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.

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.

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.

Differences in Gut Microbiota and Metabolites between Wrestlers with Varying Pre-Competition Weight Control Effect.

This study intended to analyze the effects of body weight control by the diet, training adaptation, gut microbiota metabolites of wrestlers in the week leading up to competition. According to the weight difference of wrestlers from the target weight one week prior to the competition, those whose weight control effectiveness is less than 2 kg were classified as the CW group, while more than 2 kg were classified as the CnW group. The body weight, body composition and diet of wrestlers were recorded; urine samples were taken for standard urine testing, and stool samples were collected for the analysis of gut microbiota and metabolites. The data showed that the relative values of carbohydrate and fat energy in the CnW group were significantly higher than those of the CW group, but the relative values of protein energy was significantly lower. The white blood cells, occult blood, and protein appeared in urine in the CnW group. The microbiota with higher abundance values in the CnW group were positively correlated with the relative value of carbohydrate energy, while the abundance value of Streptococcus was negatively correlated; and the functional prediction of differential bacteria was related to riboflavin and selencompound metabolism. The differential metabolites of CW/CnW group were functionally enriched in the processes of lipid and amino acid metabolism. Overall, the extent of weight control in wrestlers was correlated with sensible dietary patterns, adaptability to training load, and distinct gut microbiota and metabolites.

Elucidation of the genetic determination of body weight and size in Chinese local chicken breeds by large-scale genomic analyses.

BACKGROUND: Body weight and size are important economic traits in chickens. While many growth-related quantitative trait loci (QTLs) and candidate genes have been identified, further research is needed to confirm and characterize these findings. In this study, we investigate genetic and genomic markers associated with chicken body weight and size. This study provides new insights into potential markers for genomic selection and breeding strategies to improve meat production in chickens. METHODS: We performed whole-genome resequencing of and Wenshang Barred (WB) chickens (n = 596) and three additional breeds with varying body sizes (Recessive White (RW), WB, and Luxi Mini (LM) chickens; (n = 50)). We then used selective sweeps of mutations coupled with genome-wide association study (GWAS) to identify genomic markers associated with body weight and size. RESULTS: We identified over 9.4 million high-quality single nucleotide polymorphisms (SNPs) among three chicken breeds/lines. Among these breeds, 287 protein-coding genes exhibited positive selection in the RW and WB populations, while 241 protein-coding genes showed positive selection in the LM and WB populations. Genomic heritability estimates were calculated for 26 body weight and size traits, including body weight, chest breadth, chest depth, thoracic horn, body oblique length, keel length, pelvic width, shank length, and shank circumference in the WB breed. The estimates ranged from 0.04 to 0.67. Our analysis also identified a total of 2,522 genome-wide significant SNPs, with 2,474 SNPs clustered around two genomic regions. The first region, located on chromosome 4 (7.41-7.64 Mb), was linked to body weight after ten weeks and body size traits. LCORL, LDB2, and PPARGC1A were identified as candidate genes in this region. The other region, located on chromosome 1 (170.46-171.53 Mb), was associated with body weight from four to eighteen weeks and body size traits. This region contained CAB39L and WDFY2 as candidate genes. Notably, LCORL, LDB2, and PPARGC1A showed highly selective signatures among the three breeds of chicken with varying body sizes. CONCLUSION: Overall this study provides a comprehensive map of genomic variants associated with body weight and size in chickens. We propose two genomic regions, one on chromosome 1 and the other on chromosome 4, that could helpful for developing genome selection breeding strategies to enhance meat yield in chickens.

Improvement in insulin sensitivity after switching from an integrase inhibitor-based regimen to doravirine/tenofovir disoproxil fumarate/lamivudine in people with significant weight gain.

