Lianne van Beek

Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice.

Chronic low‐grade inflammation associated with obesity contributes to insulin resistance and type 2 diabetes. Helminth parasites are the strongest natural inducers of type 2 immune responses, and short‐lived infection with rodent nematodes was reported to improve glucose tolerance in obese mice. Here, we investigated the effects of chronic infection (12 weeks) with Schistosoma mansoni, a helminth that infects millions of humans worldwide, on whole‐body metabolic homeostasis and white adipose tissue (WAT) immune cell composition in high‐fat diet‐induced obese C57BL/6 male mice. Our data indicate that chronic helminth infection reduced body weight gain (‐62%), fat mass gain (‐89%), and adipocyte size; lowered whole‐body insulin resistance (‐23%) and glucose intolerance (‐16%); and improved peripheral glucose uptake (+25%) and WAT insulin sensitivity. Analysis of immune cell composition by flow cytometry and quantitative PCR (qPCR) revealed that S. mansoni promoted strong increases in WAT eosinophils and alternatively activated (M2) macrophages. Importantly, injections with S. mansonir‐soluble egg antigens (SEA) recapitulated the beneficial effect of parasite infection on whole‐body metabolic homeostasis and induced type 2 immune responses in WAT and liver. Taken together, we provide novel data suggesting that chronic helminth infection and helminth‐derived molecules protect against metabolic disorders by promoting a T helper 2 (Th2) response, eosinophilia, and WAT M2 polarization.—Hussaarts, L., García‐Tardón, N., van Beek, L., Heemskerk, M. M., Haeberlein, S., van der Zon, G. C., Ozir‐Fazalalikhan, A., Berbée, J. F. P., Willems van Dijk, K., van Harmelen, V., Yazdanbakhsh, M., Guigas, B. Chronic helminth infection and helminth‐derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice. FASEB J. 29, 3027‐3039 (2015). www.fasebj.org

Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance

INTRODUCTION Obesity is strongly related to type-2 diabetes (T2DM), but there is a subset of obese individuals that remains relatively insulin sensitive and metabolically healthy. This study determined to what extent differences in metabolic health in obese women are associated with differences in adipose tissue and/or systemic inflammation. METHODS The subject group consisted of age comparable lean (n=12) and obese women either with T2DM (n=28) or normal glucose tolerance (NGT; n=26). Number of crown like structures (CLS) and adipocyte size were measured in subcutaneous and visceral adipose tissue of the obese women. Circulating cytokine and free fatty acid (FFA) levels, as well as number and activation status of peripheral leukocytes were determined. RESULTS Obese T2DM subjects showed higher circulating levels of IL-6, FFA and glycerol as compared to obese NGT subjects. Obese T2DM subjects had higher absolute numbers of peripheral leukocytes which were mainly due to an increase of T helper cells. Activation status of circulating cytotoxic T (CD8+CD25+) and B (CD19+CD38+) cells was significantly increased in obese NGT subjects as compared to lean but was not different between the two obese groups. Subcutaneous adipose tissue of obese T2DM subjects contained more CLS than adipose tissue of obese NGT subjects. CONCLUSION Obese T2DM subjects show higher FFA levels and adipose tissue macrophage infiltration in addition to higher levels of circulating IL-6 and numbers of CD4+ T cells than obese NGT subjects. Hence, obese T2DM subjects show a higher extent of inflammation at both the systemic and adipose tissue level.

Identification of a selective glucocorticoid receptor modulator that prevents both diet‐induced obesity and inflammation

High‐fat diet consumption results in obesity and chronic low‐grade inflammation in adipose tissue. Whereas glucocorticoid receptor (GR) antagonism reduces diet‐induced obesity, GR agonism reduces inflammation, the combination of which would be desired in a strategy to combat the metabolic syndrome. The purpose of this study was to assess the beneficial effects of the selective GR modulator C108297 on both diet‐induced weight gain and inflammation in mice and to elucidate underlying mechanisms.

Mannose-Binding Lectin is required for the effective clearance of apoptotic cells by adipose tissue macrophages during obesity

Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL−/− mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL−/− mice. In parallel with increased adipocyte size, MBL−/− mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity.

Splenic autonomic denervation increases inflammatory status but does not aggravate atherosclerotic lesion development.

UNLABELLED The brain plays a prominent role in the regulation of inflammation. Immune cells are under control of the so-called cholinergic anti-inflammatory reflex, mainly acting via autonomic innervation of the spleen. Activation of this reflex inhibits the secretion of proinflammatory cytokines and may reduce the development of atherosclerosis. Therefore, the aim of this study was to evaluate the effects of selective parasympathetic (Px) and sympathetic (Sx) denervation of the spleen on inflammatory status and atherosclerotic lesion development. Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipid metabolism and atherosclerosis, were fed a cholesterol-containing Western-type diet for 4 wk after which they were subdivided into three groups receiving either splenic Px, splenic Sx, or sham surgery. The mice were subsequently challenged with the same diet for an additional 15 wk. Selective Px increased leukocyte counts (i.e., dendritic cells, B cells, and T cells) in the spleen and increased gene expression of proinflammatory cytokines in the liver and peritoneal leukocytes compared with Sx and sham surgery. Both Px and Sx increased circulating proinflammatory cytokines IL-1β and IL-6. However, the increased proinflammatory status in denervated mice did not affect atherosclerotic lesion size or lesion composition. CONCLUSION Predominantly selective Px of the spleen enhances the inflammatory status, which, however, does not aggravate diet-induced atherosclerotic lesion development.

FcRγ-chain deficiency reduces the development of diet-induced obesity

Pathogenic immunoglobulins are produced during the development of obesity and contribute to the development of insulin resistance (IR). However, the mechanisms by which these antibodies affect IR are largely unknown. This study investigated whether Fc‐receptors contribute to the development of diet‐induced obesity and IR by studying FcRγ−/− mice that lack the γ‐subunit necessary for signaling and cell surface expression of FcγR and FcεRI.

A Restricted Role for FcγR in the Regulation of Adaptive Immunity

By their interaction with IgG immune complexes, FcγR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcγR-knockout mice, it has been concluded that FcγRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcγRs (FcγRI/II/III/IV−/− mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcγRIIb-deficient mice, FcγRI/II/III/IV−/− mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcγRs in the modulation of the adaptive immune response in vivo. We conclude that FcγRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.

PS13 - 3. Fcγ- and ε-receptors do not play a role in the initial development of insulin resistance

It has previously been shown that during the development of obesity pathogenic immunoglobulins (Ig) are released by B-lymphocytes, which contribute to the development of insulin resistance. However, the effector pathways mediated by the antibodies are still unknown. Ig bind to specific Fc-receptors to induce immune responses.

PS13 - 1. APOA5 plays a role in high-fat diet induced inflammation

APOA5 genotype is a strong predictor of triglyceride (TG) levels and plasma APOA5 is inversely correlated to plasma TG. APOA5 is also thought to act as a positive Acute Phase Response (ARP) protein, suppressing inflammation. The role of APOA5 in obesity induced adipose tissue inflammation was examined.

PS19 - 88. Mast cell deficient mice on a high fat diet have altered immune cell infiltration in their adipose tissue

Obesity is associated with adipose tissue (AT) inflammation and dysfunction. It has previously been shown that mast cells play a role in the development of obesity and type 2 diabetes. Mast cell numbers are significantly elevated in white adipose tissue (WAT) in obesity.