Adipose failure through adipocyte overload and autoimmunity.

Metabolic syndrome poses a great worldwide threat to the health of the patients. Increased visceral adiposity is recognized as the main determinant of the detrimental clinical effects of insulin resistance. Inflammation and immune system activation in the adipose tissue (AT) have a central role in the pathophysiology of metabolic syndrome, but the mechanisms linking increased adiposity to immunity in the AT remain in part elusive. In this review, we support the central role of adipocyte overload and relative adipose failure as key determinants in triggering immune aggression to AT. This provides a mechanistic explanation of the relative metabolic wellness of metabolically normal obese people and the disruption in insulin signaling in metabolically obese lean people.

Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity.

CONTEXT: A high prevalence of vitamin D (VD) deficiency in COVID-19 patients has been reported and hypothesized to increase COVID-19 severity likely because of its negative impact on immune and inflammatory responses. Furthermore, clear associations between hypovitaminosis D and fat body mass excess and diabetes, factors associated with COVID-19 severity, have been widely recognized. OBJECTIVE: The aim of this study was to evaluate in COVID-19 patients the relationship between VD levels and inflammatory response, body mass index (BMI), blood glucose (GLU), and disease severity. METHODS: Patients admitted to San Raffaele-Hospital for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing VD metabolism. 25-Hydroxyvitamin D levels, plasma GLU levels, BMI, and inflammatory parameters were evaluated at admission. RESULTS: A total of 88 patients were included. Median VD level was 16.3 ng/mL and VD deficiency was found in 68.2% of patients. VD deficiency was found more frequently in male patients and in those affected by severe COVID-19. Regression analyses showed a positive correlation between VD and PaO2/FiO2 ratio, and negative correlations between VD and plasma GLU, BMI, neutrophil/lymphocyte ratio, C-reactive protein, and interleukin 6. Patients with both hypovitaminosis D and diabetes mellitus, as well those with hypovitaminosis D and overweight, were more frequently affected by a severe disease with worse inflammatory response and respiratory parameters, compared to those without or just one of these conditions. CONCLUSION: We showed, for the first-time, a strict association of VD levels with blood GLU and BMI in COVID-19 patients. VD deficiency might be a novel common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.

Time-Restricted Feeding Restores Obesity-Induced Alteration in Adipose Tissue Immune Cell Phenotype.

Studies suggest that time-restricted feeding (TRF) may prevent obesity and its commodities. At present, little is known about how TRF impacts immune cells, and whether such an effect is linked to altered metabolic parameters under condition of a high-fat diet (HFD)-induced obesity. To address these issues, we conducted a study in which we determined whether TRF has therapeutic efficacy against weight gain, adiposity, as well as associated immune cell disturbance found in obese mice. Six-week-old male C57BL/6 mice were fed a low-fat diet (LFD) or HFD ad libitum for six weeks, after which time a subgroup of HFD mice was switched to the 10 h TRF paradigm (HFD-TRF) for additional eight weeks. We found that TRF intervention reduced HFD-induced weight gain. Even with comparable fat mass and mean adipocyte area, the HFD-TRF group had lower mRNA levels of proinflammatory cytokine Tnfα and chemokine Ccl8, along with reduced numbers of adipose tissue macrophages (ATM), CD11c+ ATM, and CD8+ T cell compared to the HFD group, while maintaining CD8+ to CD4+ ratio at levels similar to those in the LFD group. Furthermore, TRF intervention was effective in improving glucose tolerance and reducing HOMA-IR. Taken together, our findings suggest that TRF restores the obesity-induced alteration in immune cell composition, and this effect may in part contribute to health benefits (including insulin sensitivity) of practicing TRF.

Adults with Crohn's disease exhibit elevated gynoid fat and reduced android fat irrespective of disease relapse or remission.

Crohn's disease (CD) is a debilitating inflammatory bowel condition of unknown aetiology that is growing in prevalence globally. Large-scale studies have determined associations between female obesity or low body mass index (BMI) with risk of CD at all ages or 8- < 40 years, respectively. For males, low BMI entering adult life is associated with increased incidence of CD or ulcerative colitis up to 40 years later. Body composition analysis has shown that combinations of lean tissue loss and high visceral fat predict poor CD outcomes. Here, we assessed dietary intake, physical activity and whole or regional body composition of patients with CD relapse or remission. This anthropometric approach found people with CD, irrespective of relapse or remission, differed from a large representative healthy population sample in exhibiting elevated gynoid fat and reduced android fat. CD is associated with mesenteric adipose tissue, or "creeping fat", that envelops affected intestine exclusive of other tissue; that fat is localised to the android region of the body. In this context, CD mesenteric adiposity represents a stark juxtaposition of organ-specific and regional adiposity. Although our study population was relatively small, we suggest tentatively that there is a rationale to refer to Crohn's disease as a fatty intestine condition, akin to fatty liver conditions. We suggest that our data provide early insight into a subject that potentially warrants further investigation across a larger patient cohort.

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Effects of Obesity-Associated Chronic Inflammation on Peripheral Blood Immunophenotype Are Not Mediated by TNF in Female C57BL/6J Mice.

Chronic low-grade systemic inflammation in obesity contributes to the development and progression of aspects of metabolic syndrome. In obese male mice, expanded adipose tissue releases proinflammatory cytokines, including TNF, which promotes an increase in immature, proinflammatory, peripheral blood Ly-6Chigh monocytes. The aim of this study was to characterize how TNF alters circulating cellular immunity in female mice with diet-induced obesity. We initially quantified peripheral blood immune cells by flow cytometry in female wild-type C57BL/6J mice after 3-30 wk of allocation to a high-fat (HF) or standard chow diet. We assessed effects of diet and time on neutrophil, monocyte, B cell, NK cell, CD4+ T cell, and CD8+ T cell populations. There was a significant interaction of the effects of diet type and time on the numbers and prevalence of circulating total monocytes and Ly-6Chigh, Ly-6Clow, and Ly-6C- subsets. Circulating monocytes, in particular Ly-6Chigh monocytes, were increased in HF-fed mice compared with chow-fed mice. Ly-6Chigh monocytes from HF-fed mice also had a more immature phenotype yet were highly responsive to the chemotactic ligand CCL2 and had greater intracellular production of TNF. Comparisons of the effects of HF diet feeding in littermate wild-type (TNF+/+) and TNF-/- female mice showed that genetic ablation of TNF did not protect from higher adiposity or an increase in circulating, immature, proinflammatory Ly-6Chigh monocytes during HF diet-induced obesity. These data emphasize the importance of considering biological sex when determining the mechanisms of TNF action in obesity-induced cellular inflammation and in other chronic inflammatory conditions.

Effects of Adiposity and Exercise on Breast Tissue and Systemic Metabo-Inflammatory Factors in Women at High Risk or Diagnosed with Breast Cancer.

Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a cross-sectional cohort study, breast white adipose tissue (WAT) and blood were collected from 100 women undergoing mastectomy for breast cancer risk reduction or treatment. Self-reported exercise behavior, body composition measured by dual-energy x-ray absorptiometry (DXA), and waist:hip ratio were obtained prior to surgery. Breast WAT inflammation (B-WATi) was assessed by IHC and aromatase expression was assessed by quantitative PCR. Metabolic and inflammatory blood biomarkers that are predictive of breast cancer risk and progression were measured. B-WATi was present in 56 of 100 patients and was associated with older age, elevated BMI, postmenopausal status, decreased exercise, hypertension and dyslipidemia (Ps < 0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (Ps < 0.001). Circulating C-reactive protein, IL6, insulin, and leptin positively correlated with body fat and breast aromatase levels, while negative correlations were observed for adiponectin and sex hormone binding globulin (P < 0.001). Inverse relationships were observed with exercise (Ps < 0.05). In a subgroup of 39 women with normal BMI, body fat levels positively correlated with B-WATi and aromatase expression (Ps < 0.05). In conclusion, elevated body fat levels and decreased exercise are associated with protumorigenic micro- and host environments in normal, overweight, and obese individuals. These findings support the development of BMI-agnostic lifestyle interventions that target adiposity. PREVENTION RELEVANCE: We report that individuals with high body fat and low exercise levels have breast inflammation, higher breast aromatase expression, and levels of circulating metabo-inflammatory factors that have been associated with increased breast cancer risk. These findings support interventions to lower adiposity, even among normal weight individuals, to prevent tumor growth.

