GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

Obesity and the kidney: mechanistic links and therapeutic advances.

Obesity is strongly associated with the development of diabetes mellitus and chronic kidney disease (CKD), but there is evidence for a bidirectional relationship wherein the kidney also acts as a key regulator of body weight. In this Review, we highlight the mechanisms implicated in obesity-related CKD, and outline how the kidney might modulate feeding and body weight through a growth differentiation factor 15-dependent kidney-brain axis. The favourable effects of bariatric surgery on kidney function are discussed, and medical therapies designed for the treatment of diabetes mellitus that lower body weight and preserve kidney function independent of glycaemic lowering, including sodium-glucose cotransporter 2 inhibitors, incretin-based therapies and metformin, are also reviewed. In summary, we propose that kidney function and body weight are related in a bidirectional fashion, and that this interrelationship affects human health and disease.

Weight change and all-cause and cause-specific mortality: A 25-year follow-up study.

BACKGROUND: Whether the dynamic weight change is an independent risk factor for mortality remains controversial. This study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial (NIT) cohort. METHODS: Body weight of 21,028 healthy residents of Linxian, Henan province, aged 40-69 years was measured two times from 1986 to 1991. Outcome events were prospectively collected up to 2016. Weight maintenance group (weight change <2 kg) or stable normal weight group was treated as the reference. Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the risk of mortality. RESULTS: A total of 21,028 subjects were included in the final analysis. Compared with the weight maintenance group, subjects with weight loss ≥2 kg had an increased risk of death from all-cause (HR All-cause  = 1.14, 95% CI: 1.09-1.19, P  <0.001), cancer (HR Cancer  = 1.12, 95% CI: 1.03-1.21, P  = 0.009), and heart disease (HR Heart diseases  = 1.21, 95% CI: 1.11-1.31, P  <0.001), whereas subjects with weight gain ≥5 kg had 11% (HR Cancer  = 0.89, 95% CI: 0.79-0.99, P  = 0.033) lower risk of cancer mortality and 23% higher risk of stroke mortality (HR Stroke  = 1.23,95% CI: 1.12-1.34, P  <0.001). For the change of weight status, both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death (HR Overweight to normal = 1.18, 95% CI: 1.09-1.27; HR Becoming underweight = 1.35, 95% CI: 1.25-1.46) and cancer death (HR Overweight to normal = 1.20, 95% CI: 1.04-1.39; HR Becoming underweight = 1.44, 95% CI: 1.24-1.67), while stable overweight could increase the risk of total death (HR Stable overweight = 1.11, 95% CI: 1.05-1.17) and death from stroke (HR Stable overweight = 1.44, 95% CI: 1.33-1.56). Interaction effects were observed between age and weight change on cancer mortality, as well as between baseline BMI and weight change on all-cause, heart disease, and stroke mortality (all Pinteraction  <0.01). CONCLUSIONS: Weight loss was associated with an increased risk of all-cause, cancer, and heart disease mortality, whereas excessive weight gain and stable overweight were associated with a higher risk of stroke mortality. Efforts of weight management should be taken to improve health status. TRIAL REGISTRATION: https://classic.clinicaltrials.gov/ , NCT00342654.

Bilateral Subdiaphragmatic Vagal Nerve Stimulation Using a Novel Waveform Decreases Body Weight, Food Consumption, Adiposity, and Activity in Obesity-Prone Rats.

