Nutritional and pharmacologic support in patients with pancreatic cancer

The aim of our study was to assess whether the influence of nutritional support, consisting of counseling, enteral liquids support and pharmacologic support, can slow down weight loss and whether the change in weight has the impact on the performance status in our patients. In our study 44 patients with pancreatic cancer were included--26 males (mean age 69 years +/- 2.4 years) and 18 females (mean age 63 +/- 3.2 years). Metastatic disease was found in 21 patients, 15 patients had liver metastasis. Locally advanced disease was found in 24 patients and metastatic and locally advanced disease in 17 patients. Surgery was performed in 34 patients. Forty four (100%) patients underwent nutritional counseling, 33 of them (75%) took supplemental enteral feeding and 44 (100%) took megestrol acetate 400 mg per a day. The patients were followed up during 8 weeks during 5 visits. At first visit we took initial nutritional status of patients. Appetite loss, weight gain and Karnofsky performance status were monitored at every visit. All patients were treated with gemcitabin for a 7 week period. Results: NTS score at initial visit in 44 patients (100%) was > or = 5. Using nutritional counseling, enteral food substitution and pharmacological support, weight gain was observed in 61.1% patients and appetite improved. Average KPS mostly improved after first month of therapy while after two months was again at the basal level. With nutritional counseling, supplemental feeding and pharmacologic support weight loss in our patients slowed down and appetite improved. Despite of that, Karnofsky Performance Status didn't change significantly, reflecting the impact of the disease itself and chemotherapy procedures to the patient's condition. We can conclude that nutritional and pharmacological support can temporarily stop weight loss and improve appetite, social life and quality of life in those groups of patients but have no implications on patients KPS and course of their disease.     

Gut Hormones,Appetite Suppression and Cachexia in Patients with Pulmonary TB

Background

Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown.

Methods and Findings

41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points.

Conclusions

Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression.     

Influence of progestins on serum hormone levels in postmenopausal women with advanced breast cancer--II. A differential effect of megestrol acetate and medroxyprogesterone acetate on serum estrone sulfate and sex hormone binding globulin

Serum estradiol, estrone, estrone sulfate and sex hormone binding globulin were measured in 10 postmenopausal patients with advanced breast cancer receiving sequential treatment with medroxyprogesterone acetate and megestrol acetate. Treatment with megestrol acetate caused a non-significant reduction in serum estradiol (mean reduction of 19%, 0.05 less than P less than 0.1) but significant reductions in serum estrone (mean reduction of 20%, P less than 0.02) and serum estrone sulfate (mean reduction of 54%, P less than 0.005) compared to treatment with medroxyprogesterone acetate. In contrast, treatment with medroxyprogesterone acetate reduced serum sex hormone binding globulin more compared to treatment with megestrol acetate (mean reduction of 69%, P less than 0.01). These findings suggest that the two progestins have differential effects on serum hormone levels. The finding that treatment with megestrol acetate causes a significant reduction in serum estrone sulfate level warrants further investigations of this potentially important mechanism of action of this drug in advanced breast cancer.     

醋酸曲普瑞林与醋酸甲地孕酮片治疗特发性中枢性早熟临床疗效比较

目的:对比醋酸曲普瑞林与醋酸甲地孕酮片治疗特发性中枢性早熟的临床效果。方法:选取我院自2014年2月~2015年2月期间收治的特发性中枢性早熟患儿92例,采取随机数字表法分为2组,其中46例患儿接受醋酸甲地孕酮片治疗(对照组),46例患儿接受醋酸曲普瑞林治疗(观察组),治疗6个月后,观察对比两组患儿的生长指标及性激素水平变化,并统计其不良反应发生情况。结果:观察组治疗后的体重、身高、生长速率、预测身高、骨龄/实际年龄(BA/CA)等生长指标优于对照组(P0.05);两组患者治疗后的雌激素(E2)、黄体生成素(LH)及促卵泡成熟素(FSH)水平较治疗前有明显改善(P0.05),且观察组治疗后的E2、LH、FSH水平优于对照组(P0.05);两组均未见明显不良反应发。结论:相比醋酸甲地孕酮片,醋酸曲普瑞林治疗特发性中枢性早熟患儿临床效果更好,可更好延缓患儿骨龄成熟,降低其性激素水平,在临床中具有良好的应用价值。     

