Greater Body Weight Loss Research Articles

G protein subunit Gγ13-mediated signaling pathway is critical to the inflammation resolution and functional recovery of severely injured lungs.

Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit Gγ13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the Gγ13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.

G protein subunit Gγ13-mediated signaling pathway is critical to the inflammation resolution and functional recovery of severely injured lungs

Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit Gγ13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the Gγ13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.

EOGT enables residual Notch signaling in mouse intestinal cells lacking POFUT1

Notch signaling determines cell fates in mouse intestine. Notch receptors contain multiple epidermal growth factor-like (EGF) repeats modified by O-glycans that regulate Notch signaling. Conditional deletion of protein O-fucosyltransferase 1 (Pofut1) substantially reduces Notch signaling and markedly perturbs lineage development in mouse intestine. However, mice with inactivated Pofut1 are viable, whereas complete elimination of Notch signaling in intestine is lethal. Here we investigate whether residual Notch signaling enabled by EGF-domain-specific O-linked N-acetylglucosamine transferase (Eogt) permits mice conditionally lacking Pofut1 in intestine to survive. Mice globally lacking Eogt alone were grossly unaffected in intestinal development. In contrast, mice lacking both Eogt and Pofut1 died at ~ 28 days after birth with greater loss of body weight, a greater increase in the number of goblet and Paneth cells, and greater downregulation of the Notch target gene Hes1, compared to Pofut1 deletion alone. These data reveal that both O-fucose and O-GlcNAc glycans are fundamental to Notch signaling in the intestine and provide new insights into roles for O-glycans in regulating Notch ligand binding. Finally, EOGT and O-GlcNAc glycans provide residual Notch signaling and support viability in mice lacking Pofut1 in the intestine.

A clinically managed weight loss program evaluation and the impact of COVID-19.

With the prevalence of obesity increasing, many weight-loss programs were created to aid in combating the trend. The Weight Loss Clinic (WLC) was created to provide personalized support for lifestyle changes using a multidisciplinary team with medical oversight. This study evaluated the clinically-managed weight loss program at the Wellness Institute. This was a prospective evaluation of a newly established program between January 2019-August 2020. Participants who entered the weight loss program were approached to learn about the evaluation. A total of 41 participants were included. The primary outcomes included changes in body weight and achievement of more than 5% initial body weight loss. Outcome measures were collected pre-and post-program and the data was analyzed through paired t-tests on R studio. Greater body weight-loss was seen in completers pre-COVID-19 compared to those who completed during the pandemic (Mean, ±SD; 7.51 ± 6.24 kg n = 13 p < 0.001 vs. 1.75 ± 4.43 kg n = 9, p = 0.02). Completers pre-COVID-19 demonstrated improvements in waist circumference, Framingham risk score, blood pressure, hemoglobin A1C, and body fat percentage. Though the sample size was small to show definitve evidence, the results may suggest the program worked well prior to the pandemic but the pandemic created barriers to weight-loss for participants.

Clinical outcomes associated with drugs for obesity and overweight: A systematic review and network meta-analysis of randomized controlled trials.

To compare the benefits and harms of drugs approved for weight management in adults with obesity or overweight. We performed a systematic review of drugs approved for treating obesity and overweight. We searched MEDLINE, Embase and CENTRAL through 26 February 2023. Random-effects network meta-analysis was applied. A total of 168 trials (97 938 patients) were included. There was no evidence that drugs approved for weight management had different associations with cardiovascular death (69 trials, 59 037 participants). Naltrexone/bupropion was associated with lower cardiovascular mortality than placebo (odds ratio [OR], 0.62 [95% CI: 0.39, 0.99]; low certainty evidence). All drugs were associated with greater weight loss at 12 months than placebo (33 trials, 37 616 participants), mainly semaglutide (mean difference [MD], -9.02 kg [95% CI: -10.42, -7.63]; moderate certainty) and phentermine/topiramate (MD, -8.10 kg [95% CI: -10.14, -6.05]; high certainty); and with greater waist circumference reduction at 12 months than placebo (24 trials, 35 733 participants), mainly semaglutide (MD, -7.84 cm [95% CI: -9.34, -6.34]; moderate certainty) and phentermine/topiramate (MD, -6.20 cm [95% CI: -7.46, -4.94]; high certainty). Semaglutide and phentermine/topiramate were associated with lower or no difference in the odds of treatment withdrawal compared with all other drugs (87 trials, 70 860 participants). Among adults with obesity or overweight, semaglutide and phentermine/topiramate were associated with greater body weight loss and waist circumference reduction at 12 months than all other drugs, and lower or no significant difference in risks of withdrawal. There was no evidence that drugs approved for weight management had different associations with cardiovascular death.

Influence of gonadectomy on muscle health in micro- and partial-gravity environments in rats.

Gonadal hormones, such as testosterone and estradiol, modulate muscle size and strength in males and females. However, the influence of sex hormones on muscle strength in micro- and partial-gravity environments (e.g., the Moon or Mars) is not fully understood. The purpose of this study was to determine the influence of gonadectomy (castration/ovariectomy) on progression of muscle atrophy in both micro- and partial-gravity environments in male and female rats. Male and female Fischer rats (n = 120) underwent castration/ovariectomy (CAST/OVX) or sham surgery (SHAM) at 11 wk of age. After 2 wk of recovery, rats were exposed to hindlimb unloading (0 g), partial weight bearing at 40% of normal loading (0.4 g, Martian gravity), or normal loading (1.0 g) for 28 days. In males, CAST did not exacerbate body weight loss or other metrics of musculoskeletal health. In females, OVX animals tended to have greater body weight loss and greater gastrocnemius loss. Within 7 days of exposure to either microgravity or partial gravity, females had detectable changes to estrous cycle, with greater time spent in low-estradiol phases diestrus and metestrus (∼47% in 1 g vs. 58% in 0 g and 72% in 0.4 g animals, P = 0.005). We conclude that in males testosterone deficiency at the initiation of unloading has little effect on the trajectory of muscle loss. In females, initial low estradiol status may result in greater musculoskeletal losses.NEW & NOTEWORTHY We find that removal of gonadal hormones does not exacerbate muscle loss in males or females during exposure to either simulated microgravity or partial-gravity environments. However, simulated micro- and partial gravity did affect females' estrous cycles, with more time spent in low-estrogen phases. Our findings provide important data on the influence of gonadal hormones on the trajectory of muscle loss during unloading and will help inform NASA for future crewed missions to space and other planets.

Murine models of neonatal susceptibility to a clinical strain of enterovirus A71

Enterovirus A71 (EV-A71) is neurotropic and one of the primary enteric pathogens responsible for severe central nervous system infection in infants and young children. Neonatal mice are ideal models for studying the pathogenesis of infection caused by EV-A71. In this study, we assessed the susceptibility of neonatal BALB/c, C57BL/6, ICR, Kunming, and NIH mice to a clinically isolated EV-A71 strain. One-day-old mice were challenged with a clinical isolate of EV-A71 via intraperitoneal injection, then observed for 13 days for mortality, body-weight changes, and limb paralysis. RT-qPCR was performed to quantify viral RNA in the brain, spinal cord, skeletal muscle, and lungs of BALB/c and C57BL/6 mice. The expression of murine scavenger receptor class B member 2 (mSCARB2) was measured by western blotting. Finally, lesions were assessed by histological examination. We found that neonatal BALB/c and C57BL/6 mice were both susceptible to EV-A71, leading to decreased survival rate, greater body weight loss, and prominent hind-limb paralysis. Tissue viral loads of C57BL/6J mice were markedly higher than those of BALB/c mice, indicating that EV-A71 replicated more efficiently in C57BL/6 mice. Increased expression of mSCARB2 was observed 5 days after infection in C57BL/6 mice, which coincided with the peak in EV-A71 replication. Histological examination indicated that infection caused obvious pathogenic lesions. In conclusion, C57BL/6 are most susceptible to infection caused by EV-A71 and can be used as a model for studying its pathogenesis and test therapeutic options.

The Influence of Weight Loss in Postural Control in Women Undergoing Sleeve Gastrectomy.

