Unlearned adaptive responses to heterospecific referential alarm calls in two bird species from separate evolutionary lineages.

The interspecific responses to alarm signals may be based on unlearned mechanisms but research is often constrained by the difficulties in differentiating between unlearned and learned responses in natural situations. In a field study of two Paridae species, Parus minor and Sittiparus varius, who originated from a common ancestor 8 million years ago, we found a considerable degree of between-species overlap in acoustic properties of referential snake-alarm calls. Playback of these calls triggered unlearned adaptive fledging behavior in conspecific and heterospecific naive nestlings, suggesting a between-species overlap in the hypothetical unlearned neural templates involved in nestlings' reactions to alarm calls in both species. This suggests that similar calls and similar unlearned sensitivity might have been present in the common ancestor of the two species, and possibly in the ancestor of the whole family Paridae that originated 10-15 million years ago in Asian regions rich in snakes.

Dynamics of Bacterial Communities on Eggshells and on Nest Materials During Incubation in the Oriental Tit (Parus minor).

Eggshell bacterial communities may affect hatching success and nestling's condition. Nest materials are in direct contact with the eggshells, but the relationships with the eggshell microbiome during incubation have not been fully elucidated. Here, we characterize eggshell and nest material bacterial communities and their changes during incubation in the Oriental Tit (Parus minor). Bacterial communities on the nest material were relatively stable and remained distinct from the eggshell communities and had higher diversity and greater phylogenetic clustering than the eggshell communities from the same nest, resulting in lower phylogenetic turnover rate of nest material microbiome during incubation than expected by chance. While the species diversity of both communities did not change during incubation, we found significantly greater changes in the structure of bacterial communities on the eggshell than on the nest material. However, eggshell microbiome remained distinct from nest material microbiome, suggesting independent dynamics of the two microbiomes during incubation. We detected an increase in the relative abundance of several bacterial taxa on the eggshell that likely come from the bird's skin, feathers, cloaca/intestine, or uropygial secretion which suggests some exchange of bacteria between the incubating bird and the eggshell. Furthermore, incubation appeared to promote the abundance of antibiotic producing taxa on the eggshell, which may hypothetically inhibit growth of many bacteria including pathogenic ones. Our results suggest that the future studies should focus on simultaneous monitoring of absolute abundance as well as relative abundance in communities on eggshells, nest materials, and the incubating bird's body.

Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics.

In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1+ ASCs promoted fibrotic remodeling, whereas IAT-specific CXCL14+ ASCs suppressed macrophage infiltration. Moreover, IAT-specific BST2high ASCs exhibited a high potential to become beige adipocytes. Collectively, our data broaden the understanding of ASCs with new insights into the origin of white fat depot differences.

Phenotypic Discovery of SB1501, an Anti-obesity Agent, through Modulating Mitochondrial Activity.

Obesity has become a pandemic that threatens the quality of life and discovering novel therapeutic agents that can reverse obesity and obesity-related metabolic disorders are necessary. Here, we aimed to identify new anti-obesity agents using a phenotype-based approach. We performed image-based high-content screening with a fluorogenic bioprobe (SF44), which visualizes cellular lipid droplets (LDs), to identify initial hit compounds. A structure-activity relationship study led us to yield a bioactive compound SB1501, which reduces cellular LDs in 3T3-L1 adipocytes without cytotoxicity. SB1501 induced the expression of gene products that regulate mitochondrial biogenesis and fatty acid oxidation in 3T3-L1 adipocytes. Daily treatment with SB1501 improved the metabolic states of db/db mice by reducing body fat mass, adipose tissue mass, food intake, and increasing glucose tolerance. The anti-obesity effect of SB1501 may result from perturbation of the PGC-1α-UCP1 regulatory axis in inguinal white adipose tissue and brown adipose tissue. These data suggest the therapeutic potential of SB1501 as an anti-obesity agent via modulating mitochondrial activities.

Immunopathogenesis of ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.

Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABAB receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.

SREBP1c-PAX4 Axis Mediates Pancreatic ß-Cell Compensatory Responses Upon Metabolic Stress.

SREBP1c is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic ß-cells are largely unknown. In this study, we demonstrate that SREBP1c regulates ß-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic ß-cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated ß-cell proliferation through its novel target gene, PAX4 Compared with SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, ß-cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c-overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating ß-cell compensatory responses in obesity.

Two Faces of White Adipose Tissue with Heterogeneous Adipogenic Progenitors.

