OBJECTIVE: To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer.
METHODS: We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People\'s Hospital, and Lin\'an District First People\'s Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer.
RESULTS: High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P < 0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P < 0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05).
CONCLUSIONS: Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer.

A comorbidity of anorexia nervosa (AN) and myalgic encephalomyelitis (ME/CSF) is uncommon. A 17 years-old male adolescent with possible onset of ME/CFS after an Epstein Barr Virus infection (EBV) and later onset of AN during a second period of weight loss was twice treated off-label with metreleptin for 15 and 11 days, respectively. As in previous cases, eating disorder specific cognitions and mood improved. Interestingly, fatigue and post-exertional muscle pain (P-EMP) improved, too. We discuss potential mechanisms. Treatment with metreleptin may prove beneficial in AN and in ME/CSF associated with substantial weight loss.

Background: Recently, the prevalence of thyroid cancer has increased. Although there are known risk factors for thyroid cancer, none of them can justify this recent increase. In addition to the known risk factors, other risk factors have been proposed. Leptin can be considered as one of these risk factors due to the recent increase in the prevalence of obesity in the population. Leptin is a common factor in obesity and thyroid cancer. Leptin exerts anti-apoptotic and mitogenic effects on cancer cells and also acts as an angiogenic factor. This study aimed to evaluate the serum leptin level in individuals who suffer from papillary thyroid carcinoma (PTC), cases with benign thyroid nodules (BTN), and a healthy group. Materials and Methods: In this study, newly diagnosed patients with PTC, BTNs, as well as euthyroid healthy control subjects without nodules were included. In all these participants, various clinical and laboratory parameters including thyroid function tests and serum leptin levels were measured and compared between the three study groups. For patients with PTC, leptin was assessed 12 weeks after total thyroidectomy. Results: Ninety-one cases with PTC, 90 cases with BTNs, and 88 controls were recruited. Serum leptin levels in the PTC group, benign group, and the control group were 22.34, 17.60, and 13.83 ng/ml, respectively, which was considerably higher in PTC cases compared to those with benign nodules and control group (P<0.001). There was a significant association between leptin with BMI, tumor size, and tumor stage in PTC patients. Also, in patients with BTNs, a correlation between BMI, tumor size, and leptin was observed. Conclusion: Serum leptin levels were considerably higher in cases with PTC than those with BTNs and controls and can be considered as a potential tumor marker for papillary thyroid cancer.

This study aimed to investigate the use of leptin as a marker for gestational diabetes by analyzing any correlation between serum leptin levels versus oral glucose tolerance tests (at 24 to 28 weeks of pregnancy) and increased body weight (during pregnancy). A total of 110 female cases (81 pregnant and 29 non-pregnant) were included in the study. The 81 pregnant cases were divided into 3 groups according to their oral glucose tolerance test results. A chi-square test was used for categorical variables. The distribution of numerical variables was tested with the Shapiro-Wilk test. ANOVA and a post-hoc Bonferroni test was used for parametric data. Kruskal-Wallis variance analysis was used for non-parametric data. The Mann-Whitney U-test was used for pairwise comparisons. Spearman correlation analysis and multivariate regression analysis were performed for the evaluation of the correlation analysis between the parameters. Oral glucose tolerance test results were compared with leptin levels with a cut-off value of 11.43 for leptin. The ROC curve demonstrated an 83.3% sensitivity and 72.1% specificity for leptin. Leptin may play a role in the pathophysiology of gestational diabetes mellitus. However, the relationship between leptin levels and maternal weight gain during pregnancy is still unknown.

Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB.
Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test.
Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers.
Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

Background Obstructive sleep apnea (OSA) is characterized by a combination of structural issues in the upper airway and imbalances in the respiratory control system. While numerous studies have linked OSA with obesity, it remains uncertain whether leptin, a hormone associated with fat, plays a role in the functional and anatomical defects that lead to OSA. Therefore, the aim of this study was to investigate whether leptin levels could be used as a predictor of OSA syndrome (OSAS). Methodology A case-control observational study was conducted, enrolling study participants who reported obesity (BMI > 30) within the range of >30 to <35 kg/m2, along with a short neck and a history of snoring, excessive daytime drowsiness, fatigue, or insomnia. Leptin levels and fasting blood sugar (FBS) were measured in all individuals. Additionally, the study evaluated the severity of OSAS using indicators such as the STOP BANG scores, apnea-hypopnea index, uvula grade score, and Epworth Sleepiness Scale scores. Results A total of 80 participants (40 cases and 40 controls) were included in the study. The mean leptin and FBS levels were significantly higher in cases compared to controls. Moreover, leptin levels exhibited a significant correlation with the severity indices of OSAS. Conclusion The study findings indicate that individuals with higher leptin levels tend to exhibit more severe OSAS symptoms. Furthermore, these elevated leptin levels contribute to the worsening of various OSA symptoms. Larger controlled studies have suggested that pharmacologically restoring the altered leptin levels may serve as a beneficial adjunct to treatment for alleviating OSAS symptoms.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