Bariatric surgery is the most effective procedure for obesity management, with a greater body weight loss and the remission of several diseases. The aim of this study was to analyze the relationships between the anthropometric profile and postural control outcomes in a group of obese adult women, and the effect of bariatric surgery on postural control. eighty-eight women candidates for bariatric surgery were recruited. Static balance was measured with the ARGO stabilometric platform under two conditions: open eyes (OE) and closed eyes (CE). Multiple linear regression indicated BMI as the first predictor for postural control in all parameters, except for APO in open eyes, predicted mainly by height. Changes in body weight and BMI showed no statistically significant correlations with modification of postural control parameters (OE), while they appeared to exert an influence under closed eyes conditions. Before surgery, obese patients with a higher BMI showed a better postural control. After surgery, the sway path and antero-posterior oscillation improved under open eyes conditions, while the magnitude of weight loss was negatively correlated with differences in postural control.

Combined biotin, folic acid, and vitamin B12 supplementation given during the transition period to dairy cows: Part II. Effects on energy balance and fatty acid composition of colostrum and milk

Biotin (B8), folate (B9), and vitamin B12 (B12) are involved in several metabolic reactions related to energy metabolism. We hypothesized that a low supply of one of these vitamins during the transition period would impair metabolic status. This study was undertaken to assess the interaction between B8 supplement and a supplementation of B9 and B12 regarding body weight (BW) change, dry matter intake, energy balance, and fatty acid (FA) compositions of colostrum and milk fat from d -21 to 21 relative to calving. Thirty-two multiparous Holstein cows housed in tie stalls were randomly assigned, according to their previous 305-d milk yield, to 8 incomplete blocks in 4 treatments: (1) a 2-mL weekly i.m. injection of saline (0.9% NaCl; B8-/B9B12-); (2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly i.m. injection of 0.9% NaCl (B8+/B9B12-); (3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly i.m. injection of 10 mg of B12 (B8-/B9B12+); (4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9, and 2-mL weekly i.m. injection of 10 mg of B12 (B8+/B9B12+) in a 2 × 2 factorial arrangement. Colostrum was sampled at first milking. and milk samples were collected weekly on 2 consecutive milkings and analyzed for FA composition. Body condition score and BW were recorded every week throughout the trial. Within the first 21 d of lactation, B8-/B9B12+ cows had an increased milk yield by 13.5% [45.5 (standard error, SE: 1.8) kg/d] compared with B8-/B9B12- cows [40.1 (SE: 1.9)], whereas B8 supplement had no effect. Even though body condition score was not affected by treatment, B8-/B9B12+ cows had greater BW loss by 24 kg, suggesting higher mobilization of body reserves. Accordingly, milk de novo FA decreased and preformed FA concentration increased in B8-/B9B12+ cows compared with B8-/B9B12- cows. In addition, cows in the B8+/B9B12- group had decreased milk de novo FA and increased preformed FA concentration compared with B8-/B9B12- cows. Treatment had no effect on colostrum preformed FA concentration. Supplemental B8 decreased concentrations of ruminal biohydrogenation intermediates and odd- and branched-chain FA in colostrum and milk fat. Moreover, postpartum dry matter intake for B8+ cows tended to be lower by 1.6 kg/d. These results could indicate ruminal perturbation caused by the B8 supplement, which was not protected from rumen degradation. Under the conditions of the current study, in contrast to B8+/B9B12- cows, B8-/B9B12+ cows produced more milk without increasing dry matter intake, although these cows had greater body fat mobilization in early lactation as suggested by the FA profile and BW loss.

235-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Exerts Potent and Sustained Body Weight Loss in Rodent Obesity Models

