Stuart P. Weisberg

Obesity is associated with macrophage accumulation in adipose tissue

Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

CCR2 modulates inflammatory and metabolic effects of high-fat feeding

The C-C motif chemokine receptor-2 (CCR2) regulates monocyte and macrophage recruitment and is necessary for macrophage-dependent inflammatory responses and the development of atherosclerosis. Although adipose tissue expression and circulating concentrations of CCL2 (also known as MCP1), a high-affinity ligand for CCR2, are elevated in obesity, the role of CCR2 in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity, has not been studied. To determine what role CCR2 plays in the development of metabolic phenotypes, we studied the effects of Ccr2 genotype on the development of obesity and its associated phenotypes. Genetic deficiency in Ccr2 reduced food intake and attenuated the development of obesity in mice fed a high-fat diet. In obese mice matched for adiposity, Ccr2 deficiency reduced macrophage content and the inflammatory profile of adipose tissue, increased adiponectin expression, ameliorated hepatic steatosis, and improved systemic glucose homeostasis and insulin sensitivity. In mice with established obesity, short-term treatment with a pharmacological antagonist of CCR2 lowered macrophage content of adipose tissue and improved insulin sensitivity without significantly altering body mass or improving hepatic steatosis. These data suggest that CCR2 influences the development of obesity and associated adipose tissue inflammation and systemic insulin resistance and plays a role in the maintenance of adipose tissue macrophages and insulin resistance once obesity and its metabolic consequences are established.

Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites

Monocyte recruitment to sites of inflammation is regulated by members of the chemokine family of chemotactic cytokines. However, the mechanisms that govern the migration of monocytes from bone marrow to blood and from blood to inflamed tissues are not well understood. Here we report that CC chemokine receptor 2 (CCR2) is highly expressed on a subpopulation of blood monocytes whose numbers are markedly decreased in CCR2(-/-) mice. In bone marrow, however, CCR2(-/-) mice had an increased number of monocytes, suggesting that CCR2 is critical for monocyte egress. Intravenous infusion of ex vivo-labeled WT or CCR2(-/-) bone marrow into WT recipient mice demonstrated that CCR2 is necessary for efficient monocyte recruitment from the blood to inflamed tissue. Analysis of mice lacking monocyte chemoattractant protein-1 (MCP-1), MCP-3, MCP-5, or MCP-2 plus MCP-5 revealed that MCP-3 and MCP-1 are the CCR2 agonists most critical for the maintenance of normal blood monocyte counts. These findings provide evidence that CCR2 and MCP-3/MCP-1 are critical for monocyte mobilization and suggest new roles for monocyte chemoattractants in leukocyte homeostasis.

Dietary Curcumin Significantly Improves Obesity-Associated Inflammation and Diabetes in Mouse Models of Diabesity

Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. We tested the hypothesis that the plant polyphenolic compound curcumin, which is known to exert potent antiinflammatory and antioxidant effects, would ameliorate diabetes and inflammation in murine models of insulin-resistant obesity. We found that dietary curcumin admixture ameliorated diabetes in high-fat diet-induced obese and leptin-deficient ob/ob male C57BL/6J mice as determined by glucose and insulin tolerance testing and hemoglobin A1c percentages. Curcumin treatment also significantly reduced macrophage infiltration of white adipose tissue, increased adipose tissue adiponectin production, and decreased hepatic nuclear factor-kappaB activity, hepatomegaly, and markers of hepatic inflammation. We therefore conclude that orally ingested curcumin reverses many of the inflammatory and metabolic derangements associated with obesity and improves glycemic control in mouse models of type 2 diabetes. This or related compounds warrant further investigation as novel adjunctive therapies for type 2 diabetes in man.

Reduced Adiposity in ob/ob Mice following Total Body Irradiation and Bone Marrow Transplantation

Objective: The objective of this study was to assess long‐term metabolic consequences of total body irradiation (TBI) and bone marrow transplantation. Severe obesity develops due to both hypertrophy and hyperplasia of adipocytes. We hypothesized that TBI would arrest adipose tissue growth and would affect insulin resistance (IR).

An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse: Parsing the Supporting Genetic Data

Progenitors of the nonobese diabetic mouse strain (NOD/Shi) arose spontaneously in a colony at the Shionogi Research Laboratories in Aburahi, Japan in the 1970s. The strain has been used extensively in efforts to elucidate the pathogenesis of type 1 diabetes in humans. Both the mouse model and the human disease are characterized by the appearance of autoreactive T-cells targeting pancreatic islet antigens, the elaboration of anti-insulin autoantibodies, and the development of a β-cell–toxic inflammatory cellular infiltrate within the islets leading to insulin depletion and hyperglycemia. In both NOD mice and human type 1 diabetes, the breakdown of self-tolerance to β-cells is under polygenic control of major histocompatibility complex (MHC) class II alleles as well as non-MHC loci. An important difference between the mouse model and the human disease is that in NOD mice but not human type 1 diabetes, female subjects have a higher incidence of diabetes (75–100% by 30 weeks) than males (30–60%) (1). Because the development of diabetes in NOD mice depends on interacting genetic and environmental factors comparable with those interacting in human type 1 diabetes, genes that modify the NOD phenotype deserve close attention. The article by McDuffie et al. (2 in this issue identifies such a candidate molecule.nnPrevious studies elucidating the critical steps in the development of autoimmune β-cell destruction in NOD mice have suggested several points of pathogenic relevance. β-Cell destruction in NOD mice is dependent on the production and unrestrained activation of autoreactive T-cells. Antibody-mediated elimination of T-cells and interventions that promote T-cell tolerance, such as the production of regulatory T-cells, effectively inhibit development of diabetes in …

PAS-C platelets contain less plasma protein, lower anti-A and anti-B titers, and decreased HLA antibody specificities compared to plasma platelets: TRALI MITIGATION STRATEGIES

Platelets (PLTs) collected and stored in PLT additive solution Intersol (PAS‐C) are presumed to reduce recipient exposure to donor plasma components; however, the effects of PAS‐C on PLT supernatant composition are poorly defined. Therefore, we compared the total protein concentration, isohemagglutinin titers, and HLA antibodies in supernatants of PAS‐C PLTs to plasma PLTs.