OBJECTIVES: We performed an observational, retrospective, cohort study to assess changes in insulin sensitivity after a switch from dolutegravir/lamivudine (DOL/3TC) or bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) to doravirine/tenofovir disoproxil fumarate/3TC (DOR/TDF/3TC) in virologically suppressed people living with HIV with recent significant weight gain. METHODS: All non-diabetic patients with HIV treated with DOL/3TC or BIC/F/TAF for ≥12 months, with HIV RNA <20 copies/mL, and with a weight increase ≥3 kg in the last year, who underwent a switch to DOR/TDF/3TC were enrolled into the study. Serum levels of glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were evaluated every 6 months during a 12-month follow-up. RESULTS: Overall, 81 patients were enrolled: 41 were treated with DOL/3TC and 40 with BIC/F/TAF. At baseline, median HOMA-IR index was 3.18 and insulin resistance (HOMA-IR index >2.5) was present in 49 subjects (60%). At 12 months after the switch to DOR/TDF/3TC, change in mean serum glucose concentration was not significant, but the reduction in median concentration of insulin was significant (-3.54 mcrUI/L [interquartile range -4.22 to -2.87]; p = 0.012), associated with a significant reduction in mean HOMA-IR index (-0.54 [interquartile range -0.91 to -0.18]; p = 0.021). A significant reduction in total and low-density lipoprotein cholesterol was also reported, whereas decreases in mean body weight and mean body mass index were not significant. CONCLUSIONS: In our retrospective study in virologically suppressed people living with HIV treated with DOL/3TC or BIC/F/TAF and with recent weight gain, the switch to DOR/TDF/3TC led to a significant improvement in insulin sensitivity and plasma lipids, with a trend to decreased body weight.

Switch to a raltegravir-based antiretroviral regimen in people with HIV and non-alcoholic fatty liver disease: A randomized controlled trial.

INTRODUCTION: The effect of antiretroviral therapy (ART), particularly integrase strand transfer inhibitors (INSTIs), on non-alcoholic fatty liver disease (NAFLD) in people with HIV remains unclear. We evaluated the effect of switching non-INSTI backbone antiretroviral medications to raltegravir on NAFLD and metabolic parameters. MATERIALS AND METHODS: This was a single-centre, phase IV, open-label, randomized controlled clinical trial. People living with HIV with NAFLD and undetectable viral load while receiving a non-INSTI were randomized 1:1 to the switch arm (raltegravir 400 mg twice daily) or the control arm (continuing ART regimens not containing INSTI). NAFLD was defined as hepatic steatosis by controlled attenuation parameter ≥238 dB/m in the absence of significant alcohol use and viral hepatitis co-infections. Cytokeratin 18 was used as a biomarker of non-alcoholic steatohepatitis. Changes over time in outcomes were quantified as standardized mean differences (SMDs), and a generalized linear mixed model was used to compare outcomes between study arms. RESULTS: A total of 31 people with HIV (mean age 54 years, 74% male) were randomized and followed for 24 months. Hepatic steatosis improved between baseline and end of follow-up in both the switch (SMD -43.4 dB/m) and the control arm (-26.6 dB/m); the difference between arms was not significant. At the end of follow-up, aspartate aminotransferase significantly decreased in the switch arm compared with the control arm (SMD -9.4 vs. 5.5 IU/L). No changes in cytokeratin 18, body mass index, or lipids were observed between study arms. DISCUSSION: Switching to a raltegravir-based regimen improved aspartate aminotransferase but seemed to have no effect on NAFLD, body weight, and lipids compared with remaining on any other ART.

Association Between Changes in Skeletal Muscle Quality and Prognosis in Postoperative Patients with Early Gastric Cancer.

BACKGROUND: Identifying accurate prognostic factors is crucial for postoperative management of early gastric cancer (EGC) patients. Skeletal muscle quality (SMQ), defined by muscle density on computed tomography (CT) images, has been proposed as a novel prognostic factor. This study compared the prognostic significance of SMQ changes with the well-established factor of body weight (BW) loss in the postoperative EGC setting. METHODS: This single-center retrospective study included 297 postoperative EGC patients (median age 69 years, 68.4% male) who had preoperative and 1-year-postoperative gastrectomy CT images. SMQ was defined as the modified intramuscular adipose tissue content (mIMAC = skeletal muscle density-subcutaneous fat density on CT images) and the change as ΔmIMAC. Log-rank test, Kaplan-Meier survival, and Cox proportional hazards regression analyses were used to assess the associations between prognosis and either ΔmIMAC or BW change (ΔBW). Prognosis prediction by ΔmIMAC and ΔBW was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: ΔmIMAC was significantly associated with prognosis (log-rank test; P = 0.037), but ΔBW was not (P = 0.243). Prognosis was significantly poorer in the severely decreased mIMAC group than in the preserved group (multivariate Cox proportional hazards regression analysis; P = 0.030) but was unaffected by BW changes (P = 0.697). The AUC indicated a higher prognostic value for ΔmIMAC than ΔBW (ΔmIMAC: AUC = 0.697, ΔBW: AUC = 0.542). CONCLUSIONS: One-year post-gastrectomy SMQ changes may be better prognostic EGC predictors than BW changes.

