Rol van metalloproteïnasen in adipogenese en obesitas

Obesity has become a major health problem for modern Western-type societies. The worldwide prevalence of obesity has doubled since the 1980’s and today over 600 million adults are obese. Moreover, obesity is associated with the development of chronic diseases such as type 2 diabetes, cardiovascular diseases and fatty liver disease. This presents a heavy burden to the health care sector and has major economical consequences. However, efficient therapies to achieve metabolic health are not readily available. Adipose tissue has played an essential role in the adaptation of humans during evolution, i.e to food scarcity and cold. On the one hand, white adipose tissue is programmed to store excess energy in the form of triglycerides. On the other hand, brown adipose tissue efficiently burns energy to produce heat (thermogenesis). Over the last decade a third type of adipocyte was identified, namely the beige adipocyte. This adipocyte is mainly found in subcutaneous adipose tissue and is bi-functional, meaning that it can adapt to energy storage or to thermogenesis, depending on the metabolic need. A good understanding of adipose tissue biology is necessary for the development of new therapeutic strategies against obesity. Adipose tissue expansion consists of hypertrophy (existing adipocytes increase in volume), hyperplasia (new adipocytes arise from precursor cells), angiogenesis (formation of new blood vessels) and remodeling of the extracellular matrix. The metalloproteinase family is involved in all of these processes. This superfamily can be further divided into several subfamilies including the MMP (matrix metalloproteinases) family. A potential role for MMP-2 and MMP-9 was reported in obesity, although many discrepant results were presented. In the present study, we further investigated the specific roles of MMP-2 and MMP-9 in adipogenesis in vitro. Therefore, we used established in vitro models: - murine embryonic fibroblasts (MEF) derived from wild-type and gene deficient mice were stimulated towards adipogenic differentiation. - 3T3-F442A preadipocytes were differentiated into mature adipocytes, while MMP levels were modulated by genetic knockdown (shRNA-mediated) or overexpression. In agreement with diet studies performed on mice with genetic deficiencies, we demonstrated that MMP-2 but not MMP-9 is an important player in preadipocyte differentiation. Another subfamily of the metalloproteinases is the ADAMTS (A disintegrin and metalloproteinase with thrombospondin type 1 motifs) family. Relatively little is known on the role of this subfamily in adipose tissue development, although it has been reported that several members, including ADAMTS5, are upregulated in adipose tissue of obese mice. We studied the effects of ADAMTS5 on adipogenesis both in vitro and in vivo, and on adipose tissue development in nutritionally-induced obesity in mice. Using 3T3-F442A cells and MEFs, we demonstrated that ADAMTS5 promotes adipogenesis in vitro, and also stimulates de novo adipogenesis in vivo. Moreover, mice with genetic ADAMTS5 deficiency, kept on a high fat diet, developed less visceral adipose tissue mass and were protected against liver steatosis. This hepatic phenotype appears to be due to reduced uptake of triglycerides from the circulation into the liver, thereby protecting liver integrity. It is tempting to speculate that neutralization of ADAMTS5 may protect against diet-induced steatohepatitis. Surprisingly, we also observed an increased mass of brown adipose tissue in ADAMTS5 deficient mice. Moreover, in subcutaneous white adipose tissue of ADAMTS5 deficient as compared to wild-type mice, more beige adipocytes were observed (also known as ‘browning’). The brown adipose tissue was shown to be metabolically active, but only small differences in heat production and energy expenditure were observed, without significant effects of ADAMTS deficiency on total body weight. Furthermore, browning of white adipose tissue was strongly enhanced upon exposure to cold, a known stimulator. These findings indicate that ADAMTS5 plays an important functional role in development of white and brown adipose tissue. It remains to be shown whether neutralization of ADAMTS5 is a viable strategy to enhance thermogenesis and to reduce obesity.status: publishe

The Anti-Adipogenic Potential of COUP-TFII Is Mediated by Downregulation of the Notch Target Gene Hey1

BACKGROUND: Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) belongs to the steroid/thyroid hormone receptor superfamily and may contribute to the pathogenesis of obesity. It has not conclusively been established, however, whether its role is pro- or anti-adipogenic. METHODS AND RESULTS: Gene silencing of Coup-tfII in 3T3-F442A preadipocytes resulted in enhanced differentiation into mature adipocytes. This was associated with upregulation of the Notch signaling target gene Hey1. A functional role of Hey1 was confirmed by gene silencing in 3T3-F442A preadipocytes, resulting in impaired differentiation. In vivo, de novo fat pad formation in NUDE mice was significantly stimulated following injection of preadipocytes with Coup-tfII gene silencing, but impaired with Hey1 gene silencing. Moreover, expression of Coup-tfII was lower and that of Hey1 higher in isolated adipocytes of obese as compared to lean adipose tissue. CONCLUSIONS: These in vitro and in vivo data support an anti-adipogenic role of COUP-TFII via downregulating the Notch signaling target gene Hey1.status: publishe