Glucocorticoid properties of progestogens

Single oral doses of progesterone, 17-hydroxyprogesterone acetate, medroxyprogesterone acetate, megestrol acetate, cortisol, or placebo were given to groups of fasting young men. Eosinophils, plasma glucose and corticosteroids were determined at hourly intervals for 8 hours. Maximum responses were compared between groups receiving different treatments. Progesterone is free of glucocorticoid properties in these tests, but medroxyprogesterone acetate has about 50% and megestrol acetate about 25% the eosinopenic and hyperglycemic activity of an equal weight of cortisol in the dose range tested. 17-hydroxyprogesterone acetate has no eosinopenic or hyperglycemic activity, but suppresses plasma corticosteroids similarly to equal weights of medroxyprogesterone acetate or megestrol acetate.     

Effect of megestrol acetate on milk production in sows and piglet growth

A group of 16 German Landrace sows, nursing 155 piglets, was used for the demonstration of the effect of 20 mg of the progestogen megestrol acetate, administered orally from Day 8 to 21 post-partum, on milk production, milk composition and piglet weight. Eight sows remained untreated. Megestrol acetate treatment increased significantly milk yield by 35% and piglet weight at weaning (Day 35) by 30% over controls. A carryover effect after cessation of drug treatment was dtected, which kept milk production at an increased level for 8 more days.     

Analysis of the androgenic activity of synthetic "progestins" currently used for the treatment of prostate cancer

In order to assess the androgenic activity of synthetic "progestins" currently used as "antiandrogens" for the treatment of prostate cancer in men, the effect of a series of these compounds has been measured following 14 days of treatment of adult castrated rats on specific and sensitive parameters of androgenic activity, namely ventral prostate weight and prostatic ornithine decarboxylase (ODC) activity. Medroxyprogesterone acetate (MPA) is almost equipotent with 5 alpha-dihydrotestosterone (DHT), a 49% increase in prostatic weight being observed at the low dose of 0.15 mg, twice daily (P less than 0.01). Megestrol acetate (Megace), chlormadinone acetate (CMA) and spironolactone were less potent but caused a 36-59% increase in prostatic weight at the highest dose used, namely 10 mg. At the 5 mg dose, cyproterone acetate (CPA) caused a 75% increase in prostatic weight. The androgenic activity of the compounds is even more clearly illustrated by their marked stimulatory effect on prostatic ornithine decarboxylase (ODC) activity. MPA, at the low dose of 0.15 mg, caused a 20-fold increase (relative to the effect of placebo) in the activity of the enzyme while the same dose of DHT caused a 15-fold stimulation of enzymatic activity. At the 10 mg dose, megestrol acetate, CMA and spironolactone caused 13.1, 11.8 and 8.6-fold stimulations of ODC activity, respectively. Flutamide, on the other hand, had no stimulatory effect on either ventral prostate weight or prostatic ODC activity. In agreement with glucocorticoid activity, MPA, megestrol acetate and CMA caused a marked inhibition (45-64%) of adrenal weight. The present data show that MPA is a highly potent androgen while megestrol acetate, CMA, CPA and spironolactone have lower but significant androgenic activity on all the parameters measured. It should be added that MPA, megestrol acetate and CMA are completely devoid of antiandrogenic activity while spironolactone shows weak antiandrogen action and CPA is a mixed agonist-antagonist. Flutamide, the compound used as reference, is the only compound devoid of any androgenic action and is thus acting as a pure antiandrogen on both ventral prostate weight and prostatic ODC activity. The present data have major implications for the choice of drug to be used for the treatment of androgen-sensitive diseases, especially prostate cancer. As shown by the present data, the synthetic "progestins" so-far available all possess variable levels of androgenic activity and are thus not recommended for the treatment of prostate cancer.     

