An E115A missense variant in CERS2 is associated with increased sleeping energy expenditure and hepatic insulin resistance in American Indians.

Genetic determinants of inter-individual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-hour EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (+116 kcal/day) and increased rates of endogenous glucose production during basal (+5%) and insulin-stimulated (+43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and post-absorptive sleeping metabolic rate.

Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.

[Recommendations for individual comorbidity risk assessment in adult patients with psoriasis]. / Handlungsempfehlungen zur individuellen Risikoermittlung von Komorbidität bei erwachsenen Patienten mit Psoriasis.

It has long been known that chronic inflammatory systemic diseases, such as psoriasis, pose a high risk of developing comorbidities. In everyday clinical practice, it is therefore of particular importance to identify patients who have an individually increased risk profile. In patients with psoriasis, the comorbidity patterns "metabolic syndrome", "cardiovascular comorbidity" and "mental illness" were identified as particularly relevant in epidemiological studies depending on the duration and severity of the disease. In the everyday care of patients with psoriasis in dermatological practice, the use of an interdisciplinary checklist for risk analysis and the initiation of professional follow-up care has proven valuable. On the basis of an existing checklist, the contents were critically evaluated by an interdisciplinary group of experts and a guideline-oriented update was prepared. In the opinion of the authors, the new analysis sheet represents a practicable, factually focused and updated tool for comorbidity risk assessment in patients with moderate and severe psoriasis.

Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.

Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardiometabolic health3. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate-protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure and induced 'browning' of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a 'replace me' signalling function that regulates thermogenic fat and counteracts obesity.

Contribution of Adipose Tissue Oxidative Stress to Obesity-Associated Diabetes Risk and Ethnic Differences: Focus on Women of African Ancestry.

Adipose tissue (AT) storage capacity is central in the maintenance of whole-body homeostasis, especially in obesity states. However, sustained nutrients overflow may dysregulate this function resulting in adipocytes hypertrophy, AT hypoxia, inflammation and oxidative stress. Systemic inflammation may also contribute to the disruption of AT redox equilibrium. AT and systemic oxidative stress have been involved in the development of obesity-associated insulin resistance (IR) and type 2 diabetes (T2D) through several mechanisms. Interestingly, fat accumulation, body fat distribution and the degree of how adiposity translates into cardio-metabolic diseases differ between ethnicities. Populations of African ancestry have a higher prevalence of obesity and higher T2D risk than populations of European ancestry, mainly driven by higher rates among African women. Considering the reported ethnic-specific differences in AT distribution and function and higher levels of systemic oxidative stress markers, oxidative stress is a potential contributor to the higher susceptibility for metabolic diseases in African women. This review summarizes existing evidence supporting this hypothesis while acknowledging a lack of data on AT oxidative stress in relation to IR in Africans, and the potential influence of other ethnicity-related modulators (e.g., genetic-environment interplay, socioeconomic factors) for consideration in future studies with different ethnicities.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Psychometric properties of the Patient Assessment of Chronic Illness Care measure (PACIC-5A) among patients with obesity.

BACKGROUND: The Patient Assessment of Chronic Illness Care (PACIC-5A) was developed to assess the satisfaction with patient-provider interaction based on the Chronic Care Model. The additional 5A approach (assess, advise, agree, assist, arrange) allows to score behavioral counseling. The aim of the study was to assess the psychometric properties of the German adaptation of the PACIC-5A questionnaire in a sample of general practitioners (GP) patients with obesity. METHODS: Analyses were based on data from the study "Five A's counseling in weight management of obese patients in primary care: a cluster randomized controlled trial (INTERACT)". Data were collected via standardized questionnaires containing the 26-item version of the PACIC-5A questionnaire. A total of 117 patients with obesity were included in the analyses. Statistical procedures comprised descriptive analyses, the calculation of Cronbach's alpha, test-retest analyses and factor analyses in order to assess the psychometric properties including reliability and validity of the PACIC-5A. RESULTS: The patient's mean age was 43.4 years and the sample was mostly female (59%). Middle educational level was found for the majority (78%) and the mean Body Mass Index was 38.9 kg/m2. Descriptive analyses revealed a mean PACIC score of 2.33 and 5A sum score of 2.29. Notable floor effects were found. PACIC-5A showed high level of internal consistency (Cronbach's alphas > 0.9) and exploratory factor analyses resulted in a unidimensional structure. CONCLUSION: The results of this study provide evidence regarding the psychometric properties of the German version of the PACIC-5A used in a sample of GP patients with obesity and make an important contribution to the reliable and valid assessment of the patient-GP interaction with regard to obesity counseling in primary care.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.

Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Effects of supervised vs non-supervised combined aerobic and resistance exercise programme on cardiometabolic risk factors.

OBJECTIVE: We examined the effect of a 6-month combined aerobic and resistance training programme on cardiometabolic risk factors in nondiabetic subjects and compared its effectiveness when executed under strict professional supervision or without direct supervision. METHODS: Eighty-five sedentary, non-diabetic subjects (27 men and 58 women), mean age 47.5 +/- 0.6 years, mean body mass index (BMI, 33.8 +/- 0.6 kg/m2) participated in a combined exercise programme assigned to supervised (S, n = 31), non-supervised (NS, n = 24) or control group (C, n = 30). Cardiometabolic risk parameters were assessed at baseline and after the 6-month training. RESULTS: In both the S and NS group there was a significant decrease in BMI (-1.6 +/- 0.3, p < 0.001 and -1.0 +/- 0.3 kg/m2, p = 0.004), waist circumference (-10.1 +/- 1.1 cm, p < 0.001 and -7.8 +/- 0.8 cm, p < 0.001), fat mass (-1.8 +/- 0.4%, p < 0.001 and -2.1 +/- 0.6%, p = 0.003), and a significant increase in fat-free mass (+1.7 +/- 0.4%, p < 0.001 and +2.0 +/- 0.7%, p = 0.008), and aerobic capacity (+6.9 +/- 1.1, p < 0.001 and +6.9 +/- 0.8 ml/kg per min, p = 0.008). Fasting glucose did not change in S and NS, but increased in C (p = 0.048). In the S group a significant decrease in fasting insulin (p < 0.001), homeostasis model assessment of insulin resistance (p < 0.001), highly sensitive C-reactive protein (p = 0.004), leucocytes count (p = 0.04), systolic high (p < 0.001) and diastolic (p = 0.009) blood pressure was found. Comparable significant decreases in total and low-density lipoprotein cholesterol were observed in all study groups. CONCLUSIONS: A 6-month combined exercise programme led to substantial improvement of various cardiometabolic risk factors. This programme was effective even when executed without direct supervision, although the effects were more pronounced in the supervised group. Our findings suggest that non-supervised exercise programmes may be a valuable, cost-effective tool to translate the current physical activity guidelines in a real-life setting.