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with a unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an engineered GDF15 variant-Fc fusion protein to have extended half-life and potent functional activity by enhancing binding affinity to GDF15 receptors (GFRAL/RET) . Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in humans. In efficacy studies using obese mouse models, YH34160 demonstrated a potent and sustained weight-lowering effect. After a single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight (BW) reduction compared to long-acting glucagon like peptide-1 receptor agonist (GLP-1RA) . Following a 6-week multiple-dose study in DIO mice, YH34160-treated groups exhibited a greater and more prolonged BW loss compared to the group of GLP-1RA. Marked BW reduction and improved lipid profile by YH34160 were also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. In addition, YH34160 caused significantly better anti-obesity effects, and a much more improved metabolic profile than that of albumin-GDF15, and dual GLP-1/Glucagon receptor agonist. Interestingly, YH34160 in combination with GLP-1RA or dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) achieved more potent and greater BW loss compared to each mono-treated group. Overall, these findings indicate that YH34160 would be a promising therapeutic candidate, as well as in combination with GLP-1-based therapeutics, for the treatment of obesity and obesity-related comorbidities. Disclosure S. Lim: None. D. Kim: None. J. Yang: None. M. Ju: None. S. Kim: None. B. Sim: None. J. Kim: None. S. Oh: Employee; Yuhan, Stock/Shareholder; Yuhan.

Effect of a High Protein, Low Glycemic Index Dietary Intervention on Metabolic Dysfunction-Associated Fatty Liver Disease: A Randomized Controlled Trial.

Background:Metabolic dysfunction-associated fatty liver disease (MAFLD) affects people at an increasingly younger age. The primary treatment for patients with MAFLD is diet-induced weight loss; however, excessive dieting is poorly effective.ObjectivesThe aim of this trial was to evaluate whether a high protein and low glycemic index (HPLG) dietary intervention would result in improvement of controlled attenuation parameter (CAP) and related metabolic markers in MAFLD.MethodsA 12-week controlled, parallel-group, randomized intervention trial was performed. A number of 63 participants with MAFLD were enrolled and randomized between the HPLG dietary group and the balanced diet control group. Both diets had the same hypocaloric level and were prescribed ad libitum within food limit lists. The primary outcome was CAP. The main secondary outcomes were weight loss and improvement of metabolism-related indexes at week 12 after the program initiation.ResultsA total of 59 participants completed the intervention and were included in the final analysis. The mean age was 39.3 ± 8.9 years and 66.1% were men. In this trial, protein and carbohydrate intakes were significantly higher and lower, respectively, in the HPLG group compared to controls (p < 0.001). At week 12, CAP was significantly reduced in both groups (p < 0.001). However, a significantly greater reduction in liver fat was observed in the HPLG group compared to the control group (p = 0.011), with mean relative reductions of 30.90 dB/m (95% CI, 21.53 to 40.26, p < 0.001) and 15.43 dB/m (95% CI, 7.57 to 23.30, p < 0.001), respectively. From baseline to week 12, a significantly greater loss in bodyweight was recorded in participants in the HPLG group (6.52 kg; 95% CI, 5.50 to 7.54, p < 0.001) compared to control subjects (2.00 kg; 95% CI, 0.89 to 3.11, p = 0.001). Moreover, body fat percentage in the HPLG group was significantly reduced compared with the control group (p = 0.002). Within-group improvements in visceral fat, blood pressure, cardiovascular risk factors, and blood glucose-related indicators were detected in patients with MAFLD assigned to the HPLG diet (p < 0.05), but not in those prescribed the control diet (p > 0.05).ConclusionUnder our experimental conditions, and compared to the traditional balanced diet, an HPLG diet led to a significant CAP remission, bodyweight or fat reduction, and improvement of metabolic markers in patients with MAFLD.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03972631.

Beneficial Effects of the Very-Low-Calorie Ketogenic Diet on the Symptoms of Male Accessory Gland Inflammation.

Introduction. Obesity exposes individuals to the risk of chronic inflammation of the prostate gland. Aim and design of the study. A longitudinal clinical study was conducted on selected overweight/obese patients with male accessory gland inflammation (MAGI) to evaluate the effects of body weight loss on their urogenital symptoms. Materials and methods. One hundred patients were selected and assigned to two groups undergoing two different nutritional programs. The first group (n = 50) started a Mediterranean diet (MedDiet) and the second (n = 50) a very-low-calorie ketogenic diet (VLCKD). Before and after three months on the diet, each patient was evaluated for body weight, waist circumference, and MAGI symptoms. The MAGI was assessed using the Structured Interview about MAGI (SI-MAGI), a questionnaire previously designed to assess the symptoms of MAGI. The questionnaire explores four domains, including urinary symptoms, ejaculatory pain or discomfort, sexual dysfunction, and impaired quality of life. Finally, in the two groups, the frequency of an α-blocker used to treat urinary tract symptoms was also evaluated. Results. Patients on MedDiet experienced significant amelioration in urinary symptoms and quality of life. Patients under VLCKD reported not only significant improvement of the same parameters, but also in ejaculatory pain/discomfort and sexual dysfunction. Finally, the percentage of patients on VLCKD taking the α-blocker decreased significantly. Moreover, patients under VLCKD showed a greater loss of body weight than those following the MedDiet. Discussion. The results of this study support the effectiveness of VLCKD in improving the symptoms of patients with MAGI. This improvement involved all of the domains of the SI-MAGI questionnaire and became manifest in a relatively short time. We suggest that a ketogenic nutritional approach can be used in overweight/obese patients with MAGI.

Abstract WP249: Effect Of Acute Hyperglycemia On Stroke Outcome And Immune Response

Background: Acute hyperglycemia occurs in over 40% of ischemic stroke patients, increases hemorrhagic transformation (HT) and worsens stroke outcome. Previous rodent studies reported deleterious effects of hyperglycemia on stroke outcome during acute stroke (within hours to days), however, its impact during subacute stroke period (days to weeks) remains unclear. Moreover, the mechanisms underlying hyperglycemia’s worsening of stroke outcomes remains elusive. In this study, we investigated the effect of acute hyperglycemia on immune responses and stroke outcome in acute and subacute phases. Method: Male C57/BL6 mice were subjected to middle cerebral artery occlusion (MCAO) for 30 min, followed by reperfusion to mimic ischemic stroke. Acute hyperglycemia was induced by glucose injection 10 min before MCAO. For the acute phase study, mice were sacrificed at 4.5 hrs to assess blood-brain barrier leakage (Evans blue) and brain immune cell populations (flow cytometry), and at 24 hrs to evaluate brain infarct, swelling and HT. In the sub-acute phase, mice were allowed to survive 14 days after stroke to evaluate mortality rate, neurological deficit, and motor-sensory dysfunction using a rotating beam test. Result: In the acute phase, hyperglycemia rapidly increased BBB leakage by 4.5 hrs after stroke, when compared to the normoglycemia group (p&lt;0.0001). At this early timepoint, hyperglycemic mice brains showed more Ly6C hi microglia and infiltrating myeloid cells, including neutrophils and Ly6C hi monocytes, than normoglycemic mice. By 24 hrs after stroke, hyperglycemic mice showed increased HT and larger brain edema; brain infarct volume however, was not affected. In the subacute-phase, hyperglycemic mice exhibited a higher mortality rate than normoglycemic mice (100% VS 25%, p=0.0008), with greater body weight loss, and worsened neurological deficit and rotating beam performance. Conclusion: Acute hyperglycemia adversely impacts stroke outcomes in acute and subacute phases, with HT and brain edema as the key pathological events associated with higher mortality, as well as more severe neurological and motor-sensory deficits. Rapid modulation of immune responses may play an important role in mediating the detrimental effect of hyperglycemia.

Effect of stage of lactation and dietary starch content on endocrine-metabolic status, blood amino acid concentrations, milk yield, and composition in Holstein dairy cows

Milk yield and composition are modified by level and chemical characteristics of dietary energy and protein. Those factors determine nutrient availability from a given diet, and once absorbed, they interact with the endocrine system and together determine availability of metabolites to the mammary gland. Four multiparous dairy cows in early lactation and subsequently in late lactation were fed 2 diets for 28 d in a changeover design that provided, within the same stage of lactation, similar amounts of rumen fermentable feed with either high (HS) or low starch (LS). All diets had similar dietary crude protein (15.5% dry matter) and rumen-undegradable protein (∼40% of crude protein) content. Profiles of AA were calculated to be similar to that of casein. On d 28, [1-13C] Leu was infused into one jugular vein with blood samples taken at 0, 2, 4, 6, and 8 h, and cows milked at 0, 2, 4, 5, 6, 7, and 8 h from start of infusion. Isotopic enrichments of plasma Leu, keto-isocaproic acid, and milk casein were determined for calculation of Leu kinetics. Data were subjected to ANOVA using the MIXED procedure of SAS (SAS Institute Inc.), with time as repeated factor and cow as the random effect. Dry matter intake within each stage of lactation was similar between groups. Feeding LS resulted in lower blood glucose and greater ratio of bovine somatotropin to insulin. This response was associated with greater blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, which might have contributed to greater milk fat content in LS-fed cows. Except for His, average concentrations of all AA in blood were higher in late than early lactation. Diet did not alter average plasma concentrations of AA. However, for most of the essential AA (particularly branched-chain), the HS diet led to a marked decrease in concentrations after the forage meal, resulting in significant differences between dietary groups in early lactation. In early-lactating cows fed HS, a greater reduction in plasma concentrations at 8 h relative to pre-feeding values (time zero) was observed for Met, Lys, and His, resulting in decreases of 27.9%, 33.6%, and 38.5%, respectively. A higher bovine somatotropin/insulin ratio in early lactation and in cows fed LS could possibly have led to greater breakdown and, consequently, higher AA flux from peripheral tissues. In LS-fed cows, higher mobilization of body fat and protein was confirmed by the greater body weight loss in both stages of lactation. Higher irreversible loss of [1-13C] Leu in early lactation suggested lower protein retention in peripheral tissues during early compared with late lactation. Milk yield, protein output, and composition were similar between groups at both stages of lactation, whereas milk coagulation was faster (lower curd firming rate) and with higher curd firmness in response to feeding HS in late lactation. Overall, data indicated that rate of carbohydrate fermentability in the rumen can modify the availability of metabolites to the mammary gland and consequently modify milk protein coagulation.

The Relationship Between Weight Loss Outcomes and Engagement in a Mobile Behavioral Change Intervention: Retrospective Analysis.

BackgroundThere is large variance in weight loss outcomes of digital behavior change interventions (DBCIs). It has been suggested that different patterns of engagement in the program could be responsible for this variance in outcomes. Previous studies have found that the amount of engagement on DBCIs, such as the number of meals logged or articles read, is positively associated with weight loss.ObjectiveThis retrospective study extends previous research by observing how important weight loss outcomes (high weight loss: 10% or greater body weight loss; moderate weight loss: between 5% to 10%; stable weight: 0 plus or minus 1%) are associated with engagement on a publicly available mobile DBCI (Noom) from 9 to 52 weeks.MethodsEngagement and weight data for eligible participants (N=11,252) were extracted from the Noom database. Engagement measures included the number of articles read, meals logged, steps recorded, messages to coach, exercise logged, weigh-ins, and days with 1 meal logged per week. Weight was self-reported on the program. Multiple linear regressions examined how weight loss outcome (moderate and high vs stable) was associated with each engagement measure across 3 study time periods: 9-16 weeks, 17-32 weeks, and 33-52 weeks.ResultsAt 9-16 weeks, among the 11,252 participants, 2594 (23.05%) had stable weight, 6440 (57.23%) had moderate weight loss, and 2218 (19.71%) had high weight loss. By 33-52 weeks, 525 (18.21%) had stable weight, 1214 (42.11%) had moderate weight loss, and 1144 (39.68%) had high weight loss. Regression results showed that moderate weight loss and high weight loss outcomes were associated with all engagement measures to a significantly greater degree than was stable weight (all P values <.001). These differences held across all time periods with the exception of exercise for the moderate weight loss category at 1 time period of 33-52 weeks. Exercise logging increased from 9 to 52 weeks regardless of the weight loss group.ConclusionsOur results suggest that these clinically important weight loss outcomes are related to the number of articles read, meals logged, steps recorded, messages to coach, exercise logged, weigh-ins, and days with 1 meal logged per week both in the short-term and long-term (ie, 1 year) on Noom. This provides valuable data on engagement patterns over time on a self-directed mobile DBCI, can help inform how interventions tailor recommendations for engagement depending on how much weight individuals have lost, and raises important questions for future research on engagement in DBCIs.

