotein expression in colon. And further high-throughput 16S rRNA gene sequencing result demonstrated that F exposure induced the diversity and community composition of colonic microbiota significantly changes. Linear Discriminant Analysis Effect Size (LEfSe) analysis identified 11 predominantly characteristic taxa which may be the biomarker in response to F exposure. F-induced intestinal microbiota perturbations lead to the significantly decreased SCFAs levels in colon. Immunofluorescence results showed that F increased the protein expression of interleukin-17A (IL-17A) and IL-22 (P < 0.01) and disturbed the expression of interleukin-17 receptor A (IL-17RA) and IL-22R (P < 0.05 or P < 0.01). In addition, the increased expression of IL-17A and IL-22 cooperatively enhanced the mRNA expression of AMPs which response to F-induced microbiota perturbations. Collectively, destroyed microenvironment and disturbed AMPs are the primary reason of microbiota dysbiosis in colon after F exposure. Colonic homoeostasis imbalance would be helpful for finding the source of F-induced chronic systemic diseases.

Sirtuin Modulators in Cellular and Animal Models of Human Diseases.

Sirtuins use NAD+ to remove various acyl groups from protein lysine residues. Through working on different substrate proteins, they display many biological functions, including regulation of cell proliferation, genome stability, metabolism, and cell migration. There are seven sirtuins in humans, SIRT1-7, each with unique enzymatic activities, regulatory mechanisms, subcellular localizations, and substrate scopes. They have been indicated in many human diseases, including cancer, neurodegeneration, microbial infection, metabolic and autoimmune diseases. Consequently, interests in development of sirtuin modulators have increased in the past decade. In this brief review, we specifically summarize genetic and pharmacological modulations of sirtuins in cancer, neurological, and cardiovascular diseases. We further anticipate this review will be helpful for scrutinizing the significance of sirtuins in the studied diseases.

Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in db/db Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.

Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The db/db mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue. Oral administration of pioglitazone lowered blood glucose levels in db/db mice with a corresponding increase in respiratory quotient, which indicates improved whole-body carbohydrate utilization. In addition, white adipose tissue from db/db mice and from humans treated with pioglitazone showed increased expression of glycerol kinase. Both db/db mice and humans given pioglitazone displayed increased expression of UCP-1, a marker typically associated with brown adipose tissue. Moreover, pancreatic β-cells from db/db mice treated with pioglitazone had greater expression of insulin and Nkx6.1 as well as reduced abundance of the de-differentiation marker Aldh1a3. Collectively, these findings indicate that four weeks of pioglitazone therapy improved overall metabolic health in db/db mice. Our data are consistent with published reports of human subjects administered pioglitazone and with analysis of human adipose tissue taken from subjects treated with pioglitazone. In conclusion, the current study provides evidence that pioglitazone restores key markers of metabolic health and also showcases the utility of the db/db mouse to understand mechanisms associated with human metabolic disease and interventions that provide therapeutic benefit.

Red Wine High-Molecular-Weight Polyphenolic Complex: An Emerging Modulator of Human Metabolic Disease Risk and Gut Microbiota.

Moderate red wine consumption has been linked to reduced chronic disease risk. Thus far, little has been known about the physicochemical properties and potential biological effects of high-molecular-weight polyphenolic complexes (HPPCs), a major fraction of red wine polyphenols. In this work, the stability and biochemical properties of HPPCs under simulated gastrointestinal conditions in vitro were studied. The results showed that HPPCs were resistant to simulated gastric digestion (SGD) and simulated intestinal digestion (SID). They exhibited significant inhibitory activity against key metabolic syndrome-associated digestive enzymes, achieving 17.1-90.9% inhibition of pancreatic α-amylase, lipase, and cholesterol esterase at 0.02-0.45 mg/mL. HPPCs were metabolized by gut microbiota (GM), leading to significantly enhanced antioxidant capacity when compared with the original, SGD, and SID samples. Furthermore, they favorably modulated GM profiles, which was accompanied by significantly increased short-chain fatty acid generation during the early colonic fermentation phase. These findings suggest that HPPCs are a promising modulator of human metabolic disease risk.

