The relevance of EGFR, ErbB receptors and neuregulins in human adipocytes and adipose tissue in obesity

Objective: To investigate the potential role of EGFR, ErbBs receptors and neuregulins in human adipose tissue physiology in obesity. Methods: Gene expression analysis in human subcutaneous (SAT) and visceral (VAT) adipose tissue in three independent cohorts [two cross-sectional (N = 150, N = 87) and one longitudinal (n = 25)], and in vitro gene knockdown and overexpression experiments were performed. Results: While both SAT and VAT ERBB2 and ERBB4 mRNA increased in obesity, SAT EGFR mRNA was negatively correlated with insulin resistance, but did not change in obesity. Of note, both SAT and VAT EGFR mRNA were significantly associated with adipogenesis and increased during human adipocyte differentiation. In vitro experiments revealed that EGFR, but not ERBB2 and ERBB4, gene knockdown in preadipocytes and in fully differentiated human adipocytes resulted in decreased expression of adipogenic-related genes. ERBB2 gene knockdown also reduced gene expression of fatty acid synthase in fully differentiated adipocytes. In addition, neuregulin 2 (NRG2) mRNA was associated with expression of adipogenic genes in human adipose tissue and adipocytes, and its overexpression increased expression of EGFR and relevant adipogenic genes. Conclusions: This study demonstrates the association between adipose tissue ERBB2 and obesity, confirms the relevance of EGFR on human adipogenesis, and suggests a possible adipogenic role of NRG2

Boreal permafrost thaw amplified by fire disturbance and precipitation increases

Permafrost soils store huge amounts of organic carbon, which could be released if climate change promotes thaw. Currently, modelling studies predict that thaw in boreal regions is mainly sensitive to warming, rather than changes in precipitation or vegetation cover. We evaluate this conclusion for North American boreal forests using a detailed process-based model parameterised and validated on field measurements. We show that soil thermal regimes for dominant forest types are controlled strongly by soil moisture and thus the balance between evapotranspiration and precipitation. Under dense canopy cover, high evapotranspiration means a 30% increase in precipitation causes less thaw than a 1 °C increase in temperature. However, disturbance to vegetation promotes greater thaw through reduced evapotranspiration, which results in wetter, more thermally conductive soils. In such disturbed forests, increases in precipitation rival warming as a direct driver of thaw, with a 30% increase in precipitation at current temperatures causing more thaw than 2 °C of warming. We find striking non-linear interactive effects on thaw between rising precipitation and loss of leaf area, which are of concern given projections of greater precipitation and disturbance in boreal forests. Inclusion of robust vegetation-hydrological feedbacks in global models is therefore critical for accurately predicting permafrost dynamics; thaw cannot be considered to be controlled solely by rising temperatures

Neuregulin 4 Is a Novel Marker of Beige Adipocyte Precursor Cells in Human Adipose Tissue

Background: Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action.Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMAIR and glucose infusion rate during euglycemic hyperinsulinemic clamp.Results: In both cohort 1 and cohort 2, NRG4 and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMAIR and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1.Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue

Limited release of previously-frozen C and increased new peat formation after thaw in permafrost peatlands

Permafrost stores globally significant amounts of carbon (C) which may start to decompose and be released to the atmosphere in form of carbon dioxide (CO 2 ) and methane (CH 4 ) as global warming promotes extensive thaw. This permafrost carbon feedback to climate is currently considered to be the most important carbon-cycle feedback missing from climate models. Predicting the magnitude of the feedback requires a better understanding of how differences in environmental conditions post-thaw, particularly hydrological conditions, control the rate at which C is released to the atmosphere. In the sporadic and discontinuous permafrost regions of north-west Canada, we measured the rates and sources of C released from relatively undisturbed ecosystems, and compared these with forests experiencing thaw following wildfire (well-drained, oxic conditions) and collapsing peat plateau sites (water-logged, anoxic conditions). Using radiocarbon analyses, we detected substantial contributions of deep soil layers and/or previously-frozen sources in our well-drained sites. In contrast, no loss of previously-frozen C as CO 2 was detected on average from collapsed peat plateaus regardless of time since thaw and despite the much larger stores of available C that were exposed. Furthermore, greater rates of new peat formation resulted in these soils becoming stronger C sinks and this greater rate of uptake appeared to compensate for a large proportion of the increase in CH 4 emissions from the collapse wetlands. We conclude that in the ecosystems we studied, changes in soil moisture and oxygen availability may be even more important than previously predicted in determining the effect of permafrost thaw on ecosystem C balance and, thus, it is essential to monitor, and simulate accurately, regional changes in surface wetness

Neuregulin 4 is a novel marker of beige adipocyte precursor cells in human adipose tissue

Background: Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action. Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMAIR and glucose infusion rate during euglycemic hyperinsulinemic clamp. Results: In both cohort 1 and cohort 2, NRG4 and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMAIR and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1. Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue

Neuregulin 4 is a novel marker of beige adipocyte precursor cells in human adipose tissue

Background: Nrg4 expression has been linked to brown adipose tissue activity and browning of white adipocytes in mice. Here, we aimed to investigate whether these observations could be translated to humans by investigating NRG4 mRNA and markers of brown/beige adipocytes in human visceral (VAT) and subcutaneous adipose tissue (SAT). We also studied the possible association of NRG4 with insulin action. Methods: SAT and VAT NRG4 and markers of brown/beige (UCP1, UCP3, and TMEM26)-related gene expression were analyzed in two independent cohorts (n = 331 and n = 59). Insulin resistance/sensitivity was measured using HOMAIR and glucose infusion rate during euglycemic hyperinsulinemic clamp. Results: In both cohort 1 and cohort 2, NRG4 and thermogenic/beige-related gene expression were significantly increased in VAT compared to SAT. Adipogenic-related genes followed an opposite pattern. In cohort 1, VAT NRG4 gene expression was positively correlated with BMI and expression of UCP1, UCP3, TMEM26, and negatively with adipogenic (FASN, PPARG, and SLC2A4)- and inflammatory (IL6 and IL8)-related genes. In SAT, NRG4 gene expression was negatively correlated with HOMAIR and positively with UCP1 and TMEM26 gene expression. Multiple linear regression analysis revealed that expression of TMEM26 gene was the best predictor of NRG4 gene expression in both VAT and SAT. Specifically, NRG4 and TMEM26 gene expression was significantly increased in VAT, but not in SAT stromal vascular fraction cells (p < 0.001). In cohort 2, the significant association between NRG4 and TMEM26 gene expression in both VAT and SAT was confirmed, and SAT NRG4 gene expression also was positively correlated with insulin action and the expression of UCP1. Conclusion: Current findings suggest NRG4 gene expression as a novel marker of beige adipocytes in human adipose tissue

Role of Mitochondrial Complex IV in Age-Dependent Obesity.

Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion