Yewei Ji

Mechanisms of Inflammatory Responses in Obese Adipose Tissue

The fields of immunology and metabolism are rapidly converging on adipose tissue. During obesity, many immune cells infiltrate or populate in adipose tissue and promote a low-grade chronic inflammation. Studies to date have suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to obesity-associated complications such as insulin resistance and type 2 diabetes. Despite these advances, however, many open questions remain including how inflammatory responses are initiated and maintained, how nutrients impact the function of various immune populations, and how inflammatory responses affect systemic insulin sensitivity. Here we review recent studies on the roles of various immune cells at different phases of obesity and discuss molecular mechanisms underlying obesity-associated inflammation. Better understanding of the events occurring in adipose tissue will provide insights into the pathophysiological role of inflammation in obesity and shed light on the pathogenesis of obesity-associated metabolic syndrome.

Activation of Natural Killer T Cells Promotes M2 Macrophage Polarization in Adipose Tissue and Improves Systemic Glucose Tolerance via Interleukin-4 (IL-4)/STAT6 Protein Signaling Axis in Obesity

Background: Obesity is associated with a state of chronic low grade inflammation. Results: Activation of natural killer T (NKT) cells attenuates inflammation in adipose tissue and improves systemic glucose homeostasis in mice at different stages of obesity. Conclusion: Upon activation, NKT cells have significant impact on inflammatory responses and systemic glucose tolerance in obesity. Significance: NKT-activating glycolipids may be useful in treating obesity-associated complications. Natural killer T (NKT) cells are important therapeutic targets in various disease models and are under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type 1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance. Although loss-of-function of NKT cells had no effect on glucose tolerance in animals with prolonged high fat diet feeding, activation of NKT cells by lipid agonist α-galactosylceramide enhances alternative macrophage polarization in adipose tissue and improves glucose homeostasis in animals at different stages of obesity. Furthermore, the effect of NKT cells is largely mediated by the IL-4/STAT6 signaling axis in obese adipose tissue. Thus, our data identify a novel therapeutic target for the treatment of obesity-associated inflammation and type 2 diabetes.

Short Term High Fat Diet Challenge Promotes Alternative Macrophage Polarization in Adipose Tissue via Natural Killer T Cells and Interleukin-4

Background: Our understanding of immune responses at early stages of obesity is very limited. Results: Acute HFD feeding promotes alternative macrophage polarization in adipose tissue via NKT cells and IL-4. Conclusion: NKT cells in adipose tissue play important role in linking acute HFD feeding with adipose inflammation. Significance: Acute HFD feeding is unexpectedly associated with pronounced and dynamic immune responses in adipose tissue. Inflammation in adipose tissue plays an important role in the pathogenesis of obesity-associated complications. However, the detailed cellular events underlying the inflammatory changes at the onset of obesity have not been characterized. Here we show that an acute HFD challenge is unexpectedly associated with elevated alternative (M2) macrophage polarization in adipose tissue mediated by Natural Killer T (NKT) cells. Upon 4d HFD feeding, NKT cells are activated, promote M2 macrophage polarization and induce arginase 1 expression via interleukin (IL)-4 in adipose tissue, not in the liver. In NKT-deficient CD1d−/− mice, M2 macrophage polarization in adipose tissue is reduced while systemic glucose homeostasis and insulin tolerance are impaired upon 4d HFD challenge. Thus, our study demonstrate, for the first time to our knowledge, that acute HFD feeding is associated with remarkably pronounced and dynamic immune responses in adipose tissue, and adipose-resident NKT cells may link acute HFD feeding with inflammation.

Gr-1+ CD11b+ Myeloid-derived Suppressor Cells Suppress Inflammation and Promote Insulin Sensitivity in Obesity

Activation of immune cells, including macrophages and CD8+ T cells, contributes significantly to the advancement of obesity and its associated medical complications, such as atherosclerosis, insulin resistance, and type 2 diabetes. However, how the activation of these immune cells is regulated in vivo remains largely unexplored. Here we show that a group of immature myeloid cells with cell surface markers of Gr-1+ CD11b+ are highly enriched in peripheral tissues (i.e. liver and adipose tissues) during obesity. Down-regulation of these cells in obese animals significantly increases inflammation and impairs insulin sensitivity and glucose tolerance, whereas elevation of these cells via adoptive transfer has the opposite effects. Mechanistically, we show that under obese conditions, the Gr-1+ cells suppress proliferation and induce apoptosis of CD8+ T cells and are capable of skewing differentiation of macrophages into insulin-sensitizing, alternatively activated M2 macrophages. Taken together, our study demonstrates that immature myeloid cells provide a checks-and-balances platform to counter proinflammatory immune cells in the liver and adipose tissue during obesity to prevent overt immune responses.

Direct control of hepatic glucose production by interleukin-13 in mice

Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Significance This study provides insights into the physiological role of Sel1L, an adaptor protein for the ubiquitin ligase Hrd1 in endoplasmic reticulum-associated degradation (ERAD). Using both animal and cell models, this study provides unequivocal evidence for an indispensable role of Sel1L in Hrd1 stabilization, mammalian ERAD, endoplasmic reticulum homeostasis, protein translation, and cellular and organismal survival. Moreover, generation of inducible knockout mouse and cell models deficient in both Sel1L and Hrd1 provides an unprecedented opportunity to elucidate the functional importance of this key branch of ERAD in vivo and to identify its physiological substrates. Suppressor/Enhancer of Lin-12-like (Sel1L) is an adaptor protein for the E3 ligase hydroxymethylglutaryl reductase degradation protein 1 (Hrd1) involved in endoplasmic reticulum-associated degradation (ERAD). Sel1L’s physiological importance in mammalian ERAD, however, remains to be established. Here, using the inducible Sel1L knockout mouse and cell models, we show that Sel1L is indispensable for Hrd1 stability, ER homeostasis, and survival. Acute loss of Sel1L leads to premature death in adult mice within 3 wk with profound pancreatic atrophy. Contrary to current belief, our data show that mammalian Sel1L is required for Hrd1 stability and ERAD function both in vitro and in vivo. Sel1L deficiency disturbs ER homeostasis, activates ER stress, attenuates translation, and promotes cell death. Serendipitously, using a biochemical approach coupled with mass spectrometry, we found that Sel1L deficiency causes the aggregation of both small and large ribosomal subunits. Thus, Sel1L is an indispensable component of the mammalian Hrd1 ERAD complex and ER homeostasis, which is essential for protein translation, pancreatic function, and cellular and organismal survival.

The ATP-P2X7 Signaling Axis Is Dispensable for Obesity-Associated Inflammasome Activation in Adipose Tissue

Inflammasome activation in adipose tissue has been implicated in obesity-associated insulin resistance and type 2 diabetes. However, when and how inflammasome is activated in adipose tissue remains speculative. Here we test the hypothesis that extracellular ATP, a potent stimulus of inflammasome in macrophages via purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7), may play a role in inflammasome activation in adipose tissue in obesity. Our data show that inflammasome is activated in adipose tissue upon 8-week feeding of 60% high-fat diet (HFD), coinciding with the onset of hyperglycemia and hyperinsulinemia as well as the induction of P2X7 in adipose tissue. Unexpectedly, P2X7-deficient animals on HFD exhibit no changes in metabolic phenotypes, inflammatory responses, or inflammasome activation when compared with the wild-type controls. Similar observations have been obtained in hematopoietic cell–specific P2X7-deficient animals generated by bone marrow transplantation. Thus, we conclude that inflammasome activation in adipose tissue in obesity coincides with the onset of hyperglycemia and hyperinsulinemia but, unexpectedly, is not mediated by the ATP-P2X7 signaling axis. The nature of the inflammasome-activating danger signal(s) in adipose tissue in obesity remains to be characterized.

Nonmuscle Myosin IIB Links Cytoskeleton to IRE1α Signaling during ER Stress

Here we identify and characterize a cytoskeletal myosin protein required for IRE1α oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1α. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1α aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1α signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1α activation and signaling require concerted coordination between the ER and cytoskeleton.

Diet-Induced Alterations in Gut Microflora Contribute to Lethal Pulmonary Damage in TLR2/TLR4-Deficient Mice

Chronic intake of Western diet has driven an epidemic of obesity and metabolic syndrome, but how it induces mortality remains unclear. Here, we show that chronic intake of a high-fat diet (HFD), not a low-fat diet, leads to severe pulmonary damage and mortality in mice deficient in Toll-like receptors 2 and 4 (DKO). Diet-induced pulmonary lesions are blocked by antibiotic treatment and are transmissible to wild-type mice upon either cohousing or fecal transplantation, pointing to the existence of bacterial pathogens. Indeed, diet and innate deficiency exert significant impact on gut microbiota composition. Thus, chronic intake of HFD promotes severe pulmonary damage and mortality in DKO mice in part via gut dysbiosis, a finding that may be important for immunodeficient patients, particularly those on chemotherapy or radiotherapy, where gut-microbiota-caused conditions are often life threatening.

Epithelial Sel1L is required for the maintenance of intestinal homeostasis

Endoplasmic reticulum (ER)–associated degradation (ERAD) clears misfolded proteins in the ER. Epithelial ERAD plays an indispensable role in Paneth cell biology and the maintenance of small intestine homeostasis. The findings implicate Sel1L-Hrd1 ERAD as a novel therapeutic target for Crohn’s disease.