Baicalin attenuates diet-induced obesity partially through promoting thermogenesis in adipose tissue

BackgroundAdipose tissues have essential roles on energy homeostasis and the development of metabolic syndrome and obesity, they have become critical targets for treating obesity and metabolic disorders. Baicalin is a flavonoid that derived from the root of Scutellaria baicalensis, and it has been reported to take part in the regulation of adipocyte function. All these highlighted the potential of baicalin in the regulation of fat accumulation and obesity. Yet the impact of baicalin on thermogenic function of adipocytes remains to be deciphered. ObjectiveThis study aims to explore the anti-obesity effects of baicalin. Materials & MethodsThe level of mRNA was detected by qRT-PCR and the protein expression level was examined by western blot. H&E staining was used for the observation of the structure of adipose tissue. Serum triglyceride and insulin levels were detected by commercial test kits. ResultsOur data demonstrated that baicalin up-regulates the expression of UCP1 and PGC1a in a dose-dependent manner in vitro. Baicalin also increases ERK phosphorylation, and the increased expression of UCP1 and PGC1a in adipocytes could be inhibited by an ERK inhibitor, U0126. Moreover, dietary baicalin ameliorates high fat diet (HFD)-induced obesity without affecting food intake. In addition, dietary baicalin inhibits adipocyte hypertrophy and enhances thermogenic gene program in sWAT and intrascapular brown adipose tissue (iBAT) in vivo. Discussion & ConclusionBaicalin prevents HFD-induced obesity partially through promoting adipocyte thermogenesis. Baicalin may be a promising compound against human obesity and related metabolic diseases.

The potential of Akkermansia muciniphila in inflammatory bowel disease.

Akkermansia muciniphila is a next-generation probiotic with significant application prospects. The role of A. muciniphila in metabolic diseases and tumor immunotherapy has been widely recognized. Recent clinical trials further confirmed its safety and therapeutic value in human metabolic diseases. A. muciniphila also shows potential in the treatment of intestinal inflammatory diseases, especially for inflammatory bowel disease (IBD). The improvement in the efficacy of washed microbiota transplantation (WMT) in treating IBD is closely related to the increase in the abundance of A. muciniphila in patients' gut. However, there is still controversy regarding the pro-inflammatory or anti-inflammatory effect of A. muciniphila on IBD. Currently, several studies targeting the correlation between A. muciniphila and IBD have demonstrated opposite conclusions. Similarly, the interventional studies exploring causality between them also come to conflicting results. This article therefore aims to review the relationship between A. muciniphila and IBD, the effect of intervention of A. muciniphila on IBD, and the possible reasons for the contradictory role of A. muciniphila in the treatment of IBD. KEY POINTS: The effect of A. muciniphila on inflammatory bowel disease is controversy. A. muciniphila shows anti-inflammatory potential in IBD. The colitogenicity of A. muciniphila is context dependent.

Recent advancements in the exploitation of the gut microbiome in the diagnosis and treatment of colorectal cancer.

Over the last few decades it has been established that the complex interaction between the host and the multitude of organisms that compose the intestinal microbiota plays an important role in human metabolic health and disease. Whilst there is no defined consensus on the composition of a healthy microbiome due to confounding factors such as ethnicity, geographical locations, age and sex, there are undoubtably populations of microbes that are consistently dysregulated in gut diseases including colorectal cancer (CRC). In this review, we discuss the most recent advances in the application of the gut microbiota, not just bacteria, and derived microbial compounds in the diagnosis of CRC and the potential to exploit microbes as novel agents in the management and treatment of CRC. We highlight examples of the microbiota, and their derivatives, that have the potential to become standalone diagnostic tools or be used in combination with current screening techniques to improve sensitivity and specificity for earlier CRC diagnoses and provide a perspective on their potential as biotherapeutics with translatability to clinical trials.