INTRODUCTION: Obesity affects millions of Americans. The vagal nerves convey the degree of stomach fullness to the brain via afferent visceral fibers. Studies have found that vagal nerve stimulation (VNS) promotes reduced food intake, causes weight loss, and reduces cravings and appetite. METHODS: Here, we evaluate the efficacy of a novel stimulus waveform applied bilaterally to the subdiaphragmatic vagal nerve stimulation (sVNS) for almost 13 weeks. A stimulating cuff electrode was implanted in obesity-prone Sprague Dawley rats maintained on a high-fat diet. Body weight, food consumption, and daily movement were tracked over time and compared against three control groups: sham rats on a high-fat diet that were implanted with non-operational cuffs, rats on a high-fat diet that were not implanted, and rats on a standard diet that were not implanted. RESULTS: Results showed that rats on a high-fat diet that received sVNS attained a similar weight to rats on a standard diet due primarily to a reduction in daily caloric intake. Rats on a high-fat diet that received sVNS had significantly less body fat than other high-fat controls. Rats receiving sVNS also began moving a similar amount to rats on the standard diet. CONCLUSION: Results from this study suggest that bilateral subdiaphragmatic vagal nerve stimulation can alter the rate of growth of rats maintained on a high-fat diet through a reduction in daily caloric intake, returning their body weight to that which is similar to rats on a standard diet over approximately 13 weeks.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance.

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKß deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Western diet-induced obesity interferes with the HPA axis-blunting effects of palatable food in male rats.

Limited intermittent consumption of palatable food reduces HPA axis responses to stress in chow-fed rats, and this effect is dependent on the rewarding properties of the palatable food. However, obesity may be a state of reduced consummatory food reward, suggesting that palatable foods may be less effective at blunting HPA axis reactivity in the context of diet-induced obesity (DIO). To test this hypothesis, adult male Long-Evans rats were given unlimited access to Western (high-fat, high-sugar) diet (WD) vs. normal chow (controls). After 8 weeks of diet exposure, rats were given limited sucrose intake (LSI) consisting of additional twice-daily access to a small amount (4 ml) of either 3% or 30% sucrose drink, or water (controls) for 2 weeks. Rats then received an acute restraint stress challenge, with collection of tail blood samples for measurement of plasma corticosterone. WD-fed rats had increased caloric intake, body weight and adiposity, as expected. Rats offered LSI (3% or 30%) readily drank the maximal amount allowed (8 ml/day) and reduced their dietary intake to compensate for the sucrose calories, such that LSI did not alter body weight regardless of diet type. In chow-fed lean rats, LSI with either 3% or 30% sucrose reduced the plasma corticosterone response to restraint stress, but this effect was absent in WD-fed DIO rats. Together, these data support the hypothesis that obesity attenuates stress blunting by palatable foods and suggest the possibility that consequently, individuals with obesity may need to consume larger amounts of palatable food to obtain adequate stress relief.

Identification of GDF15 peptide fragments inhibiting GFRAL receptor signaling.

Growth differentiation factor 15 (GDF15) is believed to be a major causative factor for cancer-induced cachexia. Recent elucidation of the central circuits involved in GDF15 function and its signaling through the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) has prompted the interest of targeting the GDF15-GFRAL signaling for energy homeostasis and body weight regulation. Here, we applied advanced peptide technologies to identify GDF15 peptide fragments inhibiting GFRAL signaling. SPOT peptide arrays revealed binding of GDF15 C-terminal peptide fragments to the extracellular domain of GFRAL. Parallel solid-phase peptide synthesis allowed for generation of complementary GDF15 peptide libraries and their subsequent functional evaluation in cells expressing the GFRAL/RET receptor complex. We identified a series of C-terminal fragments of GDF15 inhibiting GFRAL activity in the micromolar range. These novel GFRAL peptide inhibitors could serve as valuable tools for further development of peptide therapeutics towards the treatment of cachexia and other wasting disorders.

Efficacy of a multidimensional self-management intervention on low-education women with metabolic syndrome: a cluster randomized controlled trial.

