02234nas a2200325 4500008004100000022001400041245014800055210006900203260001600272300001100288490000700299520106600306100002701372700003201399700002401431700001701455700002601472700001901498700002101517700001801538700002201556700001701578700001901595700002901614700002001643700002301663700002301686700002401709856017501733 2023 eng d a2211-124700aDefective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis.0 aDefective extracellular matrix remodeling in brown adipose tissu c2023 Jun 13 a1126400 v423 a

The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.

1 aPellegrinelli, Vanessa1 aFigueroa-Juárez, Elizabeth1 aSamuelson, Isabella1 aU-Din, Mueez1 aRodriguez-Fdez, Sonia1 aVirtue, Samuel1 aLeggat, Jennifer1 aCubuk, Cankut1 aPeirce, Vivian, J1 aNiemi, Tarja1 aCampbell, Mark1 aRodriguez-Cuenca, Sergio1 aDopazo, Joaquin1 aCarobbio, Stefania1 aVirtanen, Kirsi, A1 aVidal-Puig, Antonio uhttps://www.clinbioinfosspa.es/content/defective-extracellular-matrix-remodeling-brown-adipose-tissue-associated-fibro-inflammation-and-reduced-diet-induced-thermogenesis02634nas a2200289 4500008004100000022001400041245015800055210006900213260001500282300000900297520167800306653001901984653001202003653000902015653000902024653002302033653001202056653002102068100002302089700001802112700003002130700002302160700002002183700002402203700002902227856008802256 2016 eng d a1607-888800aChronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice.0 aChronic subordination stress selectively downregulates the insul c2016 Mar 7 a1-113 aChronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus.10aAdipose tissue10ainsulin10aIRS110aIRS210ametabolic syndrome10aobesity10apathway analysis1 aSanghez, Valentina1 aCubuk, Cankut1 aSebastián-Leon, Patricia1 aCarobbio, Stefania1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aBartolomucci, Alessandro uhttp://www.tandfonline.com/doi/abs/10.3109/10253890.2016.1151491?journalCode=ists2003446nas a2200277 4500008004100000022001400041245011600055210006900171260001300240300001000253490000600263520251800269100001902787700002102806700002002827700002202847700001802869700001902887700001702906700002202923700002002945700002402965700001902989700002903008856013103037 2016 eng d a2212-877800aStress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.0 aStressinduced activation of brown adipose tissue prevents obesit c2016 Jan a19-330 v53 a

BACKGROUND: Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.

METHODS: We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.

RESULTS: Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.

CONCLUSION: Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.