Development of disease-specific growth charts for Korean children with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an epigenetic overgrowth syndrome. Despite its distinctive growth pattern, the detailed growth trajectories of children with BWS remain largely unknown. We retrospectively analyzed 413 anthropometric measurements over an average of 4.4 years of follow-up in 51 children with BWS. We constructed sex-specific percentile curves for height, weight, and head circumference using a generalized additive model for location, scale, and shape. Males with BWS exhibited greater height at all ages evaluated, weight before the age of 10, and head circumference before the age of 9 than those of the general population. Females with BWS showed greater height before the age of 7, weight before the age of 4.5, and head circumference before the age of 7 than those of the general population. At the latest follow-up visit at a mean 8.4 years of age, bone age was significantly higher than chronological age. Compared to paternal uniparental disomy (pUPD), males with imprinting center region 2-loss of methylation (IC2-LOM) had higher standard deviation score (SDS) for height and weight, while females with IC2-LOM showed larger SDS for head circumference. These disease-specific growth charts can serve as valuable tools for clinical monitoring of children with BWS.

Peripheral blood stem cell harvesting in young children weighing less than 15 kg.

Autologous peripheral blood stem cell (PBSC) transplantation is crucial in pediatric cancer treatment, and tandem transplantation is beneficial in certain malignancies. Collecting PBSCs in small children with low body weight is challenging. We retrospectively analyzed data of pediatric cancer patients weighing <15 kg who underwent autologous PBSC harvesting in our hospital. Collections were performed in the pediatric intensive care unit over 2 or 3 consecutive days, to harvest sufficient stem cells (goal ≥2 × 106 CD34+ cells/kg per apheresate). From April 2006 to August 2021, we performed 129 collections after 50 mobilizations in 40 patients, with a median age of 1.9 (range, 0.6-5.6) years and a body weight of 11.0 (range, 6.6-14.7) kg. The median CD34+ cells in each apheresate were 4.2 (range, 0.01-40.13) × 106/kg. 78% and 56% of mobilizations achieved sufficient cell dose for single or tandem transplantation, respectively, without additional aliquoting. The preapheresis hematopoietic progenitor cell (HPC) count was highly correlated with the CD34+ cell yield in the apheresate (r = 0.555, P < 0.001). Granulocyte colony-stimulating factor alone was not effective for mobilization in children ≥2 years of age, even without radiation exposure. By combining the preapheresis HPC count ≥20/µL and the 3 significant host factors, including age <2 years, no radiation exposure and use of chemotherapy, the prediction rate of goal achievement was increased (area under the curve 0.787).

Mitigating SUV uncertainties using total body PET imaging.

PURPOSE: Standardised uptake values (SUV) are commonly used to quantify 18F-FDG lesion uptake. However, SUVs may suffer from several uncertainties and errors. Long-axial field-of-view (LAFOV) PET/CT systems might enable image-based quality control (QC) by deriving 18F-FDG activity and weight from total body (TB) 18F-FDG PET images. In this study, we aimed to develop these image-based QC to reduce errors and mitigate SUV uncertainties. METHODS: Twenty-five out of 81 patient scans from a LAFOV PET/CT system were used to determine regression fits for deriving of image-derived activity and weight. Thereafter, the regression fits were applied to 56 independent 18F-FDG PET scans from the same scanner to determine if injected activity and weight could be obtained accurately from TB and half-body (HB) scans. Additionally, we studied the impact of image-based values on the precision of liver SUVmean and lesion SUVpeak. Finally, 20 scans were acquired from a short-axial field-of-view (SAFOV) PET/CT system to determine if the regression fits also applied to HB scans from a SAFOV system. RESULTS: Both TB and HB 18F-FDG activity and weight significantly predicted reported injected activity (r = 0.999; r = 0.984) and weight (r = 0.999; r = 0.987), respectively. After applying the regression fits, 18F-FDG activity and weight were accurately derived within 4.8% and 3.2% from TB scans and within 4.9% and 3.1% from HB, respectively. Image-derived values also mitigated liver and lesion SUV variability compared with reported values. Moreover, 18F-FDG activity and weight obtained from a SAFOV scanner were derived within 6.7% and 4.5%, respectively. CONCLUSION: 18F-FDG activity and weight can be derived accurately from TB and HB scans, and image-derived values improved SUV precision and corrected for lesion SUV errors. Therefore, image-derived values should be included as QC to generate a more reliable and reproducible quantitative uptake measurement.

