Tissue inhibitor of matrix metalloproteinase 1 (TIMP1) controls adipogenesis in obesity in mice and in humans

Aims/hypothesis: Extracellular matrix reorganisation is a crucial step of adipocyte differentiation and is controlled by the matrix metalloproteinase-tissue inhibitor of matrix metalloproteinase (TIMP) enzyme system. We therefore sought to define the role of TIMP1 in adipogenesis and to elucidate whether upregulation of TIMP1 in obesity has direct effects on adipocyte formation. Methods: TIMP1 protein levels and mRNA were measured in lean and obese mice with a focus on levels in adipose tissue. We also analysed the effect of recombinant murine TIMP1 on adipogenesis, adipocyte size and metabolic control in vitro and in vivo. Results: TIMP1 levels were increased in the serum and adipose tissue of obese mouse models. Recombinant murine TIMP1 inhibited adipocyte differentiation in 3T3-L1 as well as in subcutaneous primary pre-adipocytes. Conversely, neutralising TIMP1 with a specific antibody enhanced adipocyte differentiation. In vivo, injection of recombinant TIMP1 in mice challenged with a high-fat diet led to enlarged adipocytes. TIMP1-treated mice developed an impaired metabolic profile with increased circulating NEFA levels, hepatic triacylglycerol accumulation and accelerated insulin resistance. Altered glucose clearance in TIMP1-injected mice was due to changes in adipose tissue glucose uptake, whereas muscle glucose clearance remained unaffected. Conclusions/interpretation: TIMP1 is a negative regulator of adipogenesis. In vivo, TIMP1 leads to enlarged adipocytes in the state of overnutrition. This might contribute to the detrimental metabolic consequences seen in TIMP1-injected mice, such as systemic fatty acid overload, hepatic lipid accumulation and insulin resistanc

3D simulations of gas puff effects on edge density and ICRF coupling in ASDEX Upgrade

In recent experiments, a local gas puff was found to be an effective way to tailor the scrape-off layer (SOL) density and improve the ion cyclotron range of frequency (ICRF) power coupling in tokamaks. In order to quantitatively reproduce these experiments, to understand the corresponding physics and to optimize the gas valve positions and rates, simulations were carried out with the 3D edge plasma transport code EMC3-EIRENE in ASDEX Upgrade. An inter-ELM phase of an H-mode discharge with a moderate gas puff rate (1.2 x 10(22) electrons s(-1)) is used in our simulations. We simulated cases with gas puff in the lower divertor, the outer mid-plane and the top of the machine while keeping other conditions the same. Compared with the lower divertor gas puff, the outer mid-plane gas puff can increase the local density in front of the antennas most effectively, while a toroidally uniform but significantly smaller enhancement is found for the top gas puff. Good agreement between our simulations and experiments is obtained. With further simulations, the mechanisms of SOL density tailoring via local gas puffing and the strategies of gas puff optimization are discussed in the paper

On the stability of periodic orbits in delay equations with large delay

We prove a necessary and sufficient criterion for the exponential stability of periodic solutions of delay differential equations with large delay. We show that for sufficiently large delay the Floquet spectrum near criticality is characterized by a set of curves, which we call asymptotic continuous spectrum, that is independent on the delay.Comment: postprint versio

I-mode studies at ASDEX Upgrade: L-I and I-H transitions, pedestal and confinement properties

The I-mode is a plasma regime obtained when the usual L-H power threshold is high, e.g. with unfavourable ion B ∇ direction. It is characterised by the development of a temperature pedestal while the density remains roughly as in the L-mode. This leads to a confinement improvement above the L-mode level which can sometimes reach H-mode values. This regime, already obtained in the ASDEX Upgrade tokamak about two decades ago, has been studied again since 2009 taking advantage of the development of new diagnostics and heating possibilities. The I-mode in ASDEX Upgrade has been achieved with different heating methods such as NBI, ECRH and ICRF. The I-mode properties, power threshold, pedestal characteristics and confinement, are independent of the heating method. The power required at the L-I transition exhibits an offset linear density dependence but, in contrast to the L-H threshold, depends weakly on the magnetic field. The L-I transition seems to be mainly determined by the edge pressure gradient and the comparison between ECRH and NBI induced L-I transitions suggests that the ion channel plays a key role. The I-mode often evolves gradually over a few confinement times until the transition to H-mode which offers a very interesting situation to study the transport reduction and its link with the pedestal formation. Exploratory discharges in which n = 2 magnetic perturbations have been applied indicate that these can lead to an increase of the I-mode power threshold by flattening the edge pressure at fixed heating input power: more heating power is necessary to restore the required edge pressure gradient. Finally, the confinement properties of the I-mode are discussed in detail.European Commission (EUROfusion 633053

Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling

A striking correspondence between the dynamics generated by the vector fields and by the scalar parabolic equations

The purpose of this paper is to enhance a correspondence between the dynamics of the differential equations $\dot y(t)=g(y(t))$ on $\mathbb{R}^d$ and those of the parabolic equations $\dot u=\Delta u +f(x,u,\nabla u)$ on a bounded domain $\Omega$. We give details on the similarities of these dynamics in the cases $d=1$, $d=2$ and $d\geq 3$ and in the corresponding cases $\Omega=(0,1)$, $\Omega=\mathbb{T}^1$ and dim($\Omega$)$\geq 2$ respectively. In addition to the beauty of such a correspondence, this could serve as a guideline for future research on the dynamics of parabolic equations

Body Self-perceptions of Students in Exercise Science Major

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Development of novel adenoviral vectors to overcome challenges observed with HAdV-5 based constructs

Recombinant vectors based on human adenovirus serotype 5 (HAdV-5) have been extensively studied in pre-clinical models and clinical trials over the last two decades. However, the thorough understanding of the HAdV-5 interaction with human subjects has uncovered major concerns about its product applicability. High vector-associated toxicity and widespread pre-existing immunity have been shown to significantly impede the effectiveness of HAdV-5 mediated gene transfer. It is therefore that the in depth knowledge attained working on HAdV-5 is currently being used to develop alternative vectors. Here, we provide a comprehensive overview of data obtained in recent years disqualifying the HAdV-5 vector for systemic gene delivery as well as novel strategies being pursued to overcome the limitations observed with particular emphasis on the ongoing vectorization efforts to obtain vectors based on alternative serotypes