A Prospective Cohort Study of the Effects of Adjuvant Breast Cancer Chemotherapy on Taste Function,Food Liking,Appetite and Associated Nutritional Outcomes

Background

‘Taste’ changes are commonly reported during chemotherapy. It is unclear to what extent this relates to actual changes in taste function or to changes in appetite and food liking and how these changes affect dietary intake and nutritional status.

Patients and methods

This prospective, repeated measures cohort study recruited participants from three oncology clinics. Women (n = 52) prescribed adjuvant chemotherapy underwent standardised testing of taste perception, appetite and food liking at six time points to measure change from baseline. Associations between taste and hedonic changes and nutritional outcomes were examined.

Results

Taste function was significantly reduced early in chemotherapy cycles (p<0.05) but showed recovery by late in the cycle. Ability to correctly identify salty, sour and umami tastants was reduced. Liking of sweet food decreased early and mid-cycle (p<0.01) but not late cycle. Liking of savory food was not significantly affected. Appetite decreased early in the cycle (p<0.001). Reduced taste function was associated with lowest kilojoule intake (r = 0.31; p = 0.008) as was appetite loss with reduced kilojoule (r = 0.34; p = 0.002) and protein intake (r = 0.36; p = 0.001) early in the third chemotherapy cycle. Decreased appetite early in the third and final chemotherapy cycles was associated with a decline in BMI (p = <0.0005) over the study period. Resolution of taste function, food liking and appetite was observed 8 weeks after chemotherapy completion. There was no association between taste change and dry mouth, oral mucositis or nausea.

Conclusion

The results reveal, for the first time, the cyclical yet transient effects of adjuvant chemotherapy on taste function and the link between taste and hedonic changes, dietary intake and nutritional outcomes. The results should be used to inform reliable pre-chemotherapy education.     

Pilot Study on the Influence of Nutritional Counselling and Implant Therapy on the Nutritional Status in Dentally Compromised Patients

Objectives

To investigate the impact of implant-prosthetic rehabilitation combined with nutritional counseling on the nutritional status of patients with severely reduced dentitions.

Design

An explorative intervention study including an intra-individual comparison of 20 patients with severely reduced dentitions in terms of nutrition- and quality of life-related parameters recorded at baseline and at six and twelve months after implant-prosthetic rehabilitation.

Participants

Twenty patients from the Department of Prosthetic Dentistry of Justus-Liebig University of Giessen, with an mean age of 63 years, who had fewer than ten pairs of antagonists.

Measurements

The baseline data collection included dental status, a chewing ability test, laboratory parameters, anthropometric data (body mass index), energy supply, a 3-day dietary record, an analysis of the oral health-related quality of life (OHRQoL) with the OHIP-G14, the Mini-Mental Status (MMS) and Mini Nutritional Assessment (MNA). Six months after implantation and prosthetic rehabilitation, individual nutritional counseling was performed by a dietician. Data were again collected and analyzed. A final follow-up was conducted 12 months after prosthetic rehabilitation.

Results

Despite the highly significant improvement in masticatory ability and OHRQoL after implant-prosthetic rehabilitation, no significant changes were observed regarding MNA, anthropometric data or energy supply. Except for cholinesterase (p = 0.012), ferritin (p = 0.003), folic acid (p = 0.019) and vitamin A (p = 0.004), no laboratory parameter changed significantly during the investigation period. In addition, no general significant differences were observed for nutrient intake or food choice.

Conclusion

The present study does not confirm the assumption that the implant-prosthetic rehabilitation of patients with severely reduced residual dentitions with or without an individual nutritional counseling influences nutritional status.     

Clinical Efficacy of Chemotherapy Combined with Verapamil in Metastatic Colorectal Patients

In order to determine the clinical efficacy and adverse reactions of chemotherapy and verapamil infusion through a target artery to treat colorectal cancer patients with metastasis after failure with previous conventional treatments. Patients with metastatic colon cancer (n = 36) received an infusion of verapamil, interleukin-2, oxaliplatin (or hydroxy camptothecin or irinotecan hydrochloride), fluorouracil and calcium folinate through target artery using the Seldinger puncture technique. From the second day of infusion, the patients were treated with fluorouracil and calcium folinate via systematic intravenous injection for 2–3 days. Efficacy was evaluated after at least two treatment courses. The objective response including complete or partial response was 58.3% in the 36 patients; clinical benefit rate, evaluated by Karnofsky Performance Status score was 91.7%; by weight was 83.3%; by the amount of painkiller consumed was 80.6%. No patient experienced side effects associated with heart function. Post-treatment, the P–R period, Q–T period, QRS, and heart rate were not significantly different than before treatment. Liver function was significantly improved. Side effects of chemotherapy were minor in comparison to those observed with intravenous chemotherapy. Infusion of verapamil and chemotherapy directly into pelvic tumor tissue can increase treatment efficacy and has been shown to be a relatively safe technique.     

营养风险筛查NRS2002的临床应用观察

采用营养风险筛查2002(NRS2002),选取2012年1月至2012年12月在上海市第十人民医院呼吸内科、肝胆内科、神经内科、普通外科、脊柱外科的新入院住院患者进行营养风险筛查,并调查住院期间的营养支持状况及营养指标的变化。结果显示,共有750例患者入选,呼吸内科和神经内科营养风险最高均为42%,但存在营养风险的患者营养支持率分别为23.8%和31.7%,肝胆内科存在营养风险的患者营养支持率最高,但也仅为47.6%;营养风险≥3分的患者中体质指数(BMI)、血清前白蛋白(PA)、血红蛋白(HB)3个指标均低于营养风险<3分的患者,且存在统计学意义(p<0.05)。结果表明,NRS2002适用于住院患者营养风险筛查,存在营养风险的患者营养支持率普遍较低,相关营养指标可辅助判断营养状况。     

肠内营养联合复方氨基酸在恶性肿瘤患者化疗中的应用

为了观察肠内营养(EN)支持治疗联合复方氨基酸在恶性肿瘤化疗患者中的临床疗效及并建立相关护理方法,将68例恶性肿瘤化疗患者随机分为治疗组和对照组,每组34例,治疗组给予肠内营养支持治疗联合复方氨基酸治疗,对照组给予常规处理。对两组病人治疗前后进行生化指标监测、记录不良反应以及进行营养评估。研究结果显示,治疗组与对照组比较,人体测量值增加,血清清蛋白升高,两组比较有显著性差异(p<0.05)。本研究表明,肠内营养(EN)支持治疗联合复方氨基酸对于改善恶性肿瘤化疗病人的营养状况效果明显,并且可以提高患者对化疗的耐受力、增强免疫功能。     

Non-genomic effects of progestins--inhibition of cell growth and increased intracellular levels of cyclic nucleotides

The anti-proliferative effect of progestins was studied in human transformed cell lines from the uterine cervix (C-4I, C33A and Me-180). Progestins caused a concentration-dependent inhibition of proliferation. The maximum tested concentration (2.6-3.2 microM) inhibited C-4I cell growth by the following order of potency: progesterone (56%) > medroxyprogesterone (38%) > megestrol acetate (25%). The sensitivity, expressed as I(25) (the concentration that caused 25% inhibition of growth), showed the same order: progesterone (7.7 nM) > medroxyprogesterone (78 nM) > megestrol acetate (570 nM). The intracellular levels of cGMP and cAMP were elevated and the cellular export of these cyclic nucleotides was inhibited by a similar order of potency. The C-4I cell line was devoid of progesterone-, estrogen-, androgen- and glucocorticoid-receptors. In addition, the antiprogestins mifepristone, onapristone and ZK-112993 did not block the anti-proliferative effect of progesterone. On the other hand, antiprogestins (2.3 nM) appeared to have some progesterone-like ("mimetic") activity with inhibition of C-4I cell growth; mifepristone (11%), onapristone (12%) and ZK-112993 (16%). The observed effects of progestins and antiprogestins on C-4I cells were also presented in C33A cells (16% androgen receptor positive) and Me-180 cells (22% progesterone receptor positive, 9% androgen receptor positive and 17% glucocorticoid receptor positive). This study suggests that a non-genomic mechanism contributes to the anti-proliferative effect of progestins.     