Low-education women, a substantially older population, are subject to increased risks of metabolic syndrome and consequent cardiometabolic diseases; early detection and effective management were urgently needed. Ninety-nine women with metabolic syndrome, age 61 and education ≤ 6 years, from four community units were randomly assigned to either a self-management intervention (n = 51) or a control arm (n = 48). The intervention consisted of five dimensions, physical activity and diet modifications (daily exercise classes and two nutrition courses), goal setting, coaching and peer support, problem-solving, and self-monitoring. The control arm received an education leaflet. Assessments were performed at baseline, six months, and 18 months. Compared with the control, the intervention participants improved the overall rate of meeting the recommended servings for six health foods, including vegetables, dairy products, and nuts (except whole grains, fruits, and protein); the rate of meeting regular leisure-time physical activity; and criteria biomarkers-waist circumference, fasting blood glucose, high-density lipoprotein cholesterol (except blood pressure and triglycerides); as well as body weight and body mass index; consequently decreased the number of risk factors and rate of metabolic syndrome. In conclusion, the multidimensional self-management intervention improved physical activity, healthy eating, and metabolic syndrome risks among low-education women with metabolic syndrome.

A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese nonhuman primate model.

Growth Differentiation Factor-15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half-life is ~3 h and activates the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half-life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long-acting GLP-1 analog dulaglutide. Mechanism-based longitudinal exposure-response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure-dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose-proportional pharmacokinetics (terminal half-life ~8 days) and treatment caused exposure-dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9-12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure-dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long-acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.

Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

The metabolic cost of physical activity in mice using a physiology-based model of energy expenditure.

OBJECTIVE: Physical activity is a major component of total energy expenditure (TEE) that exhibits extreme variability in mice. Our objective was to construct a general, physiology-based model of TEE to accurately quantify the energy cost of physical activity. METHODS: Spontaneous home cage physical activity, body temperature, TEE, and energy intake were measured with frequent sampling. The energy cost of activity was modeled considering six contributors to TEE (basal metabolic rate, thermic effect of food, body temperature, cold induced thermogenesis, physical activity, and body weight). An ambient temperature of 35 °C was required to remove the contribution from cold induced thermogenesis. Basal metabolic rate was adjusted for body temperature using a Q10 temperature coefficient. RESULTS: We developed a TEE model that robustly explains 70-80% of the variance in TEE at 35 °C while fitting only two parameters, the basal metabolic rate and the mass-specific energy cost per unit of physical activity, which averaged 60 cal/km/g body weight. In Ucp1-/- mice the activity cost was elevated by 60%, indicating inefficiency and increased muscle thermogenesis. The diurnal rhythm in TEE was quantitatively explained by the combined diurnal differences in physical activity, body temperature, and energy intake. Incorporating body temperature into human basal metabolic rate measurements significantly reduced the inter-individual variation. CONCLUSIONS: The physiology-based model of TEE allows quantifying the energy cost of physical activity. While applied here to mice, the model should be generally valid across species. Due to the effect of body temperature, we suggest that basal metabolic rate measurements be corrected to a reference body temperature, including in humans. Having an accurate cost of physical activity allows mechanistic dissection of disorders of energy homeostasis, including obesity.

Comparison of the effects of six-week time-restricted eating on weight loss, body composition, and visceral fat in overweight older men and women.

The aim of this study was to determine the effectiveness of a six-week time-restricted eating (TRE) intervention in reducing body weight, fat loss, and visceral fat in overweight, older adult men and women (age range = 65-74 years). Another objective was to determine the feasibility of widespread use of TRE in older women and men. The study randomly assigned 116 healthy, non-smoking participants to one of two conditions: TRE or educational control participants. Participants in the TRE group were instructed to not consume calorie containing beverages or food for 16 h per day, from 8:00 pm to 12:00 pm. Participants in the control group were instructed to follow a meal plan based on their previous habits. The changes in body weight and body composition were determined using a SECA mBCA 515 analyzer. The six-week TRE intervention resulted in a significant decrease in body weight in both men and women (-1.8 kg and-1.3 kg, respectively; p = 0.03). In men, a significant decrease in visceral fat mass (-0.54 l; p ≤ 0.001) and waist circumference (-2.9 cm; p ≤ 0.015) was observed. No significant changes in either visceral fat or waist circumference were observed in women. Additionally, no change in skeletal muscle mass was observed in either the control or TRE group. More than 99 % of female and 98 % of male participants were able to adhere to the prescribed time-restricted eating (16/8) plan, suggesting that this dietary approach could have beneficial effects on the body composition of overweight older men and may also reduce body weight in overweight, older women.

