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Metabolic Endotoxemia Initiates Obesity and Insulin Resistance Patrice D. Cani 1 2 , Jacques Amar 3 , Miguel Angel Iglesias 1 , Marjorie Poggi 4 , Claude Knauf 1 , Delphine Bastelica 4 , Audrey M. Neyrinck 2 , Francesca Fava 5 , Kieran M. Tuohy 5 , Chantal Chabo 1 , Aurélie Waget 1 , Evelyne Delmée 2 , Béatrice Cousin 6 , Thierry Sulpice 7 , Bernard Chamontin 3 , Jean Ferrières 3 , Jean-François Tanti 8 , Glenn R. Gibson 5 , Louis Casteilla 6 , Nathalie M. Delzenne 2 , Marie Christine Alessi 4 and Rémy Burcelin 1 1 Institute of Molecular Medicine, I2MR Toulouse, France 2 Unité Pharmacokinetics, Metabolism, Nutrition, and Toxicology-73/69, Université catholique de Louvain, Brussels, Belgium 3 Institut National de la Santé et de la Recherche Médicale (INSERM) 558, Toulouse, France 4 INSERM U 626, Marseille, France 5 Food Microbial Sciences Unit, Department of Food Biosciences, University of Reading, Reading, U.K 6 Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France 7 Physiogenex S.A.S., Labège Innopole, France 8 INSERM U 568, Nice, France Address correspondence and reprint requests to Rémy Burcelin, I2MR U858, IFR 31, Hôpital Rangueil, BP 84225, Toulouse 31432 Cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr Abstract Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases. IKK, inhibitor of κB kinase IL, interleukin LPS, lipopolysaccharide PAI, plasminogen activator inhibitor TLR4, toll-like receptor 4 TNF, tumor necrosis factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db06-1491. P.D.C., J.A., and M.A.I. contributed equally to this article. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 13, 2007. Received October 24, 2006. DIABETES

Within adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties. Stroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate. This innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow-derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of AT resident macrophages. Our study describes a 3D system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in diverse physiological and pathological contexts.

Opioids are regarded as among the most effective analgesic drugs and their use for the management of pain is considered standard of care. Despite their systematic administration in the peri-operative period, their impact on tissue repair has been studied mainly in the context of scar healing and is only beginning to be documented in the context of true tissue regeneration. Indeed, in mammals, growing evidence shows that opioids direct tissue repair towards scar healing, with a loss of tissue function, instead of the regenerative process that allows for recovery of both the morphology and function of tissue. Here, we review recent studies that highlight how opioids may prevent a regenerative process by silencing nociceptive nerve activity and a powerful anti-inflammatory effect. These data open up new perspectives for inducing tissue regeneration and argue for opioid-restricted strategies for managing pain associated with tissue injury.

Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.

Normal tissue homeostasis is maintained by dynamic interactions between epithelial cells and their microenvironment. Disrupting this homeostasis can induce aberrant cell proliferation, adhesion, function and migration that might promote malignant behavior. Indeed, aberrant stromal-epithelial interactions contribute to pancreatic ductal adenocarcinoma (PDAC) spread and metastasis, and this raises the possibility that novel stroma-targeted therapies represent additional approaches for combating this malignant disease. The aim of the present study was to determine the effect of human stromal cells derived from adipose tissue (ADSC) on pancreatic tumor cell proliferation. Co-culturing pancreatic tumor cells with ADSC and ADSC-conditioned medium sampled from different donors inhibited cancer cell viability and proliferation. ADSC-mediated inhibitory effect was further extended to other epithelial cancer-derived cell lines (liver, colon, prostate). ADSC conditioned medium induced cancer cell necrosis following G1-phase arrest, without evidence of apoptosis. In vivo, a single intra-tumoral injection of ADSC in a model of pancreatic adenocarcinoma induced a strong and long-lasting inhibition of tumor growth. These data indicate that ADSC strongly inhibit PDAC proliferation, both in vitro and in vivo and induce tumor cell death by altering cell cycle progression. Therefore, ADSC may constitute a potential cell-based therapeutic alternative for the treatment of PDAC for which no effective cure is available.