The Concentration of Liver-Expressed Antimicrobial Peptide 2 in Human Milk and Infant Plasma Is Positively Associated with Adiposity and Body Weight in the First Year of Life.

BACKGROUND: The liver-expressed antimicrobial peptide 2 (LEAP2) is a recently recognized anorectic and glucose-regulating hormone with an unknown role in lactation. OBJECTIVES: The objectives of this study were as follows: 1) to assess LEAP2 presence in human milk and putative associations with infant body weight and adiposity in the first year of life, 2) to evaluate the impact of maternal weight status on LEAP2 concentration, and 3) to explore the relationship between infant plasma LEAP2 concentration and body weight and adiposity. METHODS: This prospective cohort observational study assessed LEAP2 concentration in plasma and milk from lactating women with normal weight (n = 26) or overweight or obesity (OW/OB, n = 26) at 6 mo postpartum and in 6-mo-old infant plasma, examining associations with metabolic and anthropometric variables at 6 mo and 1 y. Maternal plasma and milk leptin and insulin concentrations were also measured. LEAP2 expression in milk fat globules and single-cell-RNA-sequencing datasets was evaluated. RESULTS: LEAP2 was detected in all milk samples assessed (2.08 ± 0.65 ng/mL) and was positively associated with infant triceps (P = 0.022, Cohen f2 = 1.25) and subscapular (P = 0.008, f2 = 0.68) skinfolds at 1 y old. Maternal LEAP2 was positively associated with insulin (P = 0.005, f2 = 0.30) and prepregnancy body mass index (BMI) (P = 0.040, f2 = 0.17) and negatively associated with gestational weight gain (P = 0.008, f2 = 0.25) and postpartum weight retention (P = 0.036, f2 = 0.15). Maternal LEAP2 was higher in plasma (P = 0.039), but not milk of lactating women with OW/OB. Infant plasma LEAP2 (1.98 ± 0.28 ng/mL) was positively associated with weight (P = 0.004, f2 = 0.63), BMI (P = 0.049, f2 = 0.37), and weight-for-length (P = 0.024, f2 = 0.35) z-scores at 1 y old, predominantly in males. No evidence for LEAP2 mRNA expression was found in mammary cells. CONCLUSIONS: Milk LEAP2 is a bioactive component that plays a role in infant fat accretion in the first year of life. Although maternal LEAP2 responds to weight change in pregnancy and lactation, infant plasma LEAP2 might be involved in body weight regulation in early life. This trial was registered at clinicaltrials.gov as NCT05798676.

Glutamatergic melanocortin-4 receptor neurons regulate body weight.

The locus coeruleus (LC), enriched in vesicular glutamate transporter 2 (VGlut2) neurons, is a potential homeostasis-regulating hub. However, the identity of melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus (PVN) of the hypothalamus, PVNVGlut2::MC4R and LCVGlut2::MC4R regulation of body weight, and axonal projections of LCVGlut2 neurons remain unclear. Conditional knockout of MC4R in chimeric mice was used to confirm the effects of VGlut2. Interscapular brown adipose tissue was injected with pseudorabies virus to study the central nervous system projections. We mapped the LCVGlut2 circuitry. Based on the Cre-LoxP recombination system, specific knockdown of MC4R in VGlut2 neurons resulted in weight gain in chimeric mice. Adeno-associated virus-mediated knockdown of MC4R expression in the PVN and LC had potential superimposed effects on weight gain, demonstrating the importance of VGlut2 neurons. Unlike these wide-ranging efferent projections, the PVN, hypothalamic arcuate nucleus, supraoptic nucleus of the lateral olfactory tegmental nuclei, and nucleus tractus solitarius send excitatory projections to LCVGlut2 neurons. The PVN → LC glutamatergic MC4R long-term neural circuit positively affected weight management and could help treat obesity.

Short-Term Efficacy of Cerebello-spinal tDCS and Body Weight-Supported Treadmill Training in the Hypertrophic Olivary Degeneration: a Rare Case Report.