营养干预对局部晚期鼻咽癌患者放化疗期体质量及营养状态的影响

目的:探讨营养干预对局部晚期鼻咽癌患者在放化疗期间的营养状态及体质量的影响。方法:选取我院2015年1月-2019年12月收治的112例鼻咽癌晚期患者,按随机数表法分成营养干预组和对照组各56例,均采用同一放化疗治疗方案,观察组在此基础上给予营养干预。对比两组患者在放化疗治疗期间的生活质量(QOL)评分、营养状态、黏膜损害程度、体质量变化和近期疗效。结果:放射剂量达40Gy时,营养干预组QOL评分≥41分的比例显著高于对照组(P0.05);放疗结束后营养干预组发生Ⅲ级以上的口腔黏膜损害的患者比例显著低于对照组(P0.05);放化疗第4周营养干预组的体质量显著高于对照组(P0.05);放化疗治疗结束后两组原发灶残余比例和淋巴结转移比例比较均无统计学差异(P0.05);放化疗第4、7周营养干预组的血红蛋白(Hb)、总蛋白(TP)和白蛋白(Alb)显著高于对照组(P0.05)。结论:鼻咽癌患者在放化疗期间,营养状况下降明显,营养干预治疗能够有效改善患者的体质量和营养状况,对于患者的后续治疗具有重要意义,应在晚期鼻咽癌的临床治疗中推广营养干预。     

Metabolism of megestrol acetate and related progesterone analogues by liver preparations in vitro

1. The rates of metabolism of megestrol acetate, 17alpha-acetoxy-6alpha-methylprogesterone, 6alpha-methylprogesterone, 17alpha-acetoxyprogesterone and progesterone by liver microsome-supernatant fractions from female rats and rabbits have been compared. 2. Introduction of the 6alpha-methyl group into the progesterone molecule markedly decreased the metabolism by liver microsome-supernatant preparations in the rat but not in the rabbit. When 17alpha-acetoxy was the substituting group, metabolism was diminished in the rabbit but not in the rat preparations. Introduction of both the 6alpha-methyl and 17alpha-acetoxy groups into the progesterone molecule markedly decreased the rate of metabolism by liver microsome-supernatant preparations of both species. The Delta(6)-bond in megestrol acetate confers additional resistance to metabolism by rabbit-liver preparations. 3. It is proposed that the observed inhibition of metabolism by these substituents in the progesterone molecule partly or wholly explains the enhanced activity of megestrol acetate.     

Detection of risk factors that influence weight loss in patients undergoing radiotherapy

AimTo identify risk factors that influence weight loss in patients receiving radiotherapy.BackgroundIt is a well-known fact that cancer patients can be affected by malnutrition at the onset of the disease and during treatment due to the toxicity. Pretreatment weight loss alone does not predict those who will need nutritional supplementation. Instead, a variety of nutritional and tumor related factors needs to be taken into account.Material and methodsA retrospective study was conducted on 129 patients with different tumor locations. Weight loss was evaluated during radiotherapy and one month after treatment. The impact of age, ECOG, chemotherapy, pretreatment weight loss, tumor location, previous surgery and TNM were analyzed. We aimed to identify a high-risk group of patients before starting treatment.ResultsThe average net weight loss during radiotherapy and one month after treatment for this group of patients was 0.68 kg and 1.6 kg, respectively. Median weight loss during radiotherapy was 2.6 kg for head and neck (HN) patients and 0.27  kg for other tumor sites (p = 0.028). Median weight loss one month after radiotherapy was 3.7 kg for HN patients and 1.1 kg for the rest of the patients (p = 0.034). The median weight loss one month after treatment was 3.2 kg for patients receiving chemotherapy and 0.5 kg for those patients who did not receive chemotherapy (p < 0.001). A regression analysis determined that HN tumor location and the use of chemotherapy were independent risk factors.ConclusionsNutritional status must be monitored and managed before, during and after treatment. A variety of nutritional and tumor-related factors must be considered. According to our results, head and neck tumors and the use of chemotherapy are the only two factors considered statistically significant. Because patients continue to lose weight after treatment, we recommend close surveillance after radiotherapy.     