Chronic energy surplus increases body fat, leading to obesity. Since obesity is closely associated with most metabolic complications, pathophysiological roles of adipose tissue in obesity have been intensively studied. White adipose tissue is largely divided into subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). These two white adipose tissues are similar in their appearance and lipid storage functions. Nonetheless, emerging evidence has suggested that SAT and VAT have different characteristics and functional roles in metabolic regulation. It is likely that there are intrinsic differences between VAT and SAT. In diet-induced obese animal models, it has been reported that adipogenic progenitors in VAT rapidly proliferate and differentiate into adipocytes. In obesity, VAT exhibits elevated inflammatory responses, which are less prevalent in SAT. On the other hand, SAT has metabolically beneficial effects. In this review, we introduce recent studies that focus on cellular and molecular components modulating adipogenesis and immune responses in SAT and VAT. Given that these two fat depots show different functions and characteristics depending on the nutritional status, it is feasible to postulate that SAT and VAT have different developmental origins with distinct adipogenic progenitors, which would be a key determining factor for the response and accommodation to metabolic input for energy homeostasis.

Hypothalamic Macrophage Inducible Nitric Oxide Synthase Mediates Obesity-Associated Hypothalamic Inflammation.

Obesity-associated metabolic alterations are closely linked to low-grade inflammation in peripheral organs, in which macrophages play a central role. Using genetic labeling of myeloid lineage cells, we show that hypothalamic macrophages normally reside in the perivascular area and circumventricular organ median eminence. Chronic consumption of a high-fat diet (HFD) induces expansion of the monocyte-derived macrophage pool in the hypothalamic arcuate nucleus (ARC), which is significantly attributed to enhanced proliferation of macrophages. Notably, inducible nitric oxide synthase (iNOS) is robustly activated in ARC macrophages of HFD-fed obese mice. Hypothalamic macrophage iNOS inhibition completely abrogates macrophage accumulation and activation, proinflammatory cytokine overproduction, reactive astrogliosis, blood-brain-barrier permeability, and lipid accumulation in the ARC of obese mice. Moreover, central iNOS inhibition improves obesity-induced alterations in systemic glucose metabolism without affecting adiposity. Our findings suggest a critical role for hypothalamic macrophage-expressed iNOS in hypothalamic inflammation and abnormal glucose metabolism in cases of overnutrition-induced obesity.

Regulatory Roles of Invariant Natural Killer T Cells in Adipose Tissue Inflammation: Defenders Against Obesity-Induced Metabolic Complications.

Adipose tissue is a metabolic organ that plays a central role in controlling systemic energy homeostasis. Compelling evidence indicates that immune system is closely linked to healthy physiologic functions and pathologic dysfunction of adipose tissue. In obesity, the accumulation of pro-inflammatory responses in adipose tissue subsequently leads to dysfunction of adipose tissue as well as whole body energy homeostasis. Simultaneously, adipose tissue also activates anti-inflammatory responses in an effort to reduce the unfavorable effects of pro-inflammation. Notably, the interplay between adipocytes and resident invariant natural killer T (iNKT) cells is a major component of defensive mechanisms of adipose tissue. iNKT cells are leukocytes that recognize lipids loaded on CD1d as antigens, whereas most other immune cells are activated by peptide antigens. In adipose tissue, adipocytes directly interact with iNKT cells by presenting lipid antigens and stimulate iNKT cell activation to alleviate pro-inflammation. In this review, we provide an overview of the molecular and cellular determinants of obesity-induced adipose tissue inflammation. Specifically, we focus on the roles of iNKT cell-adipocyte interaction in maintaining adipose tissue homeostasis as well as the consequent modulation in systemic energy metabolism. We also briefly discuss future research directions regarding the interplay between adipocytes and adipose iNKT cells in adipose tissue inflammation.

Endophilin A2: A Potential Link to Adiposity and Beyond.

Adipose tissue plays a central role in regulating dynamic crosstalk between tissues and organs. A detailed description of molecules that are differentially expressed upon changes in adipose tissue mass is expected to increase our understanding of the molecular mechanisms that underlie obesity and related metabolic co-morbidities. Our previous studies suggest a possible link between endophilins (SH3Grb2 proteins) and changes in body weight. To explore this further, we sought to assess the distribution of endophilin A2 (EA2) in human adipose tissue and experimental animals. Human paired adipose tissue samples (subcutaneous and visceral) were collected from subjects undergoing elective abdominal surgery and abdominal liposuction. We observed elevated EA2 gene expression in the subcutaneous compared to that in the visceral human adipose tissue. EA2 gene expression negatively correlated with adiponectin and chemerin in visceral adipose tissue, and positively correlated with TNF-α in subcutaneous adipose tissue. EA2 gene expression was significantly downregulated during differentiation of preadipocytes in vitro. In conclusion, this study provides a description of EA2 distribution and emphasizes a need to study the roles of this protein during the progression of obesity.

Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation.

