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Objective. The objective of this study was to functionally analyze the correlation of key histological features in brown adipose tissue (BAT) with clinical metabolic traits in nonhuman primates. Methods. Axillary adipose tissue biopsies were collected from a metabolically diverse nonhuman primate cohort with clinical metabolism-related data. Expression of tyrosine hydroxylase (TH), uncoupling protein 1 (UCP1), cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX IV), beta-3 adrenergic receptor (β3-AR), and adipose cell size were quantified by immunohistochemical analysis. Computed tomography scans were performed to assess body composition. Results. Tyrosine hydroxylase was negatively correlated with whole body fat mass as a percentage of body weight (p = 0.004) and was positively correlated with the density of UCP1 (p = 0.02), COX IV (p = 0.006), CD31 (p = 0.007), and cell density (p = 0.02) of the BAT samples. Beta-3 adrenergic receptor abundance had a weak positive correlation with COX IV (p = 0.04) in BAT but did not significantly correlate to UCP1 or TH expression in BAT. Conclusions. Our findings highlight that there is a disparity in innervation provided to BAT based on body composition, as seen with the negative association between TH, a marker for innervation, and adiposity. These findings also support the importance of innervation in the functionality of BAT, as TH abundance not only supports leaner body composition but is also positively correlated with known structural elements in BAT (UCP1, COX IV, CD31, and cell density). Based on our observations, β3-AR abundance does not strongly drive these structural elements or TH, all of which are known to be important in the function of brown adipose tissue. In effect, while the role of other receptors, such as β2-AR, should be reviewed in BAT function, these results support the development of safe sympathetic nervous system stimulants to activate brown adipose tissue for obesity treatment.

Gut microbiota refers to a complex network of microbes, which exerts a marked influence on the host’s health. It is composed of bacteria, fungi, viruses, and helminths. Bacteria, or collectively, the bacteriome, comprises a significant proportion of the well-characterized microbiome. However, the other communities referred to as ‘dark matter’ of microbiomes such as viruses (virome), fungi (mycobiome), archaea (archaeome), and helminths have not been completely elucidated. Development of new and improved metagenomics methods has allowed the identification of complete genomes from the genetic material in the human gut, opening new perspectives on the understanding of the gut microbiome composition, their importance, and potential clinical applications. Here, we review the recent evidence on the viruses, fungi, archaea, and helminths found in the mammalian gut, detailing their interactions with the resident bacterial microbiota and the host, to explore the potential impact of the microbiome on host’s health. The role of fecal virome transplantations, pre-, pro-, and syn-biotic interventions in modulating the microbiome and their related concerns are also discussed.

Inflammation is a major risk factor of morbidity and mortality in older adults. Although its precise etiology is unknown, low-grade inflammation in older adults is commonly associated with increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota. The increasing older population and lack of treatments to reduce aging-related microbiota dysbiosis, leaky gut, and inflammation culminates in a rise in aging-related comorbidities, constituting a significant public health concern. Here, we demonstrate that a human-origin probiotic cocktail containing 5 Lactobacillus and 5 Enterococcus strains isolated from healthy infant gut prevented high-fat diet-induced (HFD-induced) microbiota dysbiosis, leaky gut, inflammation, metabolic dysfunctions, and physical function decline in older mice. Probiotic-modulated gut microbiota primarily reduced leaky gut by increasing tight junctions, which in turn reduced inflammation. Mechanistically, probiotics modulated microbiota in a way to increase bile salt hydrolase activity, which in turn increased taurine abundance in the gut that stimulated tight junctions and suppressed gut leakiness. Furthermore, in Caenorhabditis elegans, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function. The results suggest that such probiotic therapies could prevent or treat aging-related leaky gut and inflammation in the elderly.

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbAl, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease.

The current outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed coronavirus disease 2019 (COVID-19), has generated a notable challenge for diabetic patients. Overall, people with diabetes have a higher risk of developing different infectious diseases and demonstrate increased mortality. Type 2 diabetes mellitus (T2DM) is a significant risk factor for COVID-19 progression and its severity, poor prognosis, and increased mortality. How diabetes contributes to COVID-19 severity is unclear; however, it may be correlated with the effects of hyperglycemia on systemic inflammatory responses and immune system dysfunction. Using the envelope spike glycoprotein SARS-CoV-2, COVID-19 binds to angiotensin-converting enzyme 2 (ACE2) receptors, a key protein expressed in metabolic organs and tissues such as pancreatic islets. Therefore, it has been suggested that diabetic patients are more susceptible to severe SARS-CoV-2 infections, as glucose metabolism impairments complicate the pathophysiology of COVID-19 disease in these patients. In this review, we provide insight into the COVID-19 disease complications relevant to diabetes and try to focus on the present data and growing concepts surrounding SARS-CoV-2 infections in T2DM patients.