Differential Strain-dependent Ovarian and Metabolic Responses in a Mouse Model of PCOS.

Several mouse models have been developed to study polycystic ovarian syndrome (PCOS), a leading cause of infertility in women. Treatment of mice with DHT for 90 days causes ovarian and metabolic phenotypes similar to women with PCOS. We used this 90-day DHT treatment paradigm to investigate the variable incidence and heterogeneity in 2 inbred mouse strains, NOD/ShiLtJ and 129S1/SvlmJ. NOD mice naturally develop type 1 diabetes, and recent meta-analysis found increased androgen excess and PCOS in women with type 1 diabetes. The 129S1 mice are commonly used in genetic manipulations. Both NOD and 129S1 DHT-treated mice had early vaginal opening, increased anogenital distance, and altered estrus cycles compared with control animals. Additionally, both NOD and 129S1 mice had reduced numbers of corpora lutea after DHT exposure, whereas NOD mice had decreased numbers of preantral follicles and 129S1 mice had reduced numbers of small antral follicles. NOD mice had increased body weight, decreased white adipocyte size, and improved glucose sensitivity in response to DHT, whereas 129S1 mice had increased body weight and white adipocyte size. NOD mice had increased expression of Adiponectin, Cidea, Srebp1a, and Srebp1b and 129S1 mice had decreased Pparg in the white adipose tissues, whereas both NOD and 129S1 mice had increased expression of Glut4 and Prdm16, suggesting DHT may differentially affect glucose transport, thermogenesis, and lipid storage in white adipose tissue. DHT causes different ovarian and metabolic responses in NOD and 129S1 mice, suggesting that strain differences may allow further elucidation of genetic contributions to PCOS.

Atletas de Taekwondo apresentam desequilíbrio muscular entre os músculos flexores e extensores do joelho: achados preliminares / Taekwondo athletes have muscle imbalance between knee flexors and extensions: preliminary findings / Los atletas de Taekwondo presentan un desequilibrio muscular entre los flexores y los extensores de la rodilla: hallazgos preliminares

Durante a prática de taekwondo com movimentos repetitivos, sistematizados e com certa sobrecarga de treino, o indivíduo pode gerar possíveis adaptações orgânicas que resultam em problemas posturais com grandes chances de desencadear desequilíbrio muscular. Objetivo: Verificar a presença de desequilíbrio entre os grupos musculares agonistas e antagonistas da articulação do joelho e entre membros dominantes e não dominantes de praticantes de taekwondo por meio da dinamometria isocinética. Método: Estudo transversal, observacional e descritivo realizado com nove praticantes de taekwondo do sexo masculino. Utilizou-se um dinamômetro isocinético para investigar o pico de torque, pico de torque por peso corporal, trabalho total, potência média, relação agonista/antagonista e índice de fadiga. Os dados dos membros dominante e não dominante foram comparados por meio do teste t-student para amostras pareadas. Foram calculados o intervalo de confiança de 95% da diferença média, o tamanho de efeito e o poder das análises. Resultados: Os músculos extensores dos membros dominante e não dominante apresentaram diferença média significante de 15,49 Nm (IC95% 7,27; 23,70; p=0,002) para pico de torque e de 22,64% (IC95% 11,83; 33,46; p=0,001) para pico de torque por peso corporal a 60°/s, representando tamanho de efeito médio. Conclusão: Os atletas de taekwondo apresentaram maior pico de torque e maior pico de torque por peso corporal dos músculos extensores do joelho a 60º/s no lado dominante. A relação agonista/ antagonista foi inferior a 60% e mais da metade dos atletas apresentaram uma diferença maior que 10% no pico de torque flexor no lado não dominante.

