Genetic Deficiency of TRAF5 Promotes Adipose Tissue Inflammation and Aggravates Diet-Induced Obesity in Mice.

Objective: The accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardiometabolic disease. We previously reported that a genetic deficiency of the intracellular signaling adaptor TRAF5 (TNF [tumor necrosis factor] receptor-associated factor 5) accelerates atherosclerosis in mice by increasing inflammatory cell recruitment. Here, we tested the hypothesis that an impairment of TRAF5 signaling modulates adipose tissue inflammation and its metabolic complications in a model of diet-induced obesity in mice. Approach and Results: To induce diet-induced obesity and adipose tissue inflammation, wild-type or Traf5-/- mice consumed a high-fat diet for 18 weeks. Traf5-/- mice showed an increased weight gain, impaired insulin tolerance, and increased fasting blood glucose. Weight of livers and peripheral fat pads was increased in Traf5-/- mice, whereas lean tissue weight and growth were not affected. Flow cytometry of the stromal vascular fraction of visceral adipose tissue from Traf5-/- mice revealed an increase in cytotoxic T cells, CD11c+ macrophages, and increased gene expression of proinflammatory cytokines and chemokines. At the level of cell types, expression of TNF[alpha], MIP (macrophage inflammatory protein)-1[alpha], MCP (monocyte chemoattractant protein)-1, and RANTES (regulated on activation, normal T-cell expressed and secreted) was significantly upregulated in Traf5-deficient adipocytes but not in Traf5-deficient leukocytes from visceral adipose tissue. Finally, Traf5 expression was lower in adipocytes from obese patients and mice and recovered in adipose tissue of obese patients one year after bariatric surgery. Conclusions: We show that a genetic deficiency of TRAF5 in mice aggravates diet-induced obesity and its metabolic derangements by a proinflammatory response in adipocytes. Our data indicate that TRAF5 may promote anti-inflammatory and obesity-preventing signaling events in adipose tissue.

Helix-Loop-Helix Factor Id3 (Inhibitor of Differentiation 3): A Novel Regulator of Hyaluronan-Mediated Adipose Tissue Inflammation.

OBJECTIVE: The aim of this study was to unravel mechanisms whereby deficiency of the transcription factor Id3 (inhibitor of differentiation 3) leads to metabolic dysfunction in visceral obesity. We investigated the impact of loss of Id3 on hyaluronic acid (HA) production by the 3 HAS isoenzymes (HA synthases; -1, -2, and -3) and on obesity-induced adipose tissue (AT) accumulation of proinflammatory B cells. Approach and Results: Male Id3-/- mice and respective wild-type littermate controls were fed a 60% high-fat diet for 4 weeks. An increase in inflammatory B2 cells was detected in Id3-/- epididymal AT. HA accumulated in epididymal AT of high-fat diet-fed Id3-/- mice and circulating levels of HA were elevated. Has2 mRNA expression was increased in epididymal AT of Id3-/- mice. Luciferase promoter assays showed that Id3 suppressed Has2 promoter activity, while loss of Id3 stimulated Has2 promoter activity. Functionally, HA strongly promoted B2 cell adhesion in the AT and on cultured vascular smooth muscle cells of Id3-/- mice, an effect sensitive to hyaluronidase. CONCLUSIONS: Our data demonstrate that loss of Id3 increases Has2 expression in the epididymal AT, thereby promoting HA accumulation. In turn, elevated HA content promotes HA-dependent binding of B2 cells and an increase in the B2 cells in the AT, which contributes to AT inflammation.

Consumption of Diet Soda Sweetened with Sucralose and Acesulfame-Potassium Alters Inflammatory Transcriptome Pathways in Females with Overweight and Obesity.

SCOPE: Low-calorie sweetener (LCS) consumption is associated with metabolic disease in observational studies. However, physiologic mechanisms underlying LCS-induced metabolic impairments in humans are unclear. This study is aimed at identifying molecular pathways in adipose impacted by LCSs. METHODS AND RESULTS: Seven females with overweight or obesity, who did not report LCS use, consumed 12 ounces of diet soda containing sucralose and acesulfame-potassium (Ace-K) three times daily for 8 weeks. A subcutaneous adipose biopsy from the left abdomen and a fasting blood sample were collected at baseline and post-intervention. Global gene expression were assessed using RNA-sequencing followed by functional pathway analysis. No differences in circulating metabolic or inflammatory biomarkers were observed. However, ANOVA detected 828 differentially expressed annotated genes after diet soda consumption (p < 0.05), including transcripts for inflammatory cytokines. Fifty-eight of 140 canonical pathways represented in pathway analyses regulated inflammation, and several key upstream regulators of inflammation (e.g., TNF-alpha) were also represented. CONCLUSION: Consumption of diet soda with sucralose and Ace-K alters inflammatory transcriptomic pathways (e.g., NF-κB signaling) in subcutaneous adipose tissue but does not significantly alter circulating biomarkers. Findings highlight the need to examine molecular and metabolic effects of LCS exposure in a larger randomized control trial for a longer duration.

B Lymphocytes and Adipose Tissue Inflammation.

The immune system plays an important role in obesity-induced adipose tissue inflammation and the resultant metabolic dysfunction, which can lead to hypertension, dyslipidemia, and insulin resistance and their downstream sequelae of type 2 diabetes mellitus and cardiovascular disease. While macrophages are the most abundant immune cell type in adipose tissue, other immune cells are also present, such as B cells, which play important roles in regulating adipose tissue inflammation. This brief review will overview B-cell subsets, describe their localization in various adipose depots and summarize our knowledge about the function of these B-cell subsets in regulating adipose tissue inflammation, obesity-induced metabolic dysfunction and atherosclerosis.

Adipocyte Oncostatin Receptor Regulates Adipose Tissue Homeostasis and Inflammation.

Adipocytes are the largest cell type in terms of volume, but not number, in adipose tissue. Adipocytes are prominent contributors to systemic metabolic health. Obesity, defined by excess adipose tissue (AT), is recognized as a low-grade chronic inflammatory state. Cytokines are inflammatory mediators that are produced in adipose tissue (AT) and function in both AT homeostatic as well as pathological conditions. AT inflammation is associated with systemic metabolic dysfunction and obesity-associated infiltration and proliferation of immune cells occurs in a variety of fat depots in mice and humans. AT immune cells secrete a variety of chemokines and cytokines that act in a paracrine manner on adjacent adipocytes. TNFα, IL-6, and MCP-1, are well studied mediators of AT inflammation. Oncostatin M (OSM) is another proinflammatory cytokine that is elevated in AT in human obesity, and its specific receptor (OSMRß) is also induced in conditions of obesity and insulin resistance. OSM production and paracrine signaling in AT regulates adipogenesis and the functions of AT. This review summarizes the roles of the oncostatin M receptor (OSMRß) as a modulator of adipocyte development and function its contributions to immunological adaptations in AT in metabolic disease states.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia.

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.

Multifocal pleomorphic dermal sarcoma and the role of inflammation and immunosuppression in a lung transplant patient: a case report.