The Effect of Adiposity on Anti-Tumor Necrosis Factor-Alpha Levels and Loss of Response in Crohn's Disease Patients.

INTRODUCTION: A high body mass index is known to adversely affect antitumor necrosis factor-alpha trough levels and secondary loss of response (SLOR) in patients with Crohn's disease. We hypothesize that high levels of adiposity negatively affect these outcomes and aimed to determine if this relationship exists. METHODS: We performed a retrospective cross-sectional study of 69 patients with Crohn's disease from two tertiary inflammatory bowel disease centers between February 1, 2015, and June 30, 2018. Primary responders to infliximab (IFX) or adalimumab (ADA) who had a trough level performed within 6 months of CT or MRI scan and at least 12 months of clinical follow-up were eligible for inclusion. Body composition as measured on CT/MRI scans were correlated with trough concentration and time SLOR. Multivariate adjustments were made for established risk factors known to affect trough levels and SLOR. RESULTS: Of 69 included patients, 44 (63.8%) and 25 (36.2%) patients received IFX and ADA, respectively. Multivariate analysis revealed that IFX trough concentrations were inversely correlated with visceral fat area (-0.02 [-0.04, -0.003], P = 0.03), visceral fat index (-0.07 [-0.12, -0.01], P = 0.02) and visceral fat: skeletal muscle area ratio (-3.81 [-7.13, -0.50], P = 0.03), but not body mass index (-0.23 [-0.52, 0.06], P = 0.11). No predictive factors were found for ADA. Increased total adipose area was associated with an increased risk of SLOR in ADA-treated patients, but not IFX-treated patients (hazard ratio = 1.01 [1.002, 1.016], P = 0.011). DISCUSSION: Visceral adiposity is an important predictor of IFX trough levels, and high total adiposity predicts for SLOR to ADA.

Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19.

Coronavirus disease 2019 (COVID-19) is a novel threat that seems to result from the collusion between a new pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and an existing pandemic of metabolic disease driven by obesity. This Perspective explores the evolving epidemiological, clinical, biological, and molecular evidence to propose an unfolding paradigm in which old age, chronic metabolic disease (such as obesity, type 2 diabetes, and metabolic syndrome), and male biological sex produce a deadly symbiosis of dysregulated immunometabolism and chronic systemic inflammation that intensifies virally induced hyperinflammation associated with SARS-CoV-2 infection. It is intended to inspire new research directions and stimulate funding in this field.

Childhood Obesity and Cancer Risk in Adulthood.

PURPOSE OF REVIEW: The purpose of this review is to summarize our current understanding of the association between childhood obesity and cancer risk later in life. RECENT FINDINGS: Adipose tissue secrets a variety of adipocytokines, and expression and/or secretion rate of most of them seems to be increased or dysregulated in obesity. In addition, obesity leads to increased secretion of proinflammatory cytokines such as interferon-γ (IFN-γ), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), which promotes an infiltration of inflammatory immune cells into adipose tissue. This process may facilitate a state of "subclinical inflammation" (metaflammation) and may lead to the development of the metabolic syndrome (MetS), starting as early as during childhood. In addition, several oncogenes have been linked to inflammation and cancer development via different pathways, and several types of tumors need an inflammatory environment before a malignant change occurs. An inflammatory environment seems to promote the proliferation and survival of malignant cells as well as angiogenesis. Natural killer (NK) cells play an important role in this process, as they are able to kill transformed cells without prior sensitization and coordinate subsequent immune responses by producing distinct cytokines, thus providing antitumor immunity. First studies in children have suggested that NK cells from obese children are activated, metabolically stressed, and functionally deficient. This may lead to a suppression of antitumor immunity as early as during childhood, probably many years before the development of cancer. Epidemiological studies have shown a strong association between higher body mass index (BMI) during childhood and adolescence and increased risk for several malignancies in adulthood, including leukemia, Hodgkin's disease, colorectal cancer, and breast cancer. Underlying mechanisms are not completely understood, but several adipocytokines and inflammatory markers including NK cells seem to be "key players" in this process.

