7 research outputs found
Le rĂŽle et la rĂ©gulation du pyroglutamylated RF-amide peptide dans le tissu adipeux lors de lâobĂ©sitĂ©
LâobĂ©sitĂ© est dĂ©finie comme un surplus de masse adipeuse. Cette condition reprĂ©sente un problĂšme de santĂ© publique devenu pandĂ©mique dans les pays industrialisĂ©s. Elle prĂ©dispose Ă des maladies potentiellement mortelles comme le diabĂšte de type 2, les maladies cardiovasculaires et la stĂ©atose hĂ©patique non-alcoolique.
Lâaccumulation du tissu adipeux intra-abdominal, formĂ© dâadipocytes, est corrĂ©lĂ©e avec la rĂ©sistance Ă lâinsuline. Lâaugmentation de la masse adipeuse se fait par lâhyperplasie des prĂ©adipocytes, la diffĂ©renciation des prĂ©adipocytes en adipocytes et lâhypertrophie des adipocytes. La diffĂ©renciation des prĂ©adipocytes se fait selon lâadipogenĂšse qui est rĂ©gulĂ©e par une multitude de facteurs, mais qui est inhibĂ©e pas les stimuli inflammatoires qui sont aussi responsables de la rĂ©sistance Ă lâinsuline et de lâapparition des problĂšmes de santĂ© liĂ©s Ă lâobĂ©sitĂ©.
Nous avons identifiĂ© un nouveau systĂšme de rĂ©gulation autocrine/paracrine de lâadipogenĂšse dans les cellules du tissu adipeux. Le pyroglutamylated RF-amide peptide (QRFP), qui Ă©tait connu pour son rĂŽle dans la rĂ©gulation de lâappĂ©tit, est un activateur de lâadipogenĂšse par lâactivation de son rĂ©cepteur, le G protein-coupled receptor 103 (GPR103). Le QRFP est exprimĂ© dans les macrophages et les adipocytes alors que le GPR103 de sous-type b est exprimĂ© dans les adipocytes seulement. Un traitement des adipocytes avec le QRFP augmente le captage des acides gras, lâaccumulation de lipides ainsi que lâexpression et lâactivitĂ© de lâenzyme LPL. Le QRFP augmente aussi lâexpression des gĂšnes des transporteurs dâacides gras CD36 et FATP1, de lâenzyme activatrice dâacides gras ACSL1 et des facteurs de transcription PPAR-Îł et C/EBP-α, qui sont tous impliquĂ©s dans lâadipogenĂšse. En plus de ses effets sur lâadipogenĂšse, le QRFP possĂšde aussi un effet inhibiteur sur lâactivitĂ© lipolytique induite par les catĂ©cholamines.
Nous avons montrĂ© que lâexpression du QRFP est diminuĂ©e dans le tissu adipeux des souris obĂšses. Selon nos rĂ©sultats, cette diminution pourrait ĂȘtre expliquĂ©e par une augmentation des endotoxines circulantes chez les obĂšses, appelĂ©e endotoxĂ©mie mĂ©tabolique, qui agirait, entre autres, par lâinduction des interfĂ©rons dans les macrophages. Les voies de signalisation de ces effets ont aussi Ă©tĂ© identifiĂ©es. Nous avons montrĂ© un autre exemple de stimulus inflammatoire qui rĂ©gule les signaux adipogĂšnes Ă la baisse.Obesity is defined as an excess of fat tissue mass. Obesity is a public health problem which became pandemic in developed countries. The condition of obesity predisposes to potentially fatal diseases like type 2 diabetes, cardiovascular diseases and non-alcoholic steatohepatitis.
The increase in intra-abdominal adipose tissue mass is intimately associated with the development of insulin resistance. An increase in fat tissue mass occurs by preadipocytes hyperplasia, preadipocytes differentiation into adipocytes and adipocyte hypertrophy. The differentiation of preadipocytes occurs during adipogenesis and is regulated by multiple factors but inhibited by inflammatory stimuli that are responsible for insulin resistance and the emergence of obesity-related dysfunctions.
We identified a new autocrine/paracrine system of regulation of adipogenesis in adipose tissue cells. The pyroglutamylated RF-amide peptide (QRFP), previously known for its role in the regulation of appetite, is an activator of adipogenesis by activating its receptor, G protein-coupled receptor 103 (GPR103). QRFP is expressed in adipocytes and macrophages whereas the GPR103 subtype b is expressed in adipocytes only. Treatment of adipocytes with QRFP increases fatty acids uptake, lipid accumulation, LPL enzyme expression and activity. QRFP upregulates gene expressions of fatty acids transporters CD36 and FATP1, of the fatty acid activating enzyme ACSL1 and of transcription factors PPAR-γ and C/EBP-α, which are all involved in adipogenesis. In addition to its effects on adipogenesis, QRFP shows an inhibitory effect on lipolytic activity induced by catecholamines.
We have shown that QRFP expression is decreased in adipose tissues of obese mice. According to our results, this decrease could be explained by an increase of circulating endotoxins in obesity, called metabolic endotoxemia, which mediate its effect, in part, by the induction of interferons in macrophages. Signaling pathways of these effects have been identified. We demonstrated another example of inflammatory stimulus downregulating adipogenic signals
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNetÂź convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNetÂź model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery