Adipose tissue NAD(+)-homeostasis, sirtuins and poly(ADP-ribose) polymerases - important players in mitochondrial metabolism and metabolic health

Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD(+)/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD(+) homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD(+) pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.Peer reviewe

Short Sleep Duration and Later Overweight in Infants

Objective To provide further knowledge about the longitudinal association between sleep duration and overweight in infants. Study design The data for this study are from the CHILD-SLEEP birth cohort (n = 1679). The sleep data are based on parent-reported total sleep duration collected at 3, 8, 18, and 24 months. For a subgroup of 8-month old participants (n = 350), an actigraph recording was also made. Growth data were derived from the child health clinic records. A logistic regression model was used to study the association between sleep duration and later weight development. Results Shorter sleep duration in 3-month-old infants was cross-sectionally associated with lower weight-for-length/height (all P values Conclusions Short total sleep duration at the age of 3 months and short night-time sleep duration at the age of 8 months are associated with the risk of gaining excess weight at 24 months of age.Peer reviewe

Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial

BACKGROUND: Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m^{2} or at least 27 kg/m^{2} with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants. FINDINGS: Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%). INTERPRETATION: Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. FUNDING: Novo Nordisk A/S

Abdominal obesity and circulating metabolites : A twin study approach

Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r(g)) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference >= 3 kg/m(2)). Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r(g) = 0.40), glycoprotein (r(g) = 0.37), serum triglycerides (r(g) = 0.36), BCAAs (r(g) = 0.30-0.40), HDL particle diameter (r(g) = -0.33) and HDL cholesterol (r(g) = -0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. (C) 2015 Elsevier Inc. All rights reserved.Peer reviewe

Association of Lipidome Remodeling in the Adipocyte Membrane with Acquired Obesity in Humans

The authors describe a new approach to studying cellular lipid profiles and propose a compensatory mechanism that may help maintain the normal membrane function of adipocytes in the context of obesity

Metabolic Signatures of Adiposity in Young Adults : Mendelian Randomization Analysis and Effects of Weight Change

Peer reviewe

Association between birthweight and later body mass index : an individual-based pooled analysis of 27 twin cohorts participating in the CODATwins project

Background: There is evidence that birthweight is positively associated with body mass index (BMI) in later life, but it remains unclear whether this is explained by genetic factors or the intrauterine environment. We analysed the association between birthweight and BMI from infancy to adulthood within twin pairs, which provides insights into the role of genetic and environmental individual-specific factors. Methods: This study is based on the data from 27 twin cohorts in 17 countries. The pooled data included 78 642 twin individuals (20 635 monozygotic and 18 686 same-sex dizygotic twin pairs) with information on birthweight and a total of 214 930 BMI measurements at ages ranging from 1 to 49 years. The association between birthweight and BMI was analysed at both the individual and within-pair levels using linear regression analyses. Results: At the individual level, a 1-kg increase in birthweight was linearly associated with up to 0.9 kg/m(2) higher BMI (P <0.001). Within twin pairs, regression coefficients were generally greater (up to 1.2 kg/m(2) per kg birthweight, P <0.001) than those from the individual-level analyses. Intra-pair associations between birthweight and later BMI were similar in both zygosity groups and sexes and were lower in adulthood. Conclusions: These findings indicate that environmental factors unique to each individual have an important role in the positive association between birthweight and later BMI, at least until young adulthood.Peer reviewe

Enhanced resolution profiling in twins reveals differential methylation signatures of type 2 diabetes with links to its complications

BackgroundType 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression. MethodsWe profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites. FindingsWe find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2). InterpretationThe results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications. FundingFunding acknowledgements for each cohort can be found in the Supplementary Note

Variability in energy expenditure is much greater in males than females

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction. (C) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe