A microbial transporter of the dietary antioxidant ergothioneine.

Low-molecular-weight (LMW) thiols are small-molecule antioxidants required for the maintenance of intracellular redox homeostasis. However, many host-associated microbes, including the gastric pathogen Helicobacter pylori, unexpectedly lack LMW-thiol biosynthetic pathways. Using reactivity-guided metabolomics, we identified the unusual LMW thiol ergothioneine (EGT) in H. pylori. Dietary EGT accumulates to millimolar levels in human tissues and has been broadly implicated in mitigating disease risk. Although certain microorganisms synthesize EGT, we discovered that H. pylori acquires this LMW thiol from the host environment using a highly selective ATP-binding cassette transporter-EgtUV. EgtUV confers a competitive colonization advantage in vivo and is widely conserved in gastrointestinal microbes. Furthermore, we found that human fecal bacteria metabolize EGT, which may contribute to production of the disease-associated metabolite trimethylamine N-oxide. Collectively, our findings illustrate a previously unappreciated mechanism of microbial redox regulation in the gut and suggest that inter-kingdom competition for dietary EGT may broadly impact human health.

Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood.

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.

Rewiring of the Fruit Metabolome in Tomato Breeding.

Humans heavily rely on dozens of domesticated plant species that have been further improved through intensive breeding. To evaluate how breeding changed the tomato fruit metabolome, we have generated and analyzed a dataset encompassing genomes, transcriptomes, and metabolomes from hundreds of tomato genotypes. The combined results illustrate how breeding globally altered fruit metabolite content. Selection for alleles of genes associated with larger fruits altered metabolite profiles as a consequence of linkage with nearby genes. Selection of five major loci reduced the accumulation of anti-nutritional steroidal glycoalkaloids in ripened fruits, rendering the fruit more edible. Breeding for pink tomatoes modified the content of over 100 metabolites. The introgression of resistance genes from wild relatives in cultivars also resulted in major and unexpected metabolic changes. The study reveals a multi-omics view of the metabolic breeding history of tomato, as well as provides insights into metabolome-assisted breeding and plant biology.

Identification of a Brainstem Circuit Controlling Feeding.

Hunger, driven by negative energy balance, elicits the search for and consumption of food. While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding-DRNVgat neurons increase, whereas DRNVGLUT3 neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding. These data establish the DRN as an important node controlling energy balance. PAPERCLIP.

Bringing dynamic molecular machines into focus by methyl-TROSY NMR.

Large macromolecular assemblies, so-called molecular machines, are critical to ensuring proper cellular function. Understanding how proper function is achieved at the atomic level is crucial to advancing multiple avenues of biomedical research. Biophysical studies often include X-ray diffraction and cryo-electron microscopy, providing detailed structural descriptions of these machines. However, their inherent flexibility has complicated an understanding of the relation between structure and function. Solution NMR spectroscopy is well suited to the study of such dynamic complexes, and continued developments have increased size boundaries; insights into function have been obtained for complexes with masses as large as 1 MDa. We highlight methyl-TROSY (transverse relaxation optimized spectroscopy) NMR, which enables the study of such large systems, and include examples of applications to several cellular machines. We show how this emerging technique contributes to an understanding of cellular function and the role of molecular plasticity in regulating an array of biochemical activities.

An integrative framework to prioritize genes in more than 500 loci associated with body mass index.

Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of genetic variants that influence body mass index (BMI), a commonly used metric to assess obesity risk. Most variants are non-coding and likely act through regulating genes nearby. Here, we apply multiple computational methods to prioritize the likely causal gene(s) within each of the 536 previously reported GWAS-identified BMI-associated loci. We performed summary-data-based Mendelian randomization (SMR), FINEMAP, DEPICT, MAGMA, transcriptome-wide association studies (TWASs), mutation significance cutoff (MSC), polygenic priority score (PoPS), and the nearest gene strategy. Results of each method were weighted based on their success in identifying genes known to be implicated in obesity, ranking all prioritized genes according to a confidence score (minimum: 0; max: 28). We identified 292 high-scoring genes (≥11) in 264 loci, including genes known to play a role in body weight regulation (e.g., DGKI, ANKRD26, MC4R, LEPR, BDNF, GIPR, AKT3, KAT8, MTOR) and genes related to comorbidities (e.g., FGFR1, ISL1, TFAP2B, PARK2, TCF7L2, GSK3B). For most of the high-scoring genes, however, we found limited or no evidence for a role in obesity, including the top-scoring gene BPTF. Many of the top-scoring genes seem to act through a neuronal regulation of body weight, whereas others affect peripheral pathways, including circadian rhythm, insulin secretion, and glucose and carbohydrate homeostasis. The characterization of these likely causal genes can increase our understanding of the underlying biology and offer avenues to develop therapeutics for weight loss.

Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin.

Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.

Antiracism and positive intergenerational (infant) outcomes: A county-level examination of low birth weight and infant mortality.

Racism is associated with negative intergenerational (infant) outcomes. That is, racism, both perceived and structural, is linked to critical, immediate, and long-term health factors such as low birth weight and infant mortality. Antiracism-resistance to racism such as support for the Black Lives Matter (BLM) movement-has been linked to positive emotional, subjective, and mental health outcomes among adults and adolescents. To theoretically build on and integrate such past findings, the present research asked whether such advantageous health correlations might extend intergenerationally to infant outcomes? It examined a theoretical/correlational process model in which mental and physical health indicators might be indirectly related to associations between antiracism and infant health outcomes. Analyses assessed county-level data that measured BLM support (indexed as volume of BLM marches) and infant outcomes from 2014 to 2020. As predicted, in the tested model, BLM support was negatively correlated with 1) low birth weight (Ncounties = 1,445) and 2) mortalities (Ncounties = 409) among African American infants. Given salient, intergroup, policy debates tied to antiracism, the present research also examined associations among White Americans. In the tested model, BLM marches were not meaningfully related to rates of low birth weight among White American infants (Ncounties = 2,930). However, BLM support was negatively related to mortalities among White American infants (Ncounties = 862). Analyses controlled for structural indicators of income inequality, implicit/explicit bias, voting behavior, prior low birth weight/infant mortality rates, and demographic characteristics. Theory/applied implications of antiracism being linked to nonnegative and positive infant health associations tied to both marginalized and dominant social groups are discussed.

Low-molecular weight inhibitors of the alternative complement pathway.

Dysregulation of the alternative complement pathway predisposes individuals to a number of diseases. It can either be evoked by genetic alterations in or by stabilizing antibodies to important pathway components and typically leads to severe diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. In addition, the alternative pathway may also be involved in many other diseases where its amplifying function for all complement pathways might play a role. To identify specific alternative pathway inhibitors that qualify as therapeutics for these diseases, drug discovery efforts have focused on the two central proteases of the pathway, factor B and factor D. Although drug discovery has been challenging for a number of reasons, potent and selective low-molecular weight (LMW) oral inhibitors have now been discovered for both proteases and several molecules are in clinical development for multiple complement-mediated diseases. While the clinical development of these inhibitors initially focuses on diseases with systemic and/or peripheral tissue complement activation, the availability of LMW inhibitors may also open up the prospect of inhibiting complement in the central nervous system where its activation may also play an important role in several neurodegenerative diseases.

Global patterns in excess body weight and the associated cancer burden.

The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2 -increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2 ) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6-fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high-income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy-dense, nutrient-poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low-income countries to 7% or 8% in some high-income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high-income countries and the increasing prevalence in low- and middle-income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.

Low molecular weight heparin promotes the PPAR pathway by protecting the glycocalyx of cells to delay the progression of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most important comorbidities for diabetic patients, which is the main factor leading to end-stage renal disease. Heparin analogs can delay the progression of DN, but the mechanism is not fully understood. In this study, we found that low molecular weight heparin therapy significantly upregulated some downstream proteins of the peroxisome proliferator-activated receptor (PPAR) signaling pathway by label-free quantification of the mouse kidney proteome. Through cell model verification, low molecular weight heparin can protect the heparan sulfate of renal tubular epithelial cells from being degraded by heparanase that is highly expressed in a high-glucose environment, enhance the endocytic recruitment of fatty acid-binding protein 1, a coactivator of the PPAR pathway, and then regulate the activation level of intracellular PPAR. In addition, we have elucidated for the first time the molecular mechanism of heparan sulfate and fatty acid-binding protein 1 interaction. These findings provide new insights into understanding the role of heparin in the pathogenesis of DN and developing corresponding treatments.

Improving resilience to high temperature in drought: water replenishment enhances sucrose and amino acid metabolisms in maize grain.

Heat stress poses a significant threat to maize, especially when combined with drought. Recent research highlights the potential of water replenishment to ameliorate grain weight loss. However, the mitigating mechanisms of heat in drought stress, especially during the crucial early grain-filling stage, remain poorly understood. We investigated the mechanism for mitigating heat in drought stress by water replenishment from the 12th to the 32nd days after silking in a controlled greenhouse experiment (Exp. I) and field trial (Exp. II). A significant reduction in grain weight was observed in heat stress compared to normal conditions. When water replenishment was applied to increase soil water content (SWC) under heat stress, the grain yield exhibited a notable increase ranging from 28.4 to 76.9%. XY335 variety was used for transcriptome sequencing to analyze starch biosynthesis and amino acid metabolisms in Exp. I. With water replenishment, the transcripts of genes responsible for trehalose 6-phosphate phosphates (TPP), alpha-trehalase (TRE), ADP-glcpyrophosphorylase, and starch synthase activity were stimulated. Additionally, the expression of genes encoding TPP and TRE contributed to an enhanced conversion of trehalose to glucose. This led to the conversion of sucrose from glucose-1-phosphate to ADP-glucose and ADP-glucose to amylopectin, ultimately increasing starch production by 45.1%. Water replenishment to boost SWC during heat stress also elevated the levels of essential amino acids in maize, including arginine, serine, tyrosine, leucine, glutamic acid, and methionine, providing valuable support to maize plants in adversity. Field trials further validated the positive impact of water replenishment on SWC, resulting in a notable increase in grain yield ranging from 7.1 to 9.2%. This study highlights the vital importance of adapting to abiotic stress and underscores the necessity of developing strategies to counteract its adverse effects on crop yield.

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Infection and transmission of SARS-CoV-2 depend on heparan sulfate proteoglycans.

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.

miR-7 is recruited to the high molecular weight RNA-induced silencing complex in CD8+ T cells upon activation and suppresses IL-2 signaling.

Increasing evidence suggests mammalian Argonaute (Ago) proteins partition into distinct complexes within cells, but there is still little biochemical or functional understanding of the miRNAs differentially associated with these complexes. In naïve T cells, Ago2 is found almost exclusively in low molecular weight (LMW) complexes which are associated with miRNAs but not their target mRNAs. Upon T-cell activation, a proportion of these Ago2 complexes move into a newly formed high molecular weight (HMW) RNA-induced silencing complex (RISC), which is characterized by the presence of the GW182 protein that mediates translational repression. Here, we demonstrate distinct partitioning of miRNAs and isomiRs in LMW versus HMW RISCs upon antigen-mediated activation of CD8+ T cells. We identify miR-7 as highly enriched in HMW RISC and demonstrate that miR-7 inhibition leads to increased production of IL-2 and up-regulation of the IL-2 receptor, the transferrin receptor, CD71 and the amino acid transporter, CD98. Our data support a model where recruitment of miR-7 to HMW RISC restrains IL-2 signaling and the metabolic processes regulated by IL-2.

MCANet: shared-weight-based MultiheadCrossAttention network for drug-target interaction prediction.

Accurate and effective drug-target interaction (DTI) prediction can greatly shorten the drug development lifecycle and reduce the cost of drug development. In the deep-learning-based paradigm for predicting DTI, robust drug and protein feature representations and their interaction features play a key role in improving the accuracy of DTI prediction. Additionally, the class imbalance problem and the overfitting problem in the drug-target dataset can also affect the prediction accuracy, and reducing the consumption of computational resources and speeding up the training process are also critical considerations. In this paper, we propose shared-weight-based MultiheadCrossAttention, a precise and concise attention mechanism that can establish the association between target and drug, making our models more accurate and faster. Then, we use the cross-attention mechanism to construct two models: MCANet and MCANet-B. In MCANet, the cross-attention mechanism is used to extract the interaction features between drugs and proteins for improving the feature representation ability of drugs and proteins, and the PolyLoss loss function is applied to alleviate the overfitting problem and the class imbalance problem in the drug-target dataset. In MCANet-B, the robustness of the model is improved by combining multiple MCANet models and prediction accuracy further increases. We train and evaluate our proposed methods on six public drug-target datasets and achieve state-of-the-art results. In comparison with other baselines, MCANet saves considerable computational resources while maintaining accuracy in the leading position; however, MCANet-B greatly improves prediction accuracy by combining multiple models while maintaining a balance between computational resource consumption and prediction accuracy.

Nutritional Challenges and Treatment After Bariatric Surgery.

