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      Obesity-Related Upregulation of Monocyte Chemotactic Factors in Adipocytes : Involvement of Nuclear Factor-κB and c-Jun NH 2-Terminal Kinase Pathways

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          Abstract

          OBJECTIVE—We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity.

          RESEARCH DESIGN AND METHODS—Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated.

          RESULTS—Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of κB kinase-β (IKKβ) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3.

          CONCLUSIONS—Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKβ and JNK pathways.

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          Most cited references45

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          Rapid planetesimal formation in turbulent circumstellar discs

          The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.
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            The Dicke Quantum Phase Transition with a Superfluid Gas in an Optical Cavity

            A phase transition describes the sudden change of state in a physical system, such as the transition between a fluid and a solid. Quantum gases provide the opportunity to establish a direct link between experiment and generic models which capture the underlying physics. A fundamental concept to describe the collective matter-light interaction is the Dicke model which has been predicted to show an intriguing quantum phase transition. Here we realize the Dicke quantum phase transition in an open system formed by a Bose-Einstein condensate coupled to an optical cavity, and observe the emergence of a self-organized supersolid phase. The phase transition is driven by infinitely long-ranged interactions between the condensed atoms. These are induced by two-photon processes involving the cavity mode and a pump field. We show that the phase transition is described by the Dicke Hamiltonian, including counter-rotating coupling terms, and that the supersolid phase is associated with a spontaneously broken spatial symmetry. The boundary of the phase transition is mapped out in quantitative agreement with the Dicke model. The work opens the field of quantum gases with long-ranged interactions, and provides access to novel quantum phases.
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              MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.

              Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.
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                Author and article information

                Journal
                Diabetes
                diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                January 2009
                : 58
                : 1
                : 104-115
                Affiliations
                [1 ]Hallett Center for Diabetes and Endocrinology, Brown Medical School, Providence, Rhode Island
                [2 ]School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
                [3 ]Department of Endocrinology, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan, China
                [4 ]Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts
                Author notes

                Corresponding author: Haiyan Xu, hxu@ 123456lifespan.org

                Article
                581104
                10.2337/db07-1344
                2606857
                18835938
                6c0f9ac3-de39-4e60-a53f-e98bac905f71
                Copyright © 2009, American Diabetes Association

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 20 September 2007
                : 19 September 2008
                Categories
                Obesity Studies

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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