A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity.

In obesity, inflammation of white adipose tissue (AT) is associated with diminished generation of beige adipocytes ('beige adipogenesis'), a thermogenic and energy-dissipating function mediated by beige adipocytes that express the uncoupling protein UCP1. Here we delineated an inflammation-driven inhibitory mechanism of beige adipogenesis in obesity that required direct adhesive interactions between macrophages and adipocytes mediated by the integrin α4 and its counter-receptor VCAM-1, respectively; expression of the latter was upregulated in obesity. This adhesive interaction reciprocally and concomitantly modulated inflammatory activation of macrophages and downregulation of UCP1 expression dependent on the kinase Erk in adipocytes. Genetic or pharmacological inactivation of the integrin α4 in mice resulted in elevated expression of UCP1 and beige adipogenesis of subcutaneous AT in obesity. Our findings, established in both mouse systems and human systems, reveal a self-sustained cycle of inflammation-driven impairment of beige adipogenesis in obesity.

Robo4-mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes.

In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.

Endothelial-Specific Deficiency of ATG5 (Autophagy Protein 5) Attenuates Ischemia-Related Angiogenesis.

Objective- Pathological angiogenesis, such as exuberant retinal neovascularization during proliferative retinopathies, involves endothelial responses to ischemia/hypoxia and oxidative stress. Autophagy is a clearance system enabling bulk degradation of intracellular components and is implicated in cellular adaptation to stressful conditions. Here, we addressed the role of the ATG5 (autophagy-related protein 5) in endothelial cells in the context of pathological ischemia-related neovascularization in the murine model of retinopathy of prematurity. Approach and Results- Autophagic vesicles accumulated in neovascular tufts of the retina of retinopathy of prematurity mice. Endothelium-specific Atg5 deletion reduced pathological neovascularization in the retinopathy of prematurity model. In contrast, no alterations in physiological retina vascularization were observed in endothelial-specific ATG5 deficiency, suggesting a specific role of endothelial ATG5 in pathological hypoxia/reoxygenation-related angiogenesis. Consistently, in an aortic ring angiogenesis assay, endothelial ATG5 deficiency resulted in impaired angiogenesis under hypoxia/reoxygenation conditions. As compared to ATG5-sufficient endothelial cells, ATG5-deficient cells displayed impaired mitochondrial respiratory activity, diminished production of mitochondrial reactive oxygen species and decreased phosphorylation of the VEGFR2 (vascular endothelial growth factor receptor 2). Consistently, ATG5-deficient endothelial cells displayed decreased oxidative inactivation of PTPs (phospho-tyrosine phosphatases), likely due to the reduced reactive oxygen species levels resulting from ATG5 deficiency. Conclusions- Our data suggest that endothelial ATG5 supports mitochondrial function and proangiogenic signaling in endothelial cells in the context of pathological hypoxia/reoxygenation-related neovascularization. Endothelial ATG5, therefore, represents a potential target for the treatment of pathological neovascularization-associated diseases, such as retinopathies.

The role of the complement system in metabolic organs and metabolic diseases.

Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi-functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders.

Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation.

UNLABELLED: The low-grade inflammatory state present in obesity contributes to obesity-related metabolic dysregulation, including nonalcoholic steatohepatitis (NASH) and insulin resistance. Intercellular interactions between immune cells or between immune cells and hepatic parenchymal cells contribute to the exacerbation of liver inflammation and steatosis in obesity. The costimulatory molecules, B7.1 and B7.2, are important regulators of cell-cell interactions in several immune processes; however, the role of B7 costimulation in obesity-related liver inflammation is unknown. Here, diet-induced obesity (DIO) studies in mice with genetic inactivation of both B7.1 and B7.2 (double knockout; DKO) revealed aggravated obesity-related metabolic dysregulation, reduced insulin signalling in the liver and adipose tissue (AT), glucose intolerance, and enhanced progression to steatohepatitis resulting from B7.1/B7.2 double deficiency. The metabolic phenotype of B7.1/B7.2 double deficiency upon DIO was accompanied by increased hepatic and AT inflammation, associated with largely reduced numbers of regulatory T cells (Tregs) in these organs. In order to assess the role of B7 costimulation in DIO in a non-Treg-lacking environment, we performed antibody (Ab)-mediated inhibition of B7 molecules in wild-type mice in DIO. Antibody-blockade of both B7.1 and B7.2 improved the metabolic phenotype of DIO mice, which was linked to amelioration of hepatic steatosis and reduced inflammation in liver and AT. CONCLUSION: Our study demonstrates a dual role of B7 costimulation in the course of obesity-related sequelae, particularly NASH. The genetic inactivation of B7.1/B7.2 deteriorates obesity-related liver steatosis and metabolic dysregulation, likely a result of the intrinsic absence of Tregs in these mice, rendering DKO mice a novel murine model of NASH. In contrast, inhibition of B7 costimulation under conditions where Tregs are present may provide a novel therapeutic approach for obesity-related metabolic dysregulation and, especially, NASH.

The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance.

Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures. C5aR-sufficient and -deficient mice were fed a high-fat diet (HFD) or a normal diet (ND). C5aR deficiency was associated with increased AT weight upon ND feeding in males, but not in females, and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR(-/-) mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR(-/-) mice was associated with reduced accumulation of total and proinflammatory M1 macrophages in the obese AT, increased expression of IL-10, and decreased AT fibrosis. In contrast, no difference in ß cell mass was observed owing to C5aR deficiency under an HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.

Adipocyte-Specific Hypoxia-Inducible Factor 2α Deficiency Exacerbates Obesity-Induced Brown Adipose Tissue Dysfunction and Metabolic Dysregulation.

Angiogenesis is a central regulator for white (WAT) and brown (BAT) adipose tissue adaptation in the course of obesity. Here we show that deletion of hypoxia-inducible factor 2α (HIF2α) in adipocytes (by using Fabp4-Cre transgenic mice) but not in myeloid or endothelial cells negatively impacted WAT angiogenesis and promoted WAT inflammation, WAT dysfunction, hepatosteatosis, and systemic insulin resistance in obesity. Importantly, adipocyte HIF2α regulated vascular endothelial growth factor (VEGF) expression and angiogenesis of obese BAT as well as its thermogenic function. Consistently, obese adipocyte-specific HIF2α-deficient mice displayed BAT dysregulation, associated with reduced levels of uncoupling protein 1 (UCP1) and a dysfunctional thermogenic response to cold exposure. VEGF administration reversed WAT and BAT inflammation and BAT dysfunction in adipocyte HIF2α-deficient mice. Together, our findings show that adipocyte HIF2α is protective against maladaptation to obesity and metabolic dysregulation by promoting angiogenesis in both WAT and BAT and by counteracting obesity-mediated BAT dysfunction.