Anja Moss

Leptin Therapy in a Congenital Leptin-Deficient Patient Leads to Acute and Long-Term Changes in Homeostatic, Reward, and Food-Related Brain Areas

CONTEXT Mutations that lead to congenital leptin deficiency cause severe obesity, hyperphagia, and impaired satiety due to malfunctions of peripheral and brain-related mechanisms. DESIGN AND PATIENT In a leptin-deficient adolescent girl, we investigated brain-related changes before and at two time points after leptin therapy (3 d and 6 months). Functional magnetic resonance imaging was performed during visual stimulation with food (high and low caloric) and nonfood pictures. RESULTS Results show acute and long-term effects in the amygdala, the orbitofrontal cortex, and the substantia nigra/ventral tegmental area for the comparison of food and nonfood pictures. For the comparison of high and low caloric pictures, pure acute effects in the ventral striatum and the orbitofrontal cortex could be observed as well as acute and long-term effects in the hypothalamus. CONCLUSION This study gives additional insight in the influence of leptin therapy on brain functions in leptin deficiency.

Leptin Substitution Results in the Induction of Menstrual Cycles in an Adolescent with Leptin Deficiency and Hypogonadotropic Hypogonadism

Background: Leptin deficiency leads to midluteal-phase defect or reduced testicular volume in adults, despite normal gonadotropin levels. All children documented to date with leptin deficiency were prepubertal with physiologically low gonadotropins prior to therapy. A direct effect of leptin on pubertal development in a leptin-naive adolescent has not yet been shown. Methods: In 2010, we reported the first connatal leptin-deficient adolescent girl with clinically and chemically proven hypogonadotropic hypogonadism. In this study, we evaluated the effect of recombinant methionyl human leptin substitution. Results: Initially, the patient had prepubertal basal and stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, low growth hormone and insulin-like growth factor 1 (IGF1) levels and no pulsatile secretion of LH and FSH. After 11 weeks of therapy, basal and stimulated LH and FSH levels rose to pubertal values and nocturnal pulsatility was