The present case study reported a patient diagnosed with hypertrophic olivary degeneration, a rare condition characterized by a trans-neuronal degeneration and signal enhancement in T2-weighted images on magnetic resonance imaging, usually caused by cerebral hemorrhage, cerebral infarction, and trauma. Furthermore, the relevant literature review was performed. The existing pharmacological treatment has limited clinical benefits on the patient. Since spontaneous remission hardly occurs in the disease, there are no other effective treatments. In this case, the patient was a 55-year-old Chinese male who presented progressive gait difficulty for several months due to both-sided ataxia. Neurological examination revealed upper extremity and lower limb bilateral spasticity, ataxia, slurred speech, and dysmetria. Therefore, our study treated the patient through the inventive application of cerebello-spinal transcranial direct current stimulation and body weight-supported treadmill training. After a 4-week treatment, the patient could walk independently, without aid, speeding up by 7%, as well as the ataxia symptoms, and balance has improved significantly. It was demonstrated in this case report that the combination of cerebello-spinal tDCS and body weight-supported treadmill training can be an effective treatment for patients with Hypertrophic olivary degeneration.

The Critical Role of Physical Activity and Weight Management in Knee and Hip Osteoarthritis: A Narrative Review.

Physical activity (PA) and weight management are critical components of an effective knee and hip osteoarthritis (OA) management plan, yet most people with OA remain insufficiently active and/or overweight. Clinicians and their care teams play an important role in educating patients with OA about PA and weight management, eliciting patient motivation to engage in these strategies, and referring patients to appropriate self-management interventions. The purpose of this review is to educate clinicians about the current public health and clinical OA guidelines for PA and weight management and highlight a variety of evidence-based self-management interventions available in community and clinical settings and online.

Adolescent health-risk behaviours in Uruguay: Patterns from national cross-sectional school surveys conducted in 2006, 2012 and 2019.

BACKGROUND: There are no trend studies on various health risk behaviours among adolescents in Uruguay. Therefore, this study looked at trends in a number of health-risky behaviours among adolescents in Uruguay from three separate surveys. METHODS: Data from 9272 adolescents (age range: 11-16 years), who took part in three cross-sectional national in-school surveys in Uruguay in 2006, 2012 and 2019 were analysed. A self-administered survey was used to evaluate 24 health risk behaviours. By using logistic regression analyses to treat the study year as a categorical variable and adjusting food insecurity and age, linear trends were examined. RESULTS: We found a significant increase in the prevalence of being overweight, having obesity, inadequate fruit intake, sedentary behaviour in leisure-time, physical inactivity, bullying victimisation, loneliness, suicidal ideation, and sexual activity. We found a significant decrease in current cigarette use, physical fighting and current alcohol use. Among males, a significant increase of non-condom use, and a decrease in current other tobacco use (other than cigarettes), being physically attacked and the number of sexual partners. Among females, we found an increase in food insecurity, trouble from alcohol use, multiple sexual partners, and sleep problems. CONCLUSION: Overall, from 2006 to 2019, there was a decrease in seven health risk behaviours among boys and/or girls. Among boys, there was an increase in 10 health risk behaviours and among girls, 15 health risk behaviours increased, highlighting adolescent girls' greater vulnerability, thereby perpetuating further gendered health inequalities. In Uruguay, school health programmes for adolescents are recommended.

Tirzepatide as an innovative treatment strategy in a pre-clinical model of obesity-driven endometrial cancer.

OBJECTIVE: Interventions that combat obesity and its associated metabolic perturbations may decrease incidence and improve outcomes of endometrial cancer (EC). Potential options for weight loss include pharmacotherapeutic interventions such as tirzepatide, a dual-acting glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist. Given this, we explored the anti-obesity and anti-tumorigenic effects of tirzepatide in our pre-clinical mouse model of endometrioid EC. METHODS: Starting at 4 weeks of age, Lkb1fl/flp53fl/fl mice were fed a low-fat diet vs a high-fat diet to generate a lean or obese phenotype. Nine weeks after induction of EC, obese and lean mice were randomized to receive tirzepatide for 4 weeks. Body and tumor weights, tumor transcriptomic and metabolomic profiles, and serum metabolic markers and chemokines were assessed. RESULTS: Both obese and lean mice began to lose body weight after 2 weeks of tirzepatide treatment, ultimately achieving a significant weight loss of 20.1 % in obese mice and 16.8 % in lean mice. Tirzepatide improved obesity-induced serum adiponectin, leptin, GIP, and C-reactive protein levels. Furthermore, tirzepatide relative to vehicle, effectively reduced tumor growth in obese and lean mice, inhibited the ErbB signaling and glycolysis/gluconeogenesis in tumors of obese mice, and increased O-linked glycosylation biosynthesis and phospholipase D signaling in tumors of lean mice. CONCLUSION: Tirzepatide decreased both mouse weight and tumor growth via effects on metabolic and immune pathways in the EC tumors that differed between obese and lean mice. This novel weight loss treatment deserves further evaluation as an innovative strategy in the management of EC.

