Melanocortin receptors in rat liver cells: change of gene expression and intracellular localization during acute-phase response

MCRs are known to be expressed predominantly in the brain where they mediate metabolic and anti-inflammatory functions. Leptin plays an important role in appetite and energy regulation via signaling through melanocortin receptors (MCRs) in the brain. As serum levels of MCR ligands are elevated in a clinical situation [acute-phase response (APR)] to tissue damage, where the liver is responsible for the metabolic changes, we studied hepatic gene expression of MCRs in a model of muscle tissue damage induced by turpentine oil (TO) injection in rats. A significant increase in gene expression of all five MCRs (MC4R was the highest) in liver at the RNA and protein level was detected after TO injection. A similar pattern of increase was also found in the brain. Immunohistology showed MC4R in the cytoplasm, but also in the nucleus of parenchymal and non-parenchymal liver cells, whereas MC3R-positivity was mainly cytoplasmic. A time-dependent migration of MC4R protein from the cytoplasm into the nucleus was observed during APR, in parallel with an increase in α-MSH and leptin serum levels. An increase of MC4R was detected at the protein level in wild-type mice, while such an increase was not observed in IL-6ko mice during APR. Moreover, treatment of isolated liver cells with melanocortin agonists (α-MSH and THIQ) inhibited the endotoxin-induced upregulation of the acute-phase cytokine (IL-6, IL1β and TNF-α) gene expression in Kupffer cells and of chemokine gene expression in hepatocytes. MCRs are expressed not only in the brain, but also in liver cells and their gene expression in liver and brain tissue is upregulated during APR. Due to the presence of specific ligands in the serum, they may mediate metabolic changes and exert a protective effect on liver cells

Correlates of Food Addiction and Eating Behaviours in Patients with Morbid Obesity

Introduction: Food Addiction (FA) is a promising construct regarding the multifactorial aetiology of obesity and the search for therapeutic approaches. However, there is an ongoing debate regarding the overlap/differentiation with eating disorders and the classification as a substance- or behaviour-related addiction. Energy-dense foods, especially those combining carbohydrates and fat, are associated with addictive eating and suspected of playing a role in the genesis of FA. This study aims to further understand the clinical significance of FA and to identify possible therapeutic targets. A special focus is set on potentially addictive foods (combination of carbohydrates and fat). Methods: Based on the Yale Food Addiction Scale 2.0 a cohort of 112 German adults with morbid obesity was divided into two sub-samples (patients with and without FA), which were examined for differences in the variables listed below. Results: The prevalence of FA was 25%. Patients meeting criteria for FA showed higher degrees of hunger, emotional, binge and night eating than patients without FA. In addition, hunger and disinhibition were found to be significant predictors of FA. FA was not associated with sex, age, BMI, cognitive restraint, rigid and flexible control, prevalence of substance use, age of onset of obesity, stress level, level of social support, reduction of BMI during a weight loss programme or programme withdrawal rate. There was no significant difference in the consumption of foods rich in both carbohydrates and fat, nor of fat or carbohydrates alone. Conclusion: FA can be considered as a sub-phenotype of obesity, occurring in approximately 25% of obesity cases. Dysfunctional emotional coping mechanisms associated with low distress tolerance showed to be significantly related to FA and should be targeted therapeutically. Behavioural interventions should include a bio-psycho-social model. Binge eating episodes were found to be characteristic for FA and the already stated overlap between FA and binge eating behaviour can be confirmed. The results do not support a decisive difference due to a substance-related component of FA. Despite this, the existence of FA as a distinct entity cannot be excluded, as not all patients with FA exhibit binges

Monsoonal forcing of cold-water coral growth off southeastern Brazil during the past 160 kyr

Cold-water corals (CWCs) constitute important deep-water ecosystems that are under increasing environmental pressure due to ocean acidification and global warming. The sensitivity of these deep-water ecosystems to environmental change is demonstrated by abundant paleorecords drilled through CWC mounds that reveal characteristic alterations between rapid formation and dormant or erosive phases. Previous studies have identified several central parameters for driving or inhibiting CWC growth such as food supply, oxygenation, and the carbon saturation state of bottom water, yet there are still large uncertainties about the relative importance of the different environmental parameters. To advance this debate we have performed a multiproxy study on a sediment core retrieved from the 25 m high Bowie Mound, located at 866 m water depth on the continental slope off southeastern Brazil, a structure built up mainly by the CWC Solenosmilia variabilis. Our results indicate a multifactorial control on CWC growth at Bowie Mound during the past ∼ 160 kyr, which reveals distinct formation pulses during northern high-latitude glacial cold events (Heinrich stadials, HSs) largely associated with anomalously strong monsoonal rainfall over the continent. The ensuing enhanced runoff elevated the terrigenous nutrient and organic-matter supply to the continental margin and likely boosted marine productivity. The dispersal of food particles towards the CWC colonies during HSs was facilitated by the highly dynamic hydraulic conditions along the continental slope that prevailed throughout glacial periods. These conditions caused the emplacement of a pronounced nepheloid layer above Bowie Mound, thereby aiding the concentration and along-slope dispersal of organic matter. Our study thus emphasizes the impact of continental climate variability on a highly vulnerable deep-marine ecosystem

Living on the edge: environmental variability of a shallow late Holocene cold-water coral mound

Similar to their tropical counterparts, cold-water corals (CWCs) are able to build large three-dimensional reef structures. These unique ecosystems are at risk due to ongoing climate change. In particular, ocean warming, ocean acidification and changes in the hydrological cycle may jeopardize the existence of CWCs. In order to predict how CWCs and their reefs or mounds will develop in the near future one important strategy is to study past fossil CWC mounds and especially shallow CWC ecosystems as they experience a greater environmental variability compared to other deep-water CWC ecosystems. We present results from a CWC mound off southern Norway. A sediment core drilled from this relatively shallow (~ 100 m) CWC mound exposes in full detail hydrographical changes during the late Holocene, which were crucial for mound build-up. We applied computed tomography, 230Th/U dating, and foraminiferal geochemical proxy reconstructions of bottom-water-temperature (Mg/Ca-based BWT), δ18O for seawater density, and the combination of both to infer salinity changes. Our results demonstrate that the CWC mound formed in the late Holocene between 4 kiloannum (ka) and 1.5 ka with an average aggradation rate of 104 cm/kiloyears (kyr), which is significantly lower than other Holocene Norwegian mounds. The reconstructed BWTMg/Ca and seawater density exhibit large variations throughout the entire period of mound formation, but are strikingly similar to modern in situ observations in the nearby Tisler Reef. We argue that BWT does not exert a primary control on CWC mound formation. Instead, strong salinity and seawater density variation throughout the entire mound sequence appears to be controlled by the interplay between the Atlantic Water (AW) inflow and the overlying, outflowing Baltic-Sea water. CWC growth and mound formation in the NE Skagerrak was supported by strong current flow, oxygen replenishment, the presence of a strong boundary layer and larval dispersal through the AW, but possibly inhibited by the influence of fresh Baltic Water during the late Holocene. Our study therefore highlights that modern shallow Norwegian CWC reefs may be particularly endangered due to changes in water-column stratification associated with increasing net precipitation caused by climate change

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis

The effect of cigarette smoke exposure on the development of inflammation in lungs, gut and joints of TNFΔARE mice

The inflammatory cytokine TNF-alpha is a central mediator in many immune-mediated diseases, such as Crohn's disease (CD), spondyloarthritis (SpA) and chronic obstructive pulmonary disease (COPD). Epidemiologic studies have shown that cigarette smoking (CS) is a prominent common risk factor in these TNF-dependent diseases. We exposed TNF Delta ARE mice; in which a systemic TNF-alpha overexpression leads to the development of inflammation; to 2 or 4 weeks of air or CS. We investigated the effect of deregulated TNF expression on CS-induced pulmonary inflammation and the effect of CS exposure on the initiation and progression of gut and joint inflammation. Upon 2 weeks of CS exposure, inflammation in lungs of TNF Delta ARE mice was significantly aggravated. However, upon 4 weeks of CS-exposure, this aggravation was no longer observed. TNF Delta ARE mice have no increases in CD4+ and CD8+ T cells and a diminished neutrophil response in the lungs after 4 weeks of CS exposure. In the gut and joints of TNF Delta ARE mice, 2 or 4 weeks of CS exposure did not modulate the development of inflammation. In conclusion, CS exposure does not modulate gut and joint inflammation in TNF Delta ARE mice. The lung responses towards CS in TNF Delta ARE mice however depend on the duration of CS exposure

Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin

Changes in DNA methylation patterning have been reported to be a key hallmark of aged human skin. The altered DNA methylation patterns are correlated with deregulated gene expression and impaired tissue functionality, leading to the well-known skin aging phenotype. Searching for small molecules, which correct the aged methylation pattern therefore represents a novel and attractive strategy for the identification of anti-aging compounds. DNMT1 maintains epigenetic information by copying methylation patterns from the parental (methylated) strand to the newly synthesized strand after DNA replication. We hypothesized that a modest inhibition of this process promotes the restoration of the ground-state epigenetic pattern, thereby inducing rejuvenating effects. In this study, we screened a library of 1800 natural substances and 640 FDA-approved drugs and identified the well-known antioxidant and anti-inflammatory molecule dihydromyricetin (DHM) as an inhibitor of the DNA methyltransferase DNMT1. DHM is the active ingredient of several plants with medicinal use and showed robust inhibition of DNMT1 in biochemical assays. We also analyzed the effect of DHM in cultivated keratinocytes by array-based methylation profiling and observed a moderate, but significant global hypomethylation effect upon treatment. To further characterize DHM-induced methylation changes, we used published DNA methylation clocks and newly established age predictors to demonstrate that the DHM-induced methylation change is associated with a reduction in the biological age of the cells. Further studies also revealed re-activation of age-dependently hypermethylated and silenced genes in vivo and a reduction in age-dependent epidermal thinning in a 3-dimensional skin model. Our findings thus establish DHM as an epigenetic inhibitor with rejuvenating effects for aged human skin