During taekwondo practice with the repetitive motions, systematized and with certain training overload, the person can generate possible organic adaptations that result in postural problems with a great chances of triggering muscle imbalance. Objective: To verify the presence of imbalance between agonist and antagonist muscle groups of knee joint and between dominant and non-dominant limbs through isokinetic dynamometry. Methods: Cross-sectional, observational and descriptive study realized with nine male taekwondo practitioners. An isokinetic dynamometer was used to investigate the peak torque, peak torque by body weight, total work, average power, agonist/antagonist ratio and fatigue index. Data from the dominant and non-dominant limbs were compared by t-student test for pared samples. The 95% confidence interval of the mean difference, the effect size and the power of analyses power were calculated. Results: The extensor muscles of the dominant and non-dominant limbs showed mean difference of 15,49 Nm (IC95% 7,27; 23,70; p=0,002) for peak torque and of 22,64% (IC95% 11,83; 33,46; p=0,001) for peak torque by body weight at 60°/s, representing average effect size. Conclusion: The taekwondo athletes had higher peak torque and higher peak torque by body weight of the knee extensors muscles in the dominant side. The agonist/ antagonist ratio was less than 60% and more than half of the athletes showed a difference greater than 10% in the peak flexor torque on the non-dominant side.

Durante la práctica de taekwondo con los movimientos repetitivos, sistematizados y con cierta sobrecarga de entrenamiento, la persona puede generar posibles adaptaciones orgánicas que deriven en problemas posturales con grandes posibilidades de desencadenar desequilibrios musculares. Objetivo: Verificar la presencia de desequilibrio entre grupos musculares agonistas y antagonistas de la articulación de la rodilla y entre miembros dominantes y no dominantes mediante dinamometría isocinética. Métodos: Estudio transversal, observacional y descriptivo realizado con nueve practicantes masculinos de taekwondo. Se utilizó un dinamómetro isocinético para investigar el par máximo, el par máximo por peso corporal, el trabajo total, la potencia media, la relación agonista/antagonista y el índice de fatiga. Los datos de las extremidades dominantes y no dominantes se compararon mediante la prueba t- student para muestras de pared. Se calcularon el intervalo de confianza del 95% de la diferencia media, el tamaño del efecto y la potencia de los análisis. Resultados: Los músculos extensores de los miembros dominantes y no dominantes mostraron una diferencia media de 15,49 Nm (IC95% 7,27; 23,70; p=0,002) para el par máximo y de 22,64% (IC95% 11,83; 33,46; p=0,001) para el par máximo por peso corporal a 60°/s, lo que representa el tamaño medio del efecto. Conclusiones: Los atletas de taekwondo presentaron un mayor par máximo y un mayor par máximo por peso corporal de los músculos extensores de la rodilla en el lado dominante. La relación agonista/antagonista fue inferior al 60% y más de la mitad de los atletas mostraron una diferencia superior al 10% en el pico de par flexor en el lado no dominante.

Impact of gastrectomy on body composition within 1 month in patients with gastric cancer.

PURPOSE: The present study examined the changes in and risk factors for body composition (BC) during the first postoperative month when dynamic biological reactions occur. METHODS: We retrospectively assessed 202 patients who underwent gastrectomy. The BC was assessed using a bioelectrical impedance analysis and evaluated within 1 month preoperatively, 1 week postoperatively, and 1 month postoperatively. Multiple regression analyses were performed to identify predictive factors for BC change. RESULTS: The mean reduction rate in BC at 1 month postoperatively was - 6.0, - 10.5, - 5.6, - 1.1, - 10.1, and + 1.2% for body weight, body fat, skeletal muscle, bone mineral, extracellular water/total body water, and the whole-body phase angle, respectively. A multiple regression analysis revealed that independent risk factors for weight loss were complications, operative time, and type of gastrectomy (P = 0.004, 0.011, 0.015, respectively), and those for skeletal muscle loss were complications and gastrectomy type (P = 0.002, 0.010, respectively). A segmental lean mass analysis revealed that the lower limbs were markedly reduced at 1 week postoperatively (- 8.0%), and these independent risk factors were the female sex and Stage II/III disease (P = 0.008, 0.036, respectively). CONCLUSION: Detailed analyses of BC might help elucidate the mechanisms underlying postoperative physical changes, which might be useful for perioperative management.