Effect of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, and associated metabolic comorbidities: A systematic review.

BACKGROUND AND AIMS: The beneficial effect of Hepatitis C virus (HCV) eradication by direct antiviral agents (DAAs) on liver fibrosis is well defined. Despite this, the impact of viral eradication in both hepatic and extra-hepatic metabolic features is underreached. This systematic review aimed to synthesize the evidence on the impact of HCV eradication by DAAs on liver steatosis, carotid atherosclerosis, glucidic impairment, dyslipidaemia, and weight gain. METHODS: A systematic search of the existing literature (up to December 2022) identified 97 original studies that fulfilled the inclusion criteria. RESULTS: Whereas total cholesterol and low-density lipoprotein (LDL) seem to increase after viral eradication, the cardiovascular damage expressed as carotid plaques and intima-media thickness seems to improve. Otherwise, the effect on liver steatosis, glucidic homeostasis, and weight seems to be strictly dependent on the presence of baseline metabolic disorders. CONCLUSION: Despite high heterogeneity and relatively short follow-up of included studies, we can conclude that the presence of metabolic risk factors should be strictly evaluated due to their impact on liver steatosis, glucidic and lipid homeostasis, and on weight gain to better identify patients at risk of liver disease progression despite the virus eradication.

An increasing proportion of the population is not covered by the current RDA for vitamin C - interrogation of EPIC-Norfolk and NHANES 2017/2018 cohorts.

With the rising prevalence of obesity globally, increasing proportions of the population may not be covered by current recommended daily allowances (RDAs) that are supposed to provide 97.5% of the population with a sufficient nutrient status but are typically based on a healthy young 70 kg male reference person. Using the EPIC-Norfolk (UK) and the NHANES (US) cohorts, we estimated the effect of body weight on the dose-concentration relationship to derive weight-based requirements to achieve an 'adequate' plasma concentration of vitamin C estimated to be 50 µmol/L. Inverse correlations between body weight and vitamin C were observed in both cohorts (p < 0.0001). Moreover, only about 2/3 of the cohorts achieved an adequate plasma vitamin C status by consuming the RDA or above, while only 1/3 to 1/2 of the cohorts achieved adequacy by an intake of the local RDA ± 10%. Using vitamin C as an example, the present data demonstrate that a considerable and expectedly increasing proportion of the world population is unable to achieve an adequate target plasma concentration with the current recommended daily intakes of vitamin C. This needs to be considered in future public health recommendations.

In this paper, we highlight the inverse association between body weight and vitamin C status. Our study strongly suggests that a large proportion of the population is not covered by the current recommended intakes of vitamin C.

Counting hours or calories? Metabolic regulatory role of time-restricted eating in adults with overweight and obesity: a systematic review and meta-analysis.

Time-restricted eating (TRE) effectively improves healthspan, including controlling obesity and improving metabolic health. To date, few meta-analyses have been conducted to explore the effects of various protocols of TRE in participants with overweight/obesity. PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched up until October 15, 2022. Randomized and non-randomized clinical trials that investigated the effect of TRE on body weight, body composition and cardiometabolic parameters in participants with overweight/obesity were included. Mean differences of changes from the baseline were used for all analyses between the two groups. Prespecified subgroup analyses based on different protocols of TRE were performed. Twenty-three studies were included in the meta-analysis with 1867 participants. TRE interventions led to significant changes in body weight. When energy restriction strategies were conducted in both the TRE and control groups, the weight-loss effect of TRE remained significant. TRE with 4 ∼ 8h feeding window, morning or late eating strategies, led to reduction in body weight and fat mass for at least 8 wk. Hence TRE is a potential and effective approach for weight loss for participants with overweight/obesity. An 8h-TRE intervention with a morning eating strategy for at least eight weeks might be the optimum TRE intervention mode.