BACKGROUND: Pleomorphic dermal sarcoma is the cutaneous variant of undifferentiated pleomorphic sarcoma. It is a rare malignancy of unclear histogenesis; it is a diagnosis of exclusion that requires extensive use of immunohistochemistry to rule out other malignancies. Pleomorphic dermal sarcoma typically presents as a solitary tumor in sun-exposed areas and may have unpredictable clinical behavior, with some tumors associated with metastasis and death. CASE PRESENTATION: We present an unusual case of multifocal pleomorphic dermal sarcoma arising in the areas of alpha-1-antitrypsin deficiency panniculitis in a lung transplant patient. Our patient was a 58-year-old white woman whose initial presentation was consistent with alpha-1-antitrypsin deficiency panniculitis. She then developed extensive multifocal, bleeding, and ulcerated nodules in the areas of the panniculitis. A skin biopsy was consistent with a diagnosis of pleomorphic dermal sarcoma. Her immunosuppressive regimen was decreased, and she was treated with liposomal doxorubicin 40 mg/m2 every 3 weeks with some initial improvement in the size of her tumors. However, soon after beginning therapy, she developed pneumonia and septic shock and ultimately died from multi-organ failure. CONCLUSIONS: We hypothesize that chronic, multifocal inflammation in the skin in the setting of immunosuppression led to simultaneous, malignant transformation in numerous skin lesions. We discuss the challenges of diagnosing pleomorphic dermal sarcoma, therapeutic options, and stress the need for multidisciplinary management of these cases.

Antibody-mediated targeting of cleavage-specific OPN-T cell interactions.

T cells are crucial players in obesity-mediated adipose tissue inflammation. We hypothesized that osteopontin (OPN), an inflammatory protein with enhanced activity when proteolytically cleaved, affects the number of viable T cells in adipose tissue and assessed inhibition of the interaction between T cells and thrombin and matrix metalloproteinases-cleaved OPN using antibodies and postimmune sera. Gene expression of T cell markers in adipose tissue from wild-type (wt) and Spp1-/- (OPN deficient) mice was analyzed after 16 weeks of high fat diet (HFD) or low fat diet (LFD) feeding. CD3, CD8 and OPN gene expression in omental adipose tissue from individuals with obesity was measured. OPN-T cell interactions were assessed with a fluorescence-based adhesion assay and blocked with antibodies targeting OPN. Comparison of T cell gene expression in adipose tissue from wt and Spp1-/- mice showed that OPN affected the number of T cells while in humans, levels of OPN correlated with T cell markers in omental adipose tissue. The interaction between T cells and cleaved OPN was blocked by postimmune sera following OPN peptide vaccinations and with monoclonal antibodies. In conclusion, levels of OPN affected the number of T cells in obesity and antibodies against cleaved OPN antagonize OPN-T cell interactions.

Histoplasma panniculitis in a patient with systemic lupus erythematosus.

Histoplasmosis usually presents primarily as lung infection. Occasionally, mainly in immunocompromised hosts, it can spread and cause systemic manifestations. Skin lesions have been reported in 10 to 15 percent of cases of disseminated histoplasmosis, and panniculitis has been described as an unusual form of presentation in affected patients. We present the case of a patient with systemic lupus erythematosus who presented cellulitis due to disseminated histoplasmosis.

Histoplasma panniculitis in a patient with systemic lupus erythematosus

Abstract: Histoplasmosis usually presents primarily as lung infection. Occasionally, mainly in immunocompromised hosts, it can spread and cause systemic manifestations. Skin lesions have been reported in 10 to 15 percent of cases of disseminated histoplasmosis, and panniculitis has been described as an unusual form of presentation in affected patients. We present the case of a patient with systemic lupus erythematosus who presented cellulitis due to disseminated histoplasmosis.

Type 1 innate lymphoid cells are associated with type 2 diabetes.

AIM: Type 1 innate lymphoid cells (ILC1s) play a major role in regulating systemic inflammatory diseases. However, the relationship between ILC1s and type 2 diabetes (T2D) remains unclear. Thus, the present study investigated the relationship between ILC1s and glucose homoeostasis in humans. METHODS: A total of 37 newly diagnosed T2D patients and 32 subjects with normal glucose tolerance (NGT), matched for age and body mass index (BMI), were enrolled in the study. Flow cytometric analysis of ILC1s derived from peripheral blood mononuclear cells (PBMCs) and omental adipose tissue was performed. RESULTS: T2D patients displayed greater numbers and frequencies of circulating and adipose tissue ILC1s (P < 0.05) compared with NGT subjects, and the two types of ILC1s correlated positively with each other. Circulating ILC1s were positively associated with glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), homoeostasis model assessment for insulin resistance (HOMA-IR), adipose tissue insulin resistance index (Adipo-IR) and serum free fatty acids (FFAs). A logistic regression model revealed that patients with higher ILC1 levels exhibited a 13.481-fold greater risk of developing T2D. CONCLUSION: This study is the first to provide evidence that ILC1 abnormalities are involved in the development of diabetes. The data also suggest a potential role of ILC1s as therapeutic indicators in the treatment of T2D.

Characterization of regulatory T cells in obese omental adipose tissue in humans.

Obesity-associated visceral adipose tissue (AT) inflammation promotes insulin resistance and type 2 diabetes (T2D). In mice, lean visceral AT is populated with anti-inflammatory cells, notably regulatory T cells (Tregs) expressing the IL-33 receptor ST2. Conversely, obese AT contains fewer Tregs and more proinflammatory cells. In humans, however, there is limited evidence for a similar pattern of obesity-associated immunomodulation. We used flow cytometry and mRNA quantification to characterize human omental AT in 29 obese subjects, 18 of whom had T2D. Patients with T2D had increased proportions of inflammatory cells, including M1 macrophages, with positive correlations to body mass index. In contrast, Treg frequencies negatively correlated to body mass index but were comparable between T2D and non-T2D individuals. Compared to human thymic Tregs, omental AT Tregs expressed similar levels of FOXP3, CD25, IKZF2, and CTLA4, but higher levels of PPARG, CCR4, PRDM1, and CXCL2. ST2, however, was not detectable on omental AT Tregs from lean or obese subjects. This is the first comprehensive investigation into how omental AT immunity changes with obesity and T2D in humans, revealing important similarities and differences to paradigms in mice. These data increase our understanding of how pathways of immune regulation could be targeted to ameliorate AT inflammation in humans.

Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol®) treatment.

To fight against metabolic disorders such as insulin resistance, new alimentary behaviors are developed. For instance, hyperproteined, gluten-free, or collagen-enriched diets could be preconized in order to reduce the consequences of obesity. In this aim, this study evaluates the potential effects of warm sea fish collagen peptides (Naticol®) on representative metabolic and inflammatory parameters. For that, male C57Bl6/J mice fed with either a chow- (CD) or high-fat diet (HFD) were submitted or not to specific collagen peptides in drinking water (4 g/kg bw/d) for 20 weeks. Weight, body composition, glucose tolerance, and insulin sensitivity were followed up. Effects of fish collagen peptides on various blood parameters reflecting the metabolism status were also measured (free fatty acids, triglycerides, cholesterol, hormones) together with adipocyte inflammation. Results showed that HFD-fed mice supplemented by fish collagen peptides exhibited a significant lower increase in body weight as soon as the twelfth week of treatment whereas no effect of the peptide was observed in CD fed mice. In line with this result, a weaker increase in fat mass in HFD-fed mice supplemented with Naticol® at both 9 and 18 weeks of treatment was also observed. In spite of this resistance to obesity promoted by fish collagen peptides treatment, no difference in glucose tolerance was found between groups whereas mice treated with Naticol® exhibited a lower basal glycemia. Also, even if no effect of the treatment on adipocyte lipolysis was found, a decrease of inflammatory cytokines was retrieved in collagen-supplemented group arguing for a potential better insulin sensitivity. Altogether, these results need to be completed but are the first describing a benefic role of warm sea fish collagen peptides in a context of metabolic disease paving the route for a potential utilization in human obesity-associated disorders.

Detection of anti-neutrophil cytoplasmic antibodies in dogs with immune-mediated inflammatory diseases.

Anti-neutrophil cytoplasmic antibody (ANCA) is a type of autoantibody against neutrophil cytoplasm. In veterinary medicine, few studies have reported the detection of ANCA in dogs, and most of these studies were performed in dogs with inflammatory bowel disease (IBD). The aim of this study was to evaluate whether ANCA is detected in dogs with immune-mediated inflammatory diseases (IMIDs) other than IBD. Serum samples were collected before treatment initiation from 40 client-owned dogs with various diseases and 22 healthy beagle dogs; the dogs were classified into two groups: IMID group (n = 16) and control group (n = 46). ANCA was detected using the indirect fluorescent antibody test. Of the 16 dogs in the IMID group, 13 (81.3%) tested positive for ANCA. In contrast, of the 46 dogs in the control group, 13 (28.03%) tested positive for ANCA. Moreover, a significant association between ANCA positivity and IMIDs was identified in the IMID group than in the control group (P = 0.0003). In the control group, however, dogs with bacterial infection showed a relatively high rate of ANCA positivity. Therefore, ANCA positivity was observed in dogs with both IMIDs and bacterial infection. This suggested that ANCA positivity is associated with diseases accompanied by neutrophil activation and infiltration.

Involvement of adipose tissue inflammation and dysfunction in virus-induced type 1 diabetes.

The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas ß cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering ß cell autoimmunity.

Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis.

We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted.

Systemic Inflammation and Evidence of a Cardio-splenic Axis in Patients with Psoriasis.

The spleen is thought to play a role in atherosclerosis-associated immunity and cardiovascular research has indicated the existence of a cardio-splenic axis. The aim of this study was to assess splenic 18F-fluorodeoxyglucose uptake as a measure of systemic inflammation in patients with untreated psoriasis compared with historical controls assessed by positron emission tomography-computed tomography. Patients with moderate-to-severe psoriasis (n = 12, age 61.4 ± 4.1 years, 83% men, mean Psoriasis Area Severity Index score of 14.5) and controls (n = 23, age 60.4 ± 4.5 years, 87% men) were included in the study. Splenic inflammation was measured using the background-corrected spleen-liver-ratio (SLR) based on mean standardized uptake values. Mean ± SD SLR was increased in patients with psoriasis compared with controls (0.94 ± 0.11 vs. 0.82 ± 0.08; p = 0.001). SLR was significantly associated with aortic inflammation. These results support the existence of systemic inflammation in patients with psoriasis, and provide the rationale for a mechanistic link between psoriasis-driven inflammation and cardiovascular comorbidity through a spleen-atherosclerotic axis.

Sucrose Nonfermenting-Related Kinase Regulates Both Adipose Inflammation and Energy Homeostasis in Mice and Humans.

Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1δ and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders.

Maternal vitamin D deficiency during pregnancy affects expression of adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (PPARγ) and vitamin D receptor (VDR) in lean male mice offspring.

PURPOSE: Maternal vitamin D deficiency during pregnancy is a widespread issue that may have long-lasting consequences on offspring adiposity. We sought to determine how maternal vitamin D deficiency during the perinatal period would affect offspring adipose tissue development and gene expression. METHODS: Female C57BL/6 J mice were fed either a vitamin D deficient (VDD) or control diet from 4 weeks before pregnancy (periconception) until 7 days postparturition. Male offspring were weighed and euthanized at 75 days of age (early adult period), at which point serum was collected for biochemical analyses, and perigonadal and subcutaneous white adipose tissue (PGAT and SQAT, respectively) were excised, weighed, then flash-frozen for later histology and analyses of adipogenic gene expression. RESULTS: All adult male offspring were nonobese; there were no significant differences in body weight, adipose pad weight, or adipocyte size. However, VDD-exposed offspring had greater expression of the adipogenic-regulating genes peroxisome proliferator-activated receptor gamma (Pparg) and vitamin D receptor (Vdr). CONCLUSIONS: This study suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue in nonobese offspring. These novel findings invite further investigation into the mechanisms by which maternal vitamin D status during pregnancy affects adipose development and metabolic health of offspring.