Bariatric surgery is an important weight loss tool in individuals with severe obesity. It is currently the most effective long-term weight loss treatment that lowers obesity-related comorbidities. It also has significant physiological and nutritional consequences that can result in gastrointestinal complications and micronutrient deficiencies. After gastric bypass, clinical events that negatively affect nutritional status include malabsorption, dumping syndrome, kidney stones, altered intestinal bile acid availability, bowel obstruction, ulcers, gastroesophageal reflux, and bacterial overgrowth. Risk factors for poor nutritional status and excessive loss of lean body mass and bone include reduced dietary quality and inadequate intake, altered nutrient absorption, and poor patient compliance with nutrient supplementation. There are unique concerns in adolescents, older individuals, and individuals who become pregnant postoperatively. With careful management, health-care professionals can assist with long-term weight loss success and minimize the risk of acute and long-term nutrition complications after bariatric surgery.

Genetic distance and ancestry proportion modify the association between maternal genetic risk score of type 2 diabetes and fetal growth.

BACKGROUND: Maternal genetic risk of type 2 diabetes (T2D) has been associated with fetal growth, but the influence of genetic ancestry is not yet fully understood. We aimed to investigate the influence of genetic distance (GD) and genetic ancestry proportion (GAP) on the association of maternal genetic risk score of T2D (GRST2D) with fetal weight and birthweight. METHODS: Multi-ancestral pregnant women (n = 1,837) from the NICHD Fetal Growth Studies - Singletons cohort were included in the current analyses. Fetal weight (in grams, g) was estimated from ultrasound measurements of fetal biometry, and birthweight (g) was measured at delivery. GRST2D was calculated using T2D-associated variants identified in the latest trans-ancestral genome-wide association study and was categorized into quartiles. GD and GAP were estimated using genotype data of four reference populations. GD was categorized into closest, middle, and farthest tertiles, and GAP was categorized as highest, medium, and lowest. Linear regression analyses were performed to test the association of GRST2D with fetal weight and birthweight, adjusted for covariates, in each GD and GAP category. RESULTS: Among women with the closest GD from African and Amerindigenous ancestries, the fourth and third GRST2D quartile was significantly associated with 5.18 to 7.48 g (weeks 17-20) and 6.83 to 25.44 g (weeks 19-27) larger fetal weight compared to the first quartile, respectively. Among women with middle GD from European ancestry, the fourth GRST2D quartile was significantly associated with 5.73 to 21.21 g (weeks 18-26) larger fetal weight. Furthermore, among women with middle GD from European and African ancestries, the fourth and second GRST2D quartiles were significantly associated with 117.04 g (95% CI = 23.88-210.20, p = 0.014) and 95.05 g (95% CI = 4.73-185.36, p = 0.039) larger birthweight compared to the first quartile, respectively. The absence of significant association among women with the closest GD from East Asian ancestry was complemented by a positive significant association among women with the highest East Asian GAP. CONCLUSIONS: The association between maternal GRST2D and fetal growth began in early-second trimester and was influenced by GD and GAP. The results suggest the use of genetic GD and GAP could improve the generalizability of GRS.

Effects of repeated weight cycling on non-alcoholic steatohepatitis in diet-induced obese mice.

Lifestyle interventions remain the treatment of choice for patients with obesity and metabolic complications, yet are difficult to maintain and often lead to cycles of weight loss and regain (weight cycling). Literature on weight cycling remains controversial and we therefore investigated the association between weight cycling and metabolic complications using preexistent obese mice. Ldlr-/-.Leiden mice received a high-fat diet (HFD) for 20 weeks to induce obesity. Subsequently, weight-cycled mice were switched between the healthy chow diet and HFD for four 2-week periods and compared to mice that received HFD for the total study period. Repeated weight cycling tended to decrease body weight and significantly reduced fat mass, whereas adipose tissue inflammation was similar relative to HFD controls. Weight cycling did not significantly affect blood glucose or plasma insulin levels yet significantly reduced plasma free fatty acid and alanine transaminase/aspartate transaminase levels. Hepatic macrovesicular steatosis was similar and microvesicular steatosis tended to be increased upon weight cycling. Weight cycling resulted in a robust decrease in hepatic inflammation compared to HFD controls while hepatic fibrosis and atherosclerosis development were not affected. These results argue against the postulate that repeated weight cycling leads to unfavorable metabolic effects, when compared to a continuous unhealthy lifestyle, and in fact revealed beneficial effects on hepatic inflammation, an important hallmark of non-alcoholic steatohepatitis.

Weight management and physical activity throughout the cancer care continuum.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.