Epicardial fat thickness is increased and associated with disease severity in hidradenitis suppurativa.

Previous studies showed an association between various dermatological diseases and epicardial fat thickness (EFT). However, EFT, which has been accepted as a cardiometabolic risk factor in recent years, has not been studied in the context of hidradenitis suppurativa (HS). Therefore, we aimed to determine whether EFT is increased in HS patients, and whether EFT is associated with disease severity. Forty adult patients with HS and 100 age- and sex-matched controls were included. Patients with diabetes mellitus, cardiovascular diseases, chronic renal or hepatic diseases, or other inflammatory conditions were excluded. The EFT was measured by transthoracic echocardiography. Disease severity was assessed by Hurley stage, and stage III patients have been described as having severe disease. High-sensitivity C-reactive protein (hs-CRP) and EFT were significantly higher in HS patients compared to controls. There were positive correlations between EFT and the duration of the disease, hs-CRP, and Hurley stage. The EFT was proportionally increased in HS patients with increasing disease severity; the largest EFT was found in Hurley stage 3 patients (7.34 ± 2.30 mm), followed by Hurley stage 2 patients (6.12 ± 1.82 mm), and Hurley stage 1 patients (4.83 ± 0.98 mm). Multivariate analysis showed that male gender, hs-CRP, body mass index, and EFT ≥ 5.9 mm were independent predictors of severe disease. The EFT is increased in HS, and it is an independent predictor of disease severity in adult patients with HS.

"Western Diet"-Induced Adipose Inflammation Requires a Complex Gut Microbiota.

BACKGROUND & AIMS: Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation. METHODS: Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88. RESULTS: Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103- dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation. CONCLUSIONS: These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity.

Inflammation and fatness in adolescents with and without Down syndrome: UP & DOWN study.

BACKGROUND: The main objective of this study was to describe the inflammatory status of adolescents with Down syndrome (DS) and their relationship with adiposity. METHODS: Ninety-five adolescents with DS (44.2% girls) and a control group of 113 adolescents (47.8% girls), aged between 11 and 18 years old, from the UP & DOWN study were included in this substudy. Serum C-reactive protein, C3 and C4 complement factors, total proteins, interleukin-6, tumour necrosis factor-α, insulin, cortisol, leptin, adiponectin, galactin-3 and visfatin were analysed; homeostatic model assessment index was calculated. In order to evaluate adiposity, we measured the following body fat variables: weight, height, waist circumference and skinfold thicknesses. Birth weight was obtained by questionnaire. In addition, body mass index, waist-to-height ratio (WHtR) and body fat percentage (BF%) were calculated. RESULTS: Down syndrome group showed higher levels of body mass index, WHtR, waist circumference, BF% and lower birth weight than controls (P < 0.001). In the general linear model in the total sample, WHtR was positively associated with C3 and C4 (P < 0.001) as well as with leptin levels (P = 0.015). BF% was positively associated with total proteins (P = 0.093) and leptin levels (P < 0.001). DS was positively associated with total proteins (P < 0.001), C3 (P = 0.047) and C4 (P = 0.019). Despite the higher levels of adiposity found in DS group, no direct association was found between BF% and leptin levels, comparing with the control group. CONCLUSIONS: These findings suggest that abdominal obesity should be controlled in adolescents because of its relationship with acute phase-inflammatory biomarkers but especially in DS adolescents who may show a peculiar metabolic status according to their relationship between adiposity and inflammatory biomarkers.

Obesity-Induced Adipose Tissue Inflammation as a Strong Promotional Factor for Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon become the second leading cause of cancer related deaths in the United States. This may be due to the rising obesity prevalence, which is a recognized risk factor for PDAC. There is great interest in deciphering the underlying driving mechanisms of the obesity-PDAC link. Visceral adiposity has a strong correlation to certain metabolic diseases and gastrointestinal cancers, including PDAC. In fact, our own data strongly suggest that visceral adipose tissue inflammation is a strong promoter for PDAC growth and progression in a genetically engineered mouse model of PDAC and diet-induced obesity. In this review, we will discuss the relationship between obesity-associated adipose tissue inflammation and PDAC development, with a focus on the key molecular and cellular components in the dysfunctional visceral adipose tissue, which provides a tumor permissive environment.

The Impact of the Adipose Organ Plasticity on Inflammation and Cancer Progression.

Obesity is characterized by chronic and low-grade systemic inflammation, an increase of adipose tissue, hypertrophy, and hyperplasia of adipocytes. Adipose tissues can be classified into white, brown, beige and pink adipose tissues, which display different regulatory, morphological and functional characteristics of their adipocyte and immune cells. Brown and white adipocytes can play a key role not only in the control of energy homeostasis, or through the balance between energy storage and expenditure, but also by the modulation of immune and inflammatory responses. Therefore, brown and white adipocytes can orchestrate important immunological crosstalk that may deeply impact the tumor microenvironment and be crucial for cancer establishment and progression. Recent works have indicated that white adipose tissues can undergo a process called browning, in which an inducible brown adipocyte develops. In this review, we depict the mechanisms involved in the differential role of brown, white and pink adipocytes, highlighting their structural, morphological, regulatory and functional characteristics and correlation with cancer predisposition, establishment, and progression. We also discuss the impact of the increased adiposity in the inflammatory and immunological modulation. Moreover, we focused on the plasticity of adipocytes, describing the molecules produced and secreted by those cells, the modulation of the signaling pathways involved in the browning phenomena of white adipose tissue and its impact on inflammation and cancer.

Understanding associations of early-life adversities with mid-life inflammatory profiles: Evidence from the UK and USA.

OBJECTIVES: In two cohorts, we aimed to establish associations between early-life adversities and adult inflammation, and whether adult (a) adiposity or (b) socioeconomic disadvantage are key intermediaries. METHODS: In both cohorts (N = 7661, 1958 British birth cohort; N = 1255, MIDUS), information was used on adult inflammatory markers (C-reactive protein (CRP), fibrinogen and (MIDUS only) interleukin-6 (IL-6)), adiposity and socioeconomic disadvantage, and early-life adversities (neglect, emotional neglect, physical, psychological, sexual abuse and childhood disadvantage). RESULTS: Early-life adversities varied from 1.6% (sexual abuse, 1958 cohort) to 14.3% (socioeconomic disadvantage, MIDUS). Across the two cohorts, associations were consistent for physical abuse, e.g. 16.3%(3.01,29.7) and 17.0%(-16.4,50.3) higher CRP in the 1958 cohort and MIDUS respectively. Associations attenuated after accounting for adult adiposity, e.g. physical abuse (1958 cohort) and sexual abuse (MIDUS, non-white participants) associations were abolished. Some associations attenuated after adjustment for adult socioeconomic disadvantage; e.g. 1958 cohort neglect-CRP associations reduced from 23.2%(13.7,32.6) to 17.7%(8.18,27.2). Across the cohorts, no associations were found for psychological abuse or emotional neglect; associations for childhood socioeconomic disadvantage were inconsistent. CONCLUSIONS: Specific early-life adversities are associated with adult inflammation; adiposity is a likely intermediary factor. Weight reduction and obesity prevention may offset pro-inflammatory related adult disease among those who experienced early-life adversities.

T Cells in Adipose Tissue: Critical Players in Immunometabolism.

Adipose tissue performs immunoregulatory functions in addition to fat storage. Various T cells in different fat depots either help maintain metabolic homeostasis under healthy conditions or contribute to metabolic disorders in pathological conditions such as obesity, diabetes, cardiovascular diseases, or even cancer. These T cells play critical roles in immunometabolism, which refers to the intersection of immunity and metabolism. Numerous studies have examined the presence and changes of different T cell subsets, including helper T cells, regulatory T cells, cytotoxic T cells, and natural killer T cells, in adipose depots in health and diseases. In this review, we will discuss the adipose tissue niches that influence the patterns and functions of T cell subsets and in turn the impact of these T cells on cell- or body-based immunometabolism accounting for health and obesity.

Low-grade inflammation in the relationship between sleep disruption, dysfunctional adiposity, and cognitive decline in aging.