Leaky nitrogen cycle in pristine African montane rainforest soil

Many pristine humid tropical forests show simultaneously high nitrogen (N) richness and sustained loss of bioavailable N forms. To better understand this apparent upregulation of the N cycle in tropical forests, process-based understanding of soil N transformations, in geographically diverse locations, remains paramount. Field-based evidence is limited and entirely lacking for humid tropical forests on the African continent. This study aimed at filling both knowledge gaps by monitoring N losses and by conducting an in situ N-15 labeling experiment in the Nyungwe tropical montane forest in Rwanda. Here we show that this tropical forest shows high nitrate (NO3-) leaching losses, confirming findings from other parts of the world. Gross N transformation rates point to an open soil N cycle with mineralized N nitrified rather than retained via immobilization; gross immobilization of NH4+ and NO3- combined accounted for 37% of gross mineralization, and plant N uptake is dominated by ammonium (NH4+). This study provided new process understanding of soil N cycling in humid tropical forests and added geographically independent evidence that humid tropical forests are characterized by soil N dynamics and N inputs sustaining bioavailable N loss

Gelatinase A (MMP-2) promotes murine adipogenesis

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Functional role of ADAMTS5 in adiposity and metabolic health

<div><p>Previous studies with gene-deficient mice (ADAMTS5-P) revealed that ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs, member 5) plays a functional role in adiposity and metabolic health. To confirm these observations, we have performed similar studies with an independently generated strain of ADAMTS5 deficient mice (ADAMTS5-J). Upon cold exposure as well as after high-fat diet feeding (diet-induced obesity or DIO model), these knockout (KO) mice developed less subcutaneous and gonadal white adipose tissue (WAT) as compared to their wild-type (WT) littermates (reduction was more pronounced in ADAMTS5-P mice). Enhanced browning of WAT, as monitored by expression of UCP-1 was seen in the ADAMTS5-J KO mice upon cold exposure but not in the DIO model (seen in both conditions with the ADAMTS5-P mice). Brown adipose tissue (BAT) mass was not different between KO and WT ADAMTS5-J mice, either upon cold exposure or in the DIO model (in contrast to the enhanced BAT mass with the ADAMTS5-P mice). Energy expenditure and thermogenesis were not significantly different between KO and WT ADAMTS5-J mice (in contrast to somewhat enhanced levels in ADAMTS5-P mice). Insulin sensitivity was improved in the ADAMTS5-J KO mice, and they were protected against non-alcoholic steatohepatitis in the DIO model (as the ADAMTS5-P mice). These data are thus similar for both strains of KO mice, confirming specificity of the phenotype, but some quantitative and qualitative differences are also observed.</p></div

Effect of ADAMTS5 deficiency on diet-induced obesity.

<p>(A-C) Expression of <i>Adamts5</i> (A disintegrin and metalloproteinase with thrombospondin type 1 motifs member 5), <i>Ucp-1</i> (Uncoupling protein-1) and <i>Cidea</i> in subcutaneous (s) white adipose tissue (WAT) of ADAMTS5-J mice (n = 5–6). Data are corrected for the housekeeping gene <i>β-actin</i> and normalized to wild-type (WT) mice (+/+). Data are means ± SEM of n determinations. (D) Western blot analysis of UCP-1 protein levels in sWAT of <i>Adamts5</i>^+/+-P (n = 2), <i>Adamts5</i>^-/--P (-/-; n = 1), <i>Adamts5</i>^+/+-J (n = 5) and <i>Adamts5</i>^-/--J (-/-; n = 5) mice. The expression of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as a loading control.</p

Loss of ADAMTS5 enhances brown adipose tissue mass and promotes browning of white adipose tissue via CREB signaling

A potential strategy to treat obesity - and the associated metabolic consequences - is to increase energy expenditure. This could be achieved by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or the induction of browning of white adipose tissue (WAT). Over the last years, it has become clear that several metalloproteinases play an important role in adipocyte biology. Here, we investigated the potential role of ADAMTS5.status: publishe

Large-sized rare tree species contribute disproportionately to functional diversity in resource acquisition in African tropical forest

Increasing evidence is available for a positive effect of biodiversity on ecosystem productivity and standing biomass, also in highly diverse systems as tropical forests. Biodiversity conservation could therefore be a critical aspect of climate mitigation policies. There is, however, limited understanding of the role of individual species for this relationship, which could aid in focusing conservation efforts and forest management planning. This study characterizes the functional specialization and redundancy for 95% of all tree species (basal area weighted percentage) in a diverse tropical forest in the central Congo Basin and relates this to species' abundance, contribution to aboveground carbon, and maximum size. Functional characterization is based on a set of traits related to resource acquisition (wood density, specific leaf area, leaf carbon, nitrogen and phosphorus content, and leaf stable carbon isotope composition). We show that within both mixed and monodominant tropical forest ecosystems, the highest functional specialization and lowest functional redundancy are solely found in rare tree species and significantly more in rare species holding large-sized individuals. Rare species cover the entire range of low and high functional redundancy, contributing both unique and redundant functions. Loss of species supporting functional redundancy could be buffered by other species in the community, including more abundant species. This is not the case for species supporting high functional specialization and low functional redundancy, which would need specific conservation attention. In terms of tropical forest management planning, we argue that specific conservation of large-sized trees is imperative for long-term maintenance of ecosystem functioning

Expression of <i>Coup-tfII</i> and <i>Hey1</i> in adipose tissue and isolated cell fractions.

<p>Expression of <i>Coup-tfII</i> (A) or <i>Hey1</i> (B) in gonadal (GN) and subcutaneous (SC) adipose tissues, as well as in isolated adipocytes and stromal vascular fractions (SVF) and in microvascular endothelial cells (MEC) derived from SC and GN adipose tissues obtained from obese mice, is shown relative to samples from lean mice (dotted line). Data are means ± SEM of at least 4 samples; * p < 0.05, ** p < 0.01, *** p < 0.001.</p