Dietary fat and total energy intake modifies the association of genetic profile risk score on obesity: evidence from 48 170 UK Biobank participants

Background: Obesity is a multifactorial condition influenced by both genetics and lifestyle. The aim of this study was to investigate whether the association between a validated genetic profile risk score for obesity (GPRS-obesity) and body mass index (BMI) or waist circumference (WC) was modified by macronutrient intake in a large general population study. Methods: This study included cross-sectional data from 48 170 white European adults, aged 37–73 years, participating on the UK Biobank. Interactions between GPRS-obesity, and macronutrient intake (including total energy, protein, fat, carbohydrate and dietary fibre intake) and its effects on BMI and WC were investigated. Results: The 93-SNPs genetic profile risk score was associated with a higher BMI (β:0.57 kg.m−2 per standard deviation (s.d.) increase in GPRS, [95%CI:0.53–0.60]; P=1.9 × 10−183) independent of major confounding factors. There was a significant interaction between GPRS and total fat intake (P[interaction]=0.007). Among high fat intake individuals, BMI was higher by 0.60 [0.52, 0.67] kg.m−2 per s.d. increase in GPRS-obesity; the change in BMI with GPRS was lower among low fat intake individuals (β:0.50 [0.44, 0.57] kg.m-2). Significant interactions with similar patterns were observed for saturated fat intake (High β:0.66 [0.59, 0.73] versus Low β:0.49 [0.42, 0.55] kg.m-2, P-interaction=2 × 10-4), and total energy intake (High β:0.58 [0.51, 0.64] versus Low β:0.49 [0.42, 0.56] kg.m−2, P-interaction=0.019), but not for protein intake, carbohydrate intake and fiber intake (P-interaction >0.05). The findings were broadly similar using WC as the outcome. Conclusions: These data suggest that the benefits of reducing the intake of fats and total energy intake, may be more important in individuals with high genetic risk for obesity

Pathways for cross-boundary effects of biodiversity on ecosystem functioning

The biodiversity-ecosystem functioning concept asserts that processes in ecosystems are markedly influenced by species richness and other facets of biodiversity. However, biodiversity-ecosystem functioning studies have been largely restricted to single ecosystems, ignoring the importance of functional links - such as the exchange of matter, energy, and organisms - between coupled ecosystems. Here we present a basic concept and outline three pathways of cross boundary biodiversity effects on ecosystem processes and propose an agenda to assess such effects, focusing on terrestrial-aquatic linkages to illustrate the case. This cross-boundary perspective of biodiversity-ecosystem functioning relationships presents a promising frontier for biodiversity and ecosystem science with repercussions for the conservation, restoration, and management of biodiversity and ecosystems from local to landscape scales.Peer reviewe

Associations of the ‘weekend warrior’ physical activity pattern with all-cause, cardiovascular disease and cancer mortality: the Mexico City Prospective Study

Objectives: The objective was to investigate the benefits of the ‘weekend warrior’ physical activity pattern in Latin America, where many people take part in high levels of non-exercise physical activity. // Methods: Participants in the Mexico City Prospective Study were surveyed from 1998 to 2004 and resurveyed from 2015 to 2019. Those who exercised up to once or twice per week were termed weekend warriors. Those who exercised more often were termed regularly active. Analyses were adjusted for potential confounders. // Results: The main analysis included 26 006 deaths in 154 882 adults (67% female) aged 52±13 years followed for 18±4 years (mean±SD). Compared with those who reported no exercise, the HR (95% CI) was 0.88 (0.83 to 0.93) in the weekend warriors and 0.88 (0.84 to 0.91) in the regularly active. Similar results were observed for cardiovascular disease and cancer mortality, but associations were weaker. Stratified analyses showed that substantial reductions in all-cause mortality risk only occurred when the duration of exercise sessions was at least 30–60 min. The repeated-measures analysis included 843 deaths in 10 023 adults followed for 20±2 years. Compared with being inactive or becoming inactive, the HR was 0.86 (95% CI 0.65 to 1.12) when being a weekend warrior or becoming a weekend warrior and 0.85 (95% CI 0.70 to 1.03) when being regularly active or becoming regularly active. // Conclusions: This is the first prospective study to investigate the benefits of the weekend warrior physical activity pattern in Latin America. The results suggest that even busy adults could benefit from taking part in one or two sessions of exercise per week

Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling

Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship

The combination of physical activity and sedentary behaviors modifies the genetic predisposition to obesity

Objective: This study aimed to investigate whether the association between a validated genetic profile risk score for BMI (GPRS‐BMI) (based on 93 single‐nucleotide polymorphisms) and phenotypic obesity (BMI) was modified by the combined categories of physical activity (PA) and sedentary behaviors in a large population‐based study. Methods: This study included cross‐sectional baseline data from 338,216 white European adult men and women aged 37 to 73 years. Interaction effects of GPRS‐BMI with the combined categories of PA and sedentary behaviors on BMI were investigated. Results: There was a significant interaction between GPRS‐BMI and the combined categories of objectively measured PA and total sedentary behavior (P[interaction]  =  3.5 × 10−6); among physically inactive and highly sedentary individuals, BMI was higher by 0.60 kg/m2 per 1‐SD increase in GPRS‐obesity (P  =  8.9 × 10−50), whereas the relevant BMI difference was 38% lower among physically active individuals and those with low sedentary time (β: 0.37 kg/m2; P  =  2.3 × 10−51). A similar pattern was observed for the combined categories of objective PA and TV viewing (inactive/high TV viewing β: 0.60 vs. active/low TV viewing β: 0.40 kg/m2; P[interaction]  =  2.9 × 10−6). Conclusions: This study provides evidence that combined categories of PA and sedentary behaviors modify the extent to which genetic predisposition to obesity results in higher BMI

Do physical activity, commuting mode, cardiorespiratory fitness and sedentary behaviours modify the genetic predisposition to higher BMI? Findings from a UK Biobank study

Objective: To investigate whether the association between a genetic profile risk score for obesity (GPRS-obesity) (based on 93 SNPs) and body mass index (BMI) was modified by physical activity (PA), cardiorespiratory fitness, commuting mode, walking pace and sedentary behaviours. Methods: For the analyses we used cross-sectional baseline data from 310,652 participants in the UK Biobank study. We investigated interaction effects of GPRS-obesity with objectively measured and self-reported PA, cardiorespiratory fitness, commuting mode, walking pace, TV viewing, playing computer games, PC-screen time and total sedentary behaviour on BMI. Body mass index (BMI) was the main outcome measure. Results: GPRS-obesity was associated with BMI (β:0.54 kg.m−2 per standard deviation (SD) increase in GPRS, [95% CI: 0.53; 0.56]; P = 2.1 × 10−241). There was a significant interaction between GPRS-obesity and objectively measured PA (P[interaction] = 3.3 × 10−11): among inactive individuals, BMI was higher by 0.58 kg.m−2 per SD increase in GPRS-obesity (p = 1.3 × 10−70) whereas among active individuals the relevant BMI difference was less (β:0.33 kg.m−2, p = 6.4 × 10−41). We observed similar patterns for fitness (Unfit β:0.72 versus Fit β:0.36 kg.m−2, P[interaction] = 1.4 × 10−11), walking pace (Slow β:0.91 versus Brisk β:0.38 kg.m−2, P[interaction] = 8.1 × 10−27), discretionary sedentary behaviour (High β:0.64 versus Low β:0.48 kg.m−2, P[interaction] = 9.1 × 10−12), TV viewing (High β:0.62 versus Low β:0.47 kg.m−2, P[interaction] = 1.7 × 10−11), PC-screen time (High β:0.82 versus Low β:0.54 kg.m−2, P[interaction] = 0.0004) and playing computer games (Often β:0.69 versus Low β:0.52 kg.m−2, P[interaction] = 8.9 × 10−10). No significant interactions were found for commuting mode (car, public transport, active commuters). Conclusions: Physical activity, sedentary behaviours and fitness modify the extent to which a set of the most important known adiposity variants affect BMI. This suggests that the adiposity benefits of high PA and low sedentary behaviour may be particularly important in individuals with high genetic risk for obesity

Extensive RPA2 hyperphosphorylation promotes apoptosis in response to DNA replication stress in CHK1 inhibited cells