Background Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys ( Clorocebus aethiops sabaeus ) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides. In addition, we performed untargeted global transcriptomics, proteomics, and metabolomics analyses on liver biopsies to determine the molecular impact of a HFr diet on coordinated pathways and networks that differed by diet. Results We show that integration of omics data sets improved statistical significance for some pathways and networks, and decreased significance for others, suggesting that multiple omics datasets enhance confidence in relevant pathway and network identification. Specifically, we found that sirtuin signaling and a peroxisome proliferator activated receptor alpha (PPARA) regulatory network were significantly altered in hepatic response to HFr. Integration of metabolomics and miRNAs data further strengthened our findings. Conclusions Our integrated analysis of three types of omics data with pathway and regulatory network analysis demonstrates the usefulness of this approach for discovery of molecular networks central to a biological response. In addition, metabolites aspartic acid and docosahexaenoic acid (DHA), protein ATG3, and genes ATG7, and HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.

Fibrosis is a pathological process with few therapeutic options. Experimental molecules are being developed to counteract the fibrotic effects through TGFβ receptor inhibition. Additionally, phosphodiesterase 5 (PDE5) inhibitors also have anti-fibrotic effects; however, the mechanism of action remains unresolved. IPW5371 is an example of an experimental TGFβ-mediated anti-fibrotic compound, and tadalafil is an example of a PDE5 inhibitor. Irradiation increases the frequency of fibrotic lesions, driven by the activation of the TGFβ pathway. We hypothesized that the TGFβ receptor and PDE5 inhibitor agents would be additive in their ability to prevent fibrosis development in tissues in a sub-lethal whole-body irradiation mouse model. However, the combined use of anti-fibrotic agents, tadalafil and IPW5371, caused increased male mouse mortality associated with ascending and thoracic aortic rupture compared to mice that only received one of the drugs. Following histopathological analysis of the mouse hearts, we also observed that irradiation protected against lesions caused by the combination therapy as non-irradiated male mice had significantly worse outcomes as compared to irradiated male mice, substantiating the drug–drug interaction independent of the radiation effects. This important drug interaction needs further investigation as these agents are developed for anti-fibrosis therapy, and PDE5 inhibitors are commonly prescribed to male patients.

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a twofold to fourfold increased risk for developing Alzheimer's disease (AD), however, the exact mechanisms linking the two diseases are unknown. In both conditions, the majority of pathophysiological changes, including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau, occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and amyloid pathology including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, pre-diabetic (PreD), and T2D vervet monkeys ( ). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to PreD and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ and CSF Aβ levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with previous studies in mice, CSF Aβ and CSF Aβ were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ and CSF Aβ levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

Background Shotgun proteomics utilizes a database search strategy to compare detected mass spectra to a library of theoretical spectra derived from reference genome information. As such, the robustness of proteomics results is contingent upon the completeness and accuracy of the gene annotation in the reference genome. For animal models of disease where genomic annotation is incomplete, such as non-human primates, proteogenomic methods can improve the detection of proteins by incorporating transcriptional data from RNA-Seq to improve proteomics search databases used for peptide spectral matching. Customized search databases derived from RNA-Seq data are capable of identifying unannotated genetic and splice variants while simultaneously reducing the number of comparisons to only those transcripts actively expressed in the tissue. Results We collected RNA-Seq and proteomic data from 10 vervet monkey liver samples and used the RNA-Seq data to curate sample-specific search databases which were analyzed in the program Morpheus. We compared these results against those from a search database generated from the reference vervet genome. A total of 284 previously unannotated splice junctions were predicted by the RNA-Seq data, 92 of which were confirmed by peptide spectral matches. More than half (53/92) of these unannotated splice variants had orthologs in other non-human primates, suggesting that failure to match these peptides in the reference analyses likely arose from incomplete gene model information. The sample-specific databases also identified 101 unique peptides containing single amino acid substitutions which were missed by the reference database. Because the sample-specific searches were restricted to actively expressed transcripts, the search databases were smaller, more computationally efficient, and identified more peptides at the empirically derived 1 % false discovery rate. Conclusion Proteogenomic approaches are ideally suited to facilitate the discovery and annotation of proteins in less widely studies animal models such as non-human primates. We expect that these approaches will help to improve existing genome annotations of non-human primate species such as vervet.

Increasing heat shock protein 70 (HSP70) in aged and/or insulin-resistant animal models confers benefits to healthspan and lifespan. Heat application to increase core temperature induces HSPs in metabolically important tissues, and preliminary human and animal data suggest that heated hydrotherapy is an effective method to achieve increased HSPs. However, safety concerns exist, particularly in geriatric medicine where organ and cardiovascular disease commonly will preexist. We evaluated young vervet monkeys compared to old, insulin-resistant vervet monkeys (Chlorocebus aethiops sabaeus) in their core temperatures, glucose tolerance, muscle HSP70 level, and selected safety biomarkers after 10 sessions of hot water immersions administered twice weekly. Hot water immersion robustly induced the heat shock response in muscles. We observed that heat-treated old and young monkeys have significantly higher muscle HSP70 than control monkeys and treatment was without significant adverse effects on organ or cardiovascular health. Heat therapy improved pancreatic responses to glucose challenge and tended to normalize glucose excursions. A trend for worsened blood pressure and glucose values in the control monkeys and improved values in heat-treated monkeys were seen to support further investigation into the safety and efficacy of this intervention for metabolic syndrome or diabetes in young or old persons unable to exercise.