Obesity is closely associated with increased adipose tissue macrophages (ATMs), which contribute to systemic insulin resistance and altered lipid metabolism by creating a pro-inflammatory environment. Very low-density lipoprotein receptor (VLDLR) is involved in lipoprotein uptake and storage. However, whether lipid uptake via VLDLR in macrophages affects obesity-induced inflammatory responses and insulin resistance is not well understood. Here we show that elevated VLDLR expression in ATMs promotes adipose tissue inflammation and glucose intolerance in obese mice. In macrophages, VLDL treatment upregulates intracellular levels of C16:0 ceramides in a VLDLR-dependent manner, which potentiates pro-inflammatory responses and promotes M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance in diet-induced obese mice. These findings suggest that increased VLDL-VLDLR signaling in ATMs aggravates adipose tissue inflammation and insulin resistance in obesity.

Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity.

Firmicutes and Bacteroidetes, 2 major phyla of gut microbiota, are involved in lipid and bile acid metabolism to maintain systemic energy homeostasis in host. Recently, accumulating evidence has suggested that dietary changes promptly induce the alteration of abundance of both Firmicutes and Bacteroidetes in obesity and its related metabolic diseases. Nevertheless, the metabolic roles of Firmicutes and Bacteroidetes on such disease states remain unclear. The aim of this study was to determine the effects of antibiotic-induced depletion of Firmicutes and Bacteroidetes on dysregulation of energy homeostasis in obesity. Treatment of C57BL/6J mice with the antibiotics (vancomycin [V] and bacitracin [B]), in the drinking water, before diet-induced obesity (DIO) greatly decreased both Firmicutes and Bacteroidetes in the gut as revealed by pyrosequencing of the microbial 16S rRNA gene. Concomitantly, systemic glucose intolerance, hyperinsulinemia, and insulin resistance in DIO were ameliorated via augmentation of GLP-1 secretion (active form; 2.03-fold, total form; 5.09-fold) independently of obesity as compared with untreated DIO controls. Furthermore, there were increases in metabolically beneficial metabolites derived from the gut. Together, our data suggest that Firmicutes and Bacteroidetes potentially mediate insulin resistance through modulation of GLP-1 secretion in obesity.

The modulation of parietal gamma oscillations in the human electroencephalogram with cognitive reappraisal.

The present study examines how gamma oscillations can be modulated by cognitive reappraisal. Thirty-two participants performed cognitive reappraisal tasks to increase or decrease their emotions while viewing neutral and emotional (positive or negative) pictures. As a control task, the participants also simply viewed the pictures without an attempt to manipulate emotions. Electroencephalograms of the participants were recorded during the cognitive reappraisal tasks to extract the gamma oscillations. Gamma activity was quantified by measuring event-related changes in the gamma band power (30-55 Hz). During the tasks, the greatest gamma activity was found at the parietal regions. Greater parietal gamma activity was induced by the emotional pictures compared with the neutral ones when the participants passively viewed the pictures. No such difference in the parietal gamma activity was found when the participants performed the cognitive reappraisal tasks. In addition, parietal gamma activity during the cognitive reappraisal tasks was greater than that during the control task in response to the neutral pictures, implying the role of parietal gamma activity in the top-down cognitive execution process. In contrast, parietal gamma activity during the cognitive reappraisal task to increase emotions was greater than the levels of activity during the task to decrease emotions and during the control task in response to the emotional pictures, implying the role of parietal gamma activity in the bottom-up sensory emotional process. These results suggest that parietal gamma activity may be implicated in the multiple cognitive reappraisal processes.

Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism.

Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.

Adipocytokine orosomucoid integrates inflammatory and metabolic signals to preserve energy homeostasis by resolving immoderate inflammation.

Orosomucoid (ORM), also called alpha-1 acid glycoprotein, is an abundant plasma protein that is an immunomodulator induced by stressful conditions such as infections. In this study, we reveal that Orm is induced selectively in the adipose tissue of obese mice to suppress excess inflammation that otherwise disturbs energy homeostasis. Adipose Orm levels were elevated by metabolic signals, including insulin, high glucose, and free fatty acid, as well as by the proinflammatory cytokine tumor necrosis factor-alpha, which is found in increased levels in the adipose tissue of morbid obese subjects. In both adipocytes and macrophages, ORM suppressed proinflammatory gene expression and pathways such as NF-kappaB and mitogen-activated protein kinase signalings and reactive oxygen species generation. Concomitantly, ORM relieved hyperglycemia-induced insulin resistance as well as tumor necrosis factor-alpha-mediated lipolysis in adipocytes. Accordingly, ORM improved glucose and insulin tolerance in obese and diabetic db/db mice. Taken together, our results suggest that ORM integrates inflammatory and metabolic signals to modulate immune responses to protect adipose tissue from excessive inflammation and thereby from metabolic dysfunction.