Chemotherapy and Anticancer Drugs Adjustment in Obesity: A Narrative Review.

BACKGROUND: Obese individuals have higher rates of cancer incidence and cancer- related mortality. The worse chemotherapy outcomes observed in this subset of patients are multifactorial, including the altered physiology in obesity and its impact on pharmacokinetics, the possible increased risk of underdosing, and treatment-related toxicity. AIMS: The present review aimed to discuss recent data on physiology, providing just an overall perspective and pharmacokinetic alterations in obesity concerning chemotherapy. We also reviewed the controversies of dosing adjustment strategies in adult and pediatric patients, mainly addressing the use of actual total body weight and ideal body weight. METHODS: This narrative review tried to provide the best evidence to support antineoplastic drug dosing strategies in children, adolescents, and adults. RESULTS: Cardiovascular, hepatic, and renal alterations of obesity can affect the distribution, metabolism, and clearance of drugs. Anticancer drugs have a narrow therapeutic range, and variations in dosing may result in either toxicity or underdosing. Obese patients are underrepresented in clinical trials that focus on determining recommendations for chemotherapy dosing and administration in clinical practice. After considering associated comorbidities, the guidelines recommend that chemotherapy should be dosed according to body surface area (BSA) calculated with actual total body weight, not an estimate or ideal weight, especially when the intention of therapy is the cure. CONCLUSION: The actual total body weight dosing appears to be a better approach to dosing anticancer drugs in both adults and children when aiming for curative results, showing no difference in toxicity and no limitation in treatment outcomes compared to adjusted doses.

Association between skeletal muscle mass or percent body fat and metabolic syndrome development in Japanese women: A 7-year prospective study.

Previous cross-sectional studies have indicated that low relative appendicular lean mass (ALM) against body weight (divided by body weight, ALM/Wt, or divided by body mass index, ALM/BMI) was negatively associated with metabolic syndrome (MetS). Conversely, previous cross-sectional studies have indicated that the absolute ALM or ALM divided by squared height (ALM/Ht2) were positively associated with MetS. The aim of this longitudinal study was to investigate the association between low absolute or relative skeletal muscle mass, leg muscle power, or percent body fat and the development of MetS in Japanese women in a 7-y prospective study. The study participants included 346 Japanese women aged 26 to 85 years. The participants were divided into low and high groups based on the median values of ALM/Wt, ALM/BMI, ALM/Ht2, absolute ALM, or leg power. The longitudinal relationship between ALM indices or leg power and MetS development was examined using Kaplan-Meier curves and Cox regression models (average follow-up duration 7 years, range 1 to 10 years). During follow-up, 24 participants developed MetS. MetS incidence was higher in the low ALM/Wt group than the high ALM/Wt group even after controlling for age, obesity, waist circumference, family history of diabetes, smoking, and physical activity [adjusted hazard ratio = 5.60 (95% CI; 1.04-30.0)]. In contrast, MetS incidence was lower in the low ALM/Ht2 group than the high ALM/Ht2 group [adjusted hazard ratio = 10.6 (95%CI; 1.27-89.1)]. MetS incidence was not significantly different between the low and high ALM/BMI, absolute ALM, and leg power groups. Both ALM/Ht2 and ALM/Wt were not significant predictive variables for MetS development when fat mass or percent body fat was taken into account in the Cox model. At the very least, the results of this study underscore the importance of body composition measurements in that percent body fat, but not ALM, is associated with MetS development.

Neuromedin U-deficient rats do not lose body weight or food intake.