1 aRazzoli, Maria1 aFrontini, Andrea1 aGurney, Allison1 aMondini, Eleonora1 aCubuk, Cankut1 aKatz, Liora, S1 aCero, Cheryl1 aBolan, Patrick, J1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aCinti, Saverio1 aBartolomucci, Alessandro uhttps://www.clinbioinfosspa.es/content/stress-induced-activation-brown-adipose-tissue-prevents-obesity-conditions-low-adaptive02249nas a2200313 4500008004100000022001400041245008200055210006900137260001600206300000800222490000600230520134100236653002201577653001201599653001501611653002001626100003001646700001901676700001901695700001601714700002001730700001901750700001901769700002401788700002401812700002001836700002101856856005801877 2014 eng d a1752-050900aUnderstanding disease mechanisms with models of signaling pathway activities.0 aUnderstanding disease mechanisms with models of signaling pathwa c2014 Oct 25 a1210 v83 aBackgroundUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is one of the main challenges in the analysis of genomic data and is on the basis of the future implementation of precision medicine.ResultsHere we propose a simple probabilistic model in which signaling pathways are separated into elementary sub-pathways or signal transmission circuits (which ultimately trigger cell functions) and then transforms gene expression measurements into probabilities of activation of such signal transmission circuits. Using this model, differential activation of such circuits between biological conditions can be estimated. Thus, circuit activation statuses can be interpreted as biomarkers that discriminate among the compared conditions. This type of mechanism-based biomarkers accounts for cell functional activities and can easily be associated to disease or drug action mechanisms. The accuracy of the proposed model is demonstrated with simulations and real datasets.ConclusionsThe proposed model provides detailed information that enables the interpretation disease mechanisms as a consequence of the complex combinations of altered gene expression values. Moreover, it offers a framework for suggesting possible ways of therapeutic intervention in a pathologically perturbed system.10aDisease mechanism10apathway10asignalling10aSystems biology1 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aSalavert, Francisco1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquín uhttp://www.biomedcentral.com/1752-0509/8/121/abstract00806nas a2200241 4500008004100000245008100041210006900122260000700191300000800198490000600206100003000212700001900242700001900261700001600280700002000296700001900316700001900335700003200354700002400386700002000410700002000430856011400450 2014 eng d00aUnderstanding disease mechanisms with models of signaling pathway activities0 aUnderstanding disease mechanisms with models of signaling pathwa c10 a1210 v81 aSebastián-Leon, Patricia1 aVidal, Enrique1 aMinguez, Pablo1 aConesa, Ana1 aTarazona, Sonia1 aAmadoz, Alicia1 aArmero, Carmen1 aTorres, Francisco, Salavert1 aVidal-Puig, Antonio1 aMontaner, David1 aDopazo, Joaquin uhttps://www.clinbioinfosspa.es/content/understanding-disease-mechanisms-models-signaling-pathway-activities-102878nas a2200301 4500008004100000245015000041210006900191260001600260300001200276490000700288520183800295100001902133700002202152700002502174700002102199700002002220700002002240700001702260700002102277700002202298700002502320700002102345700002002366700001802386700002102404700002402425856012702449 2011 eng d00aDifferential Lipid Partitioning Between Adipocytes and Tissue Macrophages Modulates Macrophage Lipotoxicity and M2/M1 Polarization in Obese Mice.0 aDifferential Lipid Partitioning Between Adipocytes and Tissue Ma c2011 Jan 24 a797-8090 v603 a

OBJECTIVE Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response. RESEARCH DESIGN AND METHODS We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment. RESULTS We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization. CONCLUSIONS Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

1 aPrieur, Xavier1 aMok, Crystal, Y L1 aVelagapudi, Vidya, R1 aNúñez, Vanessa1 aFuentes, Lucía1 aMontaner, David1 aIshikawa, Ko1 aCamacho, Alberto1 aBarbarroja, Nuria1 aO’Rahilly, Stephen1 aSethi, Jaswinder1 aDopazo, Joaquin1 aOresic, Matej1 aRicote, Mercedes1 aVidal-Puig, Antonio uhttps://www.clinbioinfosspa.es/content/differential-lipid-partitioning-between-adipocytes-and-tissue-macrophages-modulates03520nas a2200493 4500008004100000022001400041245012700055210006900182260001600251300000700267490000600274520197600280653001202256653002302268653001802291653001602309653002002325653001102345653003102356653002902387653002302416653002802439653000902467653001202476653002402488653002002512653001502532653002402547653002702571653003602598100001802634700003002652700002302682700002902705700002102734700002002755700001902775700001602794700001602810700002002826700002402846700002302870856013302893 2011 eng d a1755-879400aEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.0 aEarly peroxisome proliferatoractivated receptor gamma regulated  c2011 Dec 30 a860 v43 a

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansion

RESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.

CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

10aAnimals10aCell Proliferation10aCell Survival10aCholesterol10aDown-Regulation10aFemale10aGene Expression Regulation10aGene Knockout Techniques10aInsulin Resistance10aInsulin-Secreting Cells10aMice10aobesity10aOxidation-Reduction10aPhosphorylation10aPPAR gamma10aSignal Transduction10aTranscription, Genetic10aTransforming Growth Factor beta1 aVivas, Yurena1 aMartinez-Garcia, Cristina1 aIzquierdo, Adriana1 aGarcia-Garcia, Francisco1 aCallejas, Sergio1 aVelasco, Ismael1 aCampbell, Mark1 aRos, Manuel1 aDopazo, Ana1 aDopazo, Joaquin1 aVidal-Puig, Antonio1 aMedina-Gomez, Gema uhttps://www.clinbioinfosspa.es/content/early-peroxisome-proliferator-activated-receptor-gamma-regulated-genes-involved-expansion