Megestrol acetate drives endometrial carcinoma cell senescence via interacting with progesterone receptor B/FOXO1 axis

Megestrol acetate is a common and efficient anticancer progesterone. To explore the activity and the therapeutic mechanisms of megestrol acetate in endometrial cancer, human endometrial cancer cell lines Ishikawa and HHUA overexpressing progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were treated with megestrol acetate. Cell viability, apoptosis, cycle arrest, and senescence, as well as the expressions of p21 and p16, two hallmarks of cellular senescence, were evaluated. Compared with the control, >10 nmol/L megestrol acetate treatment could significantly reduce endometrial cancer cell growth, and induce the irreversible G1 arrest and cell senescence. The expression of cyclin D1 in megestrol acetate treated cells was downregulated, while the expressions of p21 and p16 were upregulated via PR-B isoform. FOXO1 inhibitor AS1842856 could significantly abrogate megestrol acetate-induced cell senescence, suggesting that FOXO1 was involved in megestrol acetate/PR-B axis. These findings may provide a new understanding for the treatment of human endometrial cancer.     

肺功能康复训练联合肠外氨基酸营养支持对非小细胞肺癌化疗患者营养状态、癌因性疲乏及生活质量的影响

摘要 目的：探讨肺功能康复训练联合肠外氨基酸营养支持对非小细胞肺癌（NSCLC）化疗患者营养状态、癌因性疲乏及生活质量的影响。方法：选取2016年6月~2019年10月期间本院收治的NSCLC化疗患者137例。根据随机数字表法将患者分为对照组（68例,给予常规干预）、观察组（69例,在对照组基础上给予肠外氨基酸营养支持联合肺功能康复训练）,对比两组干预前后的营养状态、肺功能、癌因性疲乏及生活质量。结果：与对照组相比,观察组干预后白蛋白、总蛋白、血红蛋白更高（P<0.05）。干预后观察组用力肺活量（FVC）、第1s用力呼气容积占预计值百分比（FEV₁%）、呼气峰流速值（PEF）高于对照组（P<0.05）。观察组干预后Piper 疲乏量表（PFS）的行为疲乏、情感疲乏、躯体疲乏、认知疲乏评分低于对照组（P<0.05）。观察组干预后生活质量评估量表（EORTC QLQ-C30）各维度评分较对照组更高（P<0.05）。结论：肺功能康复训练联合肠外氨基酸营养支持干预NSCLC化疗患者,可改善患者的营养状态及肺功能,缓解患者癌因性疲乏程度,改善其生活质量。     

Malnutrition and the heart.

Earlier concepts that the heart is spared in malnutrition have been shown to be incorrect. Inadequate intake of protein and energy results in proportional loss of skeletal and myocardial muscle. As myocardial mass decreases, so does the ability to generate cardiac output; however, various compensatory factors come into play. Nutritional supplementation for malnourished patients reverses the compensatory factors and may increase the short-term potential for heart failure. Severe cardiac debility results in poor nutrition, which may in turn produce unsuspected but clinically significant myocardial atrophy. Nutritional support may play a role in improving cardiac function in selected patients with cardiac cachexia who are being prepared for cardiac surgery and in patients with rapid weight loss who are at risk for sudden death due to arrhythmias. Malnutrition is common in hospitalized patients, and many patients in hospital now receive nutritional supplementation; both facts have important cardiac implications.     

Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance

Obesity-related leptin resistance manifests in loss of?leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the?kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.