Medullary and extra-medullary hematopoiesis has been shown to govern inflammatory cell infiltration and subsequently cardiac remodeling and function after acute myocardial infarction (MI). Emerging evidence positions adipose tissue (AT) as an alternative source of immune cell production. We, therefore, hypothesized that AT could act as a reservoir of inflammatory cells that participate in cardiac homeostasis after MI. To reveal the distinct role of inflammatory cells derived from AT or bone marrow (BM), chimeric mice were generated using standard repopulation assays. We showed that AMI increased the number of AT-derived macrophages in the cardiac tissue. These macrophages exhibit pro-inflammatory characteristics and their specific depletion improved cardiac function as well as decreased infarct size and interstitial fibrosis. We then reasoned that the alteration of AT-immune compartment in type 2 diabetes could, thus, contribute to defects in cardiac remodeling. However, in these conditions, myeloid cells recruited in the infarcted heart mainly originate from the BM, and AT was no longer used as a myeloid cell reservoir. Altogether, we showed here that a subpopulation of cardiac inflammatory macrophages emerges from myeloid cells of AT origin and plays a detrimental role in cardiac remodeling and function after MI. Diabetes abrogates the ability of AT-derived myeloid cells to populate the infarcted heart.

Inhibition of regeneration and induction of tissue fibrosis are classic outcomes of tissue repair in adult mammals. Here, using a newly developed model of regeneration in adult mammals i.e. regeneration after massive resection of an inguinal fat pad, we demonstrate that both endogenous and exogenous opioids prevent tissue regeneration in adults, by inhibiting the early production of reactive oxygen species (ROS) that generally occurs after lesion and is required for regeneration. These effects can be overcome and regeneration induced by the use of an opioid antagonist. The results obtained in both our new model and the gold standard adult zebrafish demonstrate that this mechanism can be considered as a general paradigm in vertebrates. This work clearly demonstrates that ROS is required for tissue regeneration in adult mammals and shows the deleterious effect of opioids on tissue regeneration through the control of this ROS production. It thus raises questions about opioid-based analgesia in perioperative care.

Introduction: Within adipose tissue (AT), different macrophage subsets have been described that played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties. Methods: Stroma-vascular cells isolated from murine subcutaneous adipose tissue were seeded on ultra-low adherent plates in the presence of M-CSF. After four days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate. Results: This innovative 3-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow-derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single cell analysis, AT macrophages generated in 3D culture mirror the phenotypic and functional traits of in vivo AT resident macrophages. Discussion: Our study describes a 3D in vitro system for generating and culturing functional AT resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

Activation and increased numbers of inflammatory macrophages, in adipose tissue (AT) are deleterious in metabolic diseases. Up to now, AT macrophages (ATM) accumulation was considered to be due to blood infiltration or local proliferation, although the presence of resident hematopoietic stem/progenitor cells (Lin-/Sca+/c-Kit+; LSK phenotype) in the AT (AT-LSK) has been reported. By using transplantation of sorted AT-LSK and gain and loss of function studies we show that some of the inflammatory ATM inducing metabolic disease, originate from resident AT-LSK. Transplantation of AT-LSK sorted from high fat diet-fed (HFD) mice is sufficient to induce ATM accumulation, and to transfer metabolic disease in control mice. Conversely, the transplantation of control AT-LSK improves both AT-inflammation and glucose homeostasis in HFD mice. Our results clearly demonstrate that resident AT-LSK are one of the key point of metabolic disease, and could thus constitute a new promising therapeutic target to fight against metabolic disease.

Calibrating biological models is challenging due to high-dimensional parameter spaces and the limited availability of reliable experimental data. In this study, we propose a hybrid calibration framework that integrates expert knowledge into a multi-objective optimization process using NSGA-II algorithm. Our approach combines hard constraints derived from biological measurements with soft constraints encoding qualitative domain expertise, such as expected curve shapes or event timing. This dual-constraint strategy guides the search toward biologically plausible parameter sets while preserving flexibility and interpretability. We demonstrate the effectiveness of our method on a benchmark model of skin wound healing, comparing it to standard and unconstrained optimization strategies. Results show that incorporating expert guidance significantly improves the biological relevance of simulated dynamics and mitigates overfitting, especially in underdetermined or uncertain settings. The framework is flexible, iterative, and generalizable, offering a principled way to leverage domain knowledge for model calibration in complex biological systems.