Major depressive disorder (MDD) is a heterogeneous mental disorder having a very diverse course and causing a significant changes in daily life. Though the exact pathophysiology of depression is still not known, an alteration in the serum levels of cytokines and neurotrophic factors was seen in MDD subjects. In this study, we compared the serum levels of \'pro-inflammatory cytokine leptin and neurotrophic factor EGF\' in healthy controls (HCs) and MDD patients. To make the findings more accurate, we eventually looked for a correlation between altered serum leptin and EGF levels and the severity of the disease condition.
For this case-control study, about 205 MDD patients were enrolled from the Department of Psychiatry, Bangabandhu Sheikh Mujib Medical University, Dhaka, and about 195 HCs were enrolled from various parts of Dhaka. The DSM-5 was utilized to evaluate and diagnose the participants. The HAM-D 17 scale was used to measure the severity of depression. After collecting blood samples, they were centrifuged to produce clear serum samples. These serum samples were analyzed using enzyme-linked immunosorbent assay (ELISA) kits to measure serum leptin and EGF levels.
We observed lowered serum EGF levels in MDD patients compared to HCs (524.70 ± 27.25 pg/ml vs. 672.52 ± 49.64 pg/ml, p = 0.009), and HAM-D score was elevated in MDD patients compared to HCs (17.17 ± 0.56 vs. 2.49 ± 0.43, p<0.001). But no correlation was established between serum EGF levels and the severity of depression. However, no significant differences were observed between MDD patients and HCs in the case of serum leptin levels (p = 0.231).
Our study findings suggest that reduced serum EGF levels have an impact on the pathogenesis of depression. But as per our investigation, the severity of depression is not correlated with altered EGF levels. Our findings regarding the association of EGF with MDD would help to use EGF as a risk indicator of depression. We suggest further clinical investigations to determine the precise function of leptin and EGF in depression.

Severe metabolic complications generally manifest at an early age in Berardinelli - Seip congenital lipodystrophy (BSCL) and their management is especially challenging. Nutritional intervention with low lipid diets is considered by experts to be fundamental in treating the disease when associated with medical therapy, however little is known about the beneficial effects of dietary interventions alone.
To underline the importance of a well-structured low-fat diet in BSCL patients.
A BSCL male patient strictly followed a hypocaloric hypolipemic diet (60% carbohydrates, 22% fats and 18% proteins) since clinical diagnosis at the age of one year. Interestingly, pharmacological interventions were not required at any point during the follow-up. Aged 16 years the patient was referred to our center. Biochemistry, hormonal evaluation, 75 mg oral glucose tolerance test, cardiac evaluation and abdominal ultrasound were performed, revealing no abnormalities. Genetic analysis and leptin dosage were carried out, confirming the diagnosis of BSCL type 1 (homozygosity for c.493-1G>C pathogenic variant in AGPAT2 gene) and showing undetectable circulating levels of leptin (< 0.2 mcg/L). Diet therapy alone was therefore maintained, scheduling follow-up visits every six months, with acceptable disease control ever since.
This report proves how a low-fat diet is of great help in the management of BSCL and its complications. In addition, a specific hypolipemic diet could be used alone as an effective treatment in selected cases with high compliance and, probably, a milder phenotype.

UNASSIGNED: Behaviorally, the most pronounced effects of leptin substitution in leptin deficiency are the hunger-decreasing and postprandial satiety-prolonging effects of the adipokine. Previously, with functional magnetic resonance imaging (MRI), we and others showed that eating behavior-controlling effects are at least in part conveyed by the reward system. However, to date, it is unclear if leptin only modulates eating behavior specific brain reward action or if it also alters the reward function of the brain unrelated to eating behavior.
UNASSIGNED: We investigated with functional MRI the effects of metreleptin on the reward system in a reward task unrelated to eating behavior, the monetary incentive delay task.
UNASSIGNED: Measurements in 4 patients with the very rare disease of lipodystrophy (LD), resulting in leptin deficiency, and 3 untreated healthy control persons were performed at 4 different time points: before start and over 12 weeks of metreleptin treatment. Inside the MRI scanner, participants performed the monetary incentive delay task and brain activity during the reward receipt phase of the trial was analyzed.
UNASSIGNED: We found a reward-related brain activity decrease in our 4 patients with LD over the 12 weeks of metreleptin treatment in the subgenual region, a brain area associated with the reward network, which was not observed in our 3 untreated healthy control persons.
UNASSIGNED: These results suggest that leptin replacement in LD induces changes of brain activity during reward reception processing completely unrelated to eating behavior or food stimuli. This could suggest eating behavior-unrelated functions of leptin in the human reward system.
UNASSIGNED: The trial is registered as trial No. 147/10-ek at the ethics committee of the University of Leipzig and at the State Directorate of Saxony (Landesdirektion Sachsen).