Aging is characterized by a progressive increase in proinflammatory status. This state, known as inflammaging, has been associated with cognitive decline in normal and pathological aging. However, this relationship has been inconsistently reported, likely because it is conditioned by other factors also affected by the aging process. Sleep and adiposity are two factors in particular that show significant alterations with aging and have been related to both cognitive decline and inflammaging. Given the consequences this state also has for brain integrity and cognition, we discuss here evidence supporting the potential mediating role of chronic low-grade systemic inflammation in the complex relationship between impaired sleep, dysfunctional adiposity, and cognitive decline through the common pathway of neuroinflammation. This review proposes a multi-factor model of aging-related cognitive decline that highlights the reciprocal interactions between sleep, the circadian system, and inflammation on the one hand, and between sleep, adiposity, and hormone resistance on the other. The model identifies sleep and adiposity as modifiable lifestyle factors that can be targeted to maximize cognitive function and quality of life in the elderly.

Islet autoantibody positivity in overweight and obese adults with type 2 diabetes.

Islet autoantibodies are typically associated with type 1 diabetes, but have been found in patients diagnosed with type 2 diabetes in whom they are associated with lower adiposity. The significance of autoantibody positivity in overweight and obese patients is not well understood. The aim of this study was to determine the prevalence and clinical significance of islet autoantibodies in overweight/obese adults diagnosed with type 2 diabetes. This study includes 204 participants at one site of the multicenter Look AHEAD (Action for Health in Diabetes) trial (ClinicalTrials.gov identifier: NCT00017953) which randomized overweight/obese adults diagnosed with type 2 diabetes to an intensive lifestyle intervention or diabetes support and education. We measured antibodies to glutamic acid decarboxylase, insulinoma antigen-2, and zinc transporter 8. Participants with and without autoantibodies were compared with respect to baseline clinical features, and longitudinal changes in weight, hemoglobin A1c, and antihyperglycemic medications. We found that 13 participants (6.4%) were autoantibody positive, including six of 47 participants (12.8%) with BMI ≥40 kg/m2. At baseline, autoantibody positive participants had higher HDL cholesterol (1.27 vs. 1.09 mmol/L, p = .034) and lower fasting C-peptide (0.32 vs. 0.57 nmol/L, p = .049). Over four years, autoantibody positive participants lost 5.1 kg more weight than autoantibody negative participants (p = .056). Longitudinal changes in hemoglobin A1c did not differ by autoantibody status, though autoantibody positive participants were more likely to increase the number of antihyperglycemic medications or initiate insulin (p = .011). In conclusion, islet autoantibodies were present in 6.4% of overweight/obese adults with type 2 diabetes including those with severe obesity, and were associated with distinct clinical features. The effect of autoantibody positivity on weight loss interventions requires further study.

Longitudinal associations of the alternative and terminal pathways of complement activation with adiposity: The CODAM study.

OBJECTIVE: To investigate longitudinal associations of components of the alternative (C3, C3a, Bb, factor D [FD], factor H [FH], and properdin) and the terminal complement pathway (C5a, sC5b-9) with adiposity. METHODS: A prospective human cohort study (n=574 at baseline, n=489 after 7 years follow-up) was analyzed. Generalized estimating equations were used to evaluate the longitudinal associations between complement components (standardized values) and adiposity (main outcome BMI [kg/m2]). Multiple linear regression models were used to investigate the associations between change in complement levels and change in BMI. Analyses were adjusted for age, sex, medication and lifestyle. RESULTS: Over the 7-year period, baseline C3 was positively associated with BMI (ß=1.72 [95% confidence interval (CI): 1.35; 2.09]). Positive associations were also observed for C3a (ß=0.64 [0.31; 0.97]), FD (ß=1.00 [0.59; 1.42]), FH (ß=1.17 [0.82; 1.53]), and properdin (ß=0.60 [0.28; 0.92]), but not for Bb, C5a or sC5b-9. Moreover, changes in C3 (ß=0.52 [0.34; 0.71]) and FH (ß=0.51 [0.32; 0.70]) were significantly associated with changes in BMI. CONCLUSIONS: The complement system, particularly activation of the alternative pathway, may be involved in development of adiposity. Whether individual aspects of alternative pathway activation have a causal role in human obesity, remains to be investigated.