Studies in genetically modified mice establish that essential roles of endogenous neuromedin U (NMU) are anorexigenic function and metabolic regulation, indicating that NMU is expected to be a potential target for anti-obesity agents. However, in central administration experiments in rats, inconsistent results have been obtained, and the essential role of NMU energy metabolism in rats remain unclear. This study aims to elucidate the role of endogenous NMU in rats. We generated NMU knockout (KO) rats that unexpectedly showed no difference in body weight, adiposity, circulating metabolic markers, body temperature, locomotor activity, and food consumption in both normal and high fat chow feeding. Furthermore, unlike reported in mice, expressions of Nmu and NMU receptor type 2 (Nmur2) mRNA were hardly detectable in the rat hypothalamic nuclei regulating feeding and energy metabolism, including the arcuate nucleus and paraventricular nucleus, while Nmu was expressed in pars tuberalis and Nmur2 was expressed in the ependymal cell layer of the third ventricle. These results indicate that the species-specific expression pattern of Nmu and Nmur2 may allow NMU to have distinct functions across species, and that endogenous NMU does not function as an anorexigenic hormone in rats.

Impact of One-Year Dietary Education on Change in Selected Anthropometric and Biochemical Parameters in Children with Excess Body Weight.

Obesity is regarded as a civilization disease that increases mortality and the risk of cardiovascular complications. In Poland, the prevalence of excess body weight in the paediatric population has been steadily increasing. The consequences of excess body weight in the developmental age population affect children's health and destabilize their development. Appropriate dietary interventions are the main non-invasive methods of preventing and treating obesity. They should be aimed at the whole family, optimally with the use of simple tools such as the Healthy Eating Pyramid. Due to the increasing prevalence of excess body weight in the developmental age population and the problems with the treatment of this condition, studies were undertaken in order to determine the impact of a dietary intervention on anthropometric and biochemical parameters in children with excess body weight. A total of 68 (72.3%) children completed the study. Based on BMI SDS, 59 (86.8%) were diagnosed with obesity and 9 (13.2%) with overweight. After the completion of the one-year dietary educational program, a significant improvement in weight loss, waist and hip circumference, as well as the value of the WHtR index was demonstrated. There was also a significant increase in the percentage of muscle tissue and a decrease in the content of adipose tissue in the bodies of examined children. A significant improvement in the parameters of carbohydrate metabolism, and almost all parameters of lipid metabolism, except for total cholesterol. A significant (by 28.0%) reduction in the incidence of fatty liver was also noted. No influence of dietary education on arterial blood pressure was observed.

Socs3 ablation in kisspeptin cells partially prevents lipopolysaccharide-induced body weight loss.

Many cytokines have been proposed to regulate reproduction due to their actions on hypothalamic kisspeptin cells, the main modulators of gonadotropin-releasing hormone (GnRH) neurons. Hormones such as leptin, prolactin and growth hormone are good examples of cytokines that lead to Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, consequently exerting effects in kisspeptin neurons. Different studies have investigated how specific components of the JAK/STAT signaling pathway affect the functions of kisspeptin cells, but the role of the suppressor of cytokine signaling 3 (SOCS3) in mediating cytokine actions in kisspeptin cells remains unknown. Cre-Loxp technology was used in the present study to ablate Socs3 expression in kisspeptin cells (Kiss1/Socs3-KO). Then, male and female control and Kiss1/Socs3-KO mice were evaluated for sexual maturation, energy homeostasis features, and fertility. It was found that hypothalamic Kiss1 mRNA expression is significantly downregulated in Kiss1/Socs3-KO mice. Despite reduced hypothalamic Kiss1 mRNA content, these mice did not present any sexual maturation or fertility impairments. Additionally, body weight gain, leptin sensitivity and glucose homeostasis were similar to control mice. Interestingly, Kiss1/Socs3-KO mice were partially protected against lipopolysaccharide (LPS)-induced body weight loss. Our results suggest that Socs3 ablation in kisspeptin cells partially prevents the sickness behavior induced by LPS, suggesting that kisspeptin cells can modulate energy metabolism in mice in certain situations.