Matrix lumican endocytosed by immune cells controls receptor ligand trafficking to promote TLR4 and restrict TLR9 in sepsis

Infections and inflammation are profoundly influenced by the extracellular matrix (ECM), but their molecular underpinnings are ill defined. Here, we demonstrate that lumican, an ECM protein normally associated with collagens, is elevated in sepsis patients' blood, while lumican-null mice resolve polymicrobial sepsis poorly, with reduced bacterial clearance and greater body weight loss. Secreted by activated fibroblasts, lumican promotes Toll-like receptor (TLR) 4 response to bacterial lipopolysaccharides (LPS) but restricts nucleic acid-specific TLR9 in macrophages and dendritic cells. The underlying mechanism involves lumican attachment to the common TLR coreceptor CD14 and caveolin 1 (Cav1) in lipid rafts on immune cell surfaces via two epitopes, which may be cryptic in collagen-associated lumican. The Cav1 binding epitope alone is sufficient for cell surface enrichment of Cav1, while both are required for lumican to increase cell surface TLR4, CD14, and proinflammatory cytokines in response to LPS. Endocytosed lumican colocalizes with TLR4 and LPS and promotes endosomal induction of type I interferons. Lumican-null macrophages show elevated TLR9 in signal-permissive endolysosomes and increased response, while wild types show lumican colocalization with CpG DNA but not TLR9, consistent with a ligand sequestering, restrictive role for lumican in TLR9 signaling. In vitro, lumican competes with CD14 to bind CpG DNA; biglycan, a lumican paralog, also binds CpG DNA and suppresses TLR9 response. Thus, lumican and other ECM proteins, synthesized de novo or released from collagen association during ECM remodeling, may be internalized by immune cells to regulate their transcriptional programs and effector responses that may be harnessed in future therapeutics.

657-P: Potential Effect of a Novel Combination of GLP-1RA (efpeglenatide) and Long-Acting Glucagon Analog (HM15136) in Animal Models of Metabolic Disorders

In addition to glycemic control, GLP-1RA efficacy is established in obesity. However, more efforts are still required to close efficacy gap with bariatric surgery. Recent studies demonstrate the favorable effect of glucagon (GCG) receptor activation on energy expenditure and hepatic lipid metabolism. So, combination of GCG with GLP-1RA not only enhances body weight loss (BWL) barely achieved by current therapy, but also expands its therapeutic utility to various metabolic disorders. Previously, we confirmed the long-acting GCG properties of HM15136 from animal to human. In addition, GLP-1 class effect of efpeglenatide (Efpe), once-weekly GLP-1RA, was confirmed in clinical studies. Thus, to develop a novel combination therapy, we investigated potential effects of Efpe and HM15136 combination in animal models of metabolic disorders. In DIO mice, 4 weeks treatment of Efpe and HM15136 combination (COMBO) showed more BWL than Efpe mono treatment. Of note, greater BWL was also confirmed for COMBO treatment compared to acylated GLP-1/GIP co-agonist (-18.5, -55.9, -44.9% vs. vehicle for Efpe, COMBO, GLP-1/GIP). Similar results were observed when measuring fat mass (-19.5%, -83.8%, -77.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) and blood lipid profiles (total cholesterol: -41.8%, -82.0%, -63.2% vs. vehicle for Efpe, COMBO, GLP-1/GIP) in DIO mice. To further demonstrate benefits of this novel COMBO, additional study was performed in DIO/STZ rats, and COMBO treatment consistently showed more BWL than Efpe (-5.1, -12.1% vs. vehicle for Efpe, COMBO) along with numerically more HbA1c reduction (-1.0, -1.5% vs. vehicle for Efpe, COMBO). Therefore, HM15136 might be a novel COMBO partner for Efpe, providing enhanced BWL and favorable metabolic profiles. These results warrants further evaluation for therapeutic potential of this novel COMBO in various metabolic disorders including dyslipidemia and NASH. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Choi: Employee; Self; Hanmi Pharmaceutical. E. Park: Employee; Self; Hanmi Pharmaceutical. D. Kim: Employee; Self; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. I. Choi: Employee; Self; Hanmi Pharmaceutical.

IL-27/IL-27R Mediates Protective Immunity against Chlamydial Infection by Suppressing Excessive Th17 Responses and Reducing Neutrophil Inflammation.

IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Chlamydia muridarum respiratory infection and further investigated the immunological mechanism. Our results showed that IL-27 was involved in C. muridarum infection and that IL-27R knockout mice (WSX-1-/- mice) suffered more severe disease, with greater body weight loss, higher chlamydial loads, and more severe inflammatory reactions in the lungs than C57BL/6 wild-type mice. There were excessive IL-17-producing CD4+ T cells and many more neutrophils, neutrophil-related proteins, cytokines, and chemokines in the lungs of WSX-1-/- mice than in wild-type mice following C. muridarum infection. In addition, IL-17/IL-17A-blocking Ab treatment improved disease after C. muridarum infection in WSX-1-/- mice. Overall, we conclude that IL-27/IL-27R mediates protective immunity during chlamydial respiratory infection in mice by suppressing excessive Th17 responses and reducing neutrophil inflammation.

Response of domestic chickens to fasting and non-fast moulting programmes in a humid tropical environment

The study evaluates the effect of fasting and non-fasting (Zn supplementation) moulting methods on performance of indigenous (IC) and Shaver brown (SB) hens in the hot humid tropical environment of Nsukka, Southeastern Nigeria. One hundred and twenty indigenous and Shaver brown hens (60/genotype) aged between 75 and 80 weeks were shared into three groups (20/group), T : hens fed layers diet at 125 g/bird/day (control group), T : hens fed 1 2layers mash supplemented with 20,000ppm Zn as ZnO at 125 g/bird/day for 14 days, and T : 3 hens subjected to feed deprivation (FD) for 14 days. Water was given ad libitum to all birds. Data analyzed were pre-moult and moulting body weight, hen day egg production (HDEP), and egg weight. Moulting method significantly (p&lt;0.05) affected body weight in SB but not in indigenous hens; hen day egg production and day to stoppage of egg production in bothgenotypes with FD resulting in greater loss in body weight and an early cessation of egg production compared to zinc supplementation. Shaver Brown hens subjected to ZnO and FD lost 15.6 and 26.7 % of their initial body weight, respectively while IC lost 16.2 and 32.6 %, respectively. Hen day egg production was 0.00 ± 0.00 % in the last week of moulting in SB and IC moulted by FD but 8.32 ± 6.47 % for SB and 10.71 ± 3.25 % for IC moulted by ZnO. Egg production stopped on day 10 (D10) and 6 in SB hens submitted to ZnO and FD, respectively and on D13 and 5, respectively for the IC. In conclusion, zinc supplementation at 20,000ppm in the diet of laying chickens as moulting agent is a milder but equally effective moulting method as fasting and is recommended for intensive commercial and rural indigenous poultry production.

Potency of gastrointestinal colonization and virulence of Candida auris in a murine endogenous candidiasis.

Candida auris infections have recently emerged worldwide, and this species is highly capable of colonization and is associated with high levels of mortality. However, strain-dependent differences in colonization capabilities and virulence have not yet been reported. In the present study, we aimed to clarify the differences between clinically isolated invasive and non-invasive strains of C. auris. We evaluated colonization, dissemination, and survival rates in wild C57BL/6J mice inoculated with invasive or non-invasive strains of C. auris under cortisone acetate immunosuppression, comparing with those of Candida albicans and Candida glabrata infections. We also evaluated the potency of biofilm formation. Stool fungal burdens were significantly higher in mice inoculated with the invasive strains than in those infected with the non-invasive strain. Along with intestinal colonization, liver and kidney fungal burdens were also significantly higher in mice inoculated with the invasive strains. In addition, histopathological findings revealed greater dissemination and colonization of the invasive strains. Regarding biofilm-forming capability, the invasive strain of C. auris exhibited a significantly higher capacity of producing biofilms. Moreover, inoculation with the invasive strains resulted in significantly greater loss of body weight than that noted following infection with the non-invasive strain. Invasive strains showed higher colonization capability and rates of dissemination from gastrointestinal tracts under cortisone acetate immunosuppression than non-invasive strains, although the mortality rates caused by C. auris were lower than those caused by C. albicans.