The replication protein A (RPA)-ssDNA complex formed at arrested replication forks recruits key proteins to activate the ATR-CHK1 signalling cascade. When CHK1 is inhibited during DNA replication stress, RPA2 is extensively hyperphosphorylated. Here, we investigated the role of RPA2 hyperphosphorylation in the fate of cells when CHK1 is inhibited. We show that proteins normally involved in DNA repair (RAD51) or control of RPA phosphorylation (the PP4 protein phosphatase complex) are not recruited to the genome after treatment with CHK1 and DNA synthesis inhibitors. This is not due to RPA2 hyperphosphorylation as suppression of this response does not restore loading suggesting that recruitment requires active CHK1. To determine whether RPA2 hyperphosphorylation protects stalled forks from collapse or induction of apoptosis in CHK1 inhibited cells during replication stress, cells expressing RPA2 genes mutated at key phosphorylation sites were characterized. Mutant RPA2 rescued cells from RPA2 depletion and reduced the level of apoptosis induced by treatment with CHK1 and replication inhibitors however the incidence of double strand breaks was not affected. Our data indicate that RPA2 hyperphosphorylation promotes cell death during replication stress when CHK1 function is compromised but does not appear to be essential for replication fork integrity

Exploring the underlying mechanisms linking adiposity and cardiovascular disease: a prospective cohort study of 404,332 UK Biobank participants

Background and Aims Obesity is causally associated with multiple cardiovascular outcomes but effective population measure to control obesity is limited. This study aims to decipher to which extent excess atherosclerotic cardiovascular diseases (ASCVD) and heart failure (HF) risk due to obesity can be explained by conventional risk factors. Methods This is a prospective cohort study of 404,332 White UK Biobank participants. Participants with prior CVDs or other chronic diseases at baseline, or body mass index (BMI) <18·5 kg/m2 were excluded. Data were collected at the baseline assessment between 2006 and 2010. Linkage to death registrations and hospital admission records was used to ascertain ASCVD and HF outcomes up to late 2021. Obesity was defined as BMI ≥30 kg/m2. Candidate mediators included lipids, blood pressure, glycated haemoglobin (HbA1c), and liver and kidney function markers, which were chosen based on clinical trials and Mendelian randomisation studies. Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CIs). Mediation analysis based on g-formula was used to separately estimate the relative importance of mediators for ASCVD and HF. Results Compared with people without obesity, obese people had an increased risk of ASCVD (HR 1.30, 95% CI 1.26–1.35) and HF (HR 2.04, 95% CI 1.96–2.13) after adjusting for sociodemographic and lifestyle factors and medications for cholesterol, blood pressure and insulin. The strongest mediators for ASCVD were renal function (eGFR: mediation proportion: 44.6%), blood pressure (SBP: 24.4%; DBP: 31.1%), triglycerides (19.6%), and hyperglycaemia (HbA1c 18.9%). These mediators collectively explained more excess risk of ASCVD than that of HF. Conclusions Interventions that help obese individuals to maintain healthy lipid concentrations, blood pressure, glycaemic control and kidney function could potentially alleviate a sizable proportion of the ASCVD burden. However, HF burden could not be meaningfully reduced without weight management

Plant Species Loss Affects Life-History Traits of Aphids and Their Parasitoids

The consequences of plant species loss are rarely assessed in a multi-trophic context and especially effects on life-history traits of organisms at higher trophic levels have remained largely unstudied. We used a grassland biodiversity experiment and measured the effects of two components of plant diversity, plant species richness and the presence of nitrogen-fixing legumes, on several life-history traits of naturally colonizing aphids and their primary and secondary parasitoids in the field. We found that, irrespective of aphid species identity, the proportion of winged aphid morphs decreased with increasing plant species richness, which was correlated with decreasing host plant biomass. Similarly, emergence proportions of parasitoids decreased with increasing plant species richness. Both, emergence proportions and proportions of female parasitoids were lower in plots with legumes, where host plants had increased nitrogen concentrations. This effect of legume presence could indicate that aphids were better defended against parasitoids in high-nitrogen environments. Body mass of emerged individuals of the two most abundant primary parasitoid species was, however, higher in plots with legumes, suggesting that once parasitoids could overcome aphid defenses, they could profit from larger or more nutritious hosts. Our study demonstrates that cascading effects of plant species loss on higher trophic levels such as aphids, parasitoids and secondary parasitoids begin with changed life-history traits of these insects. Thus, life-history traits of organisms at higher trophic levels may be useful indicators of bottom-up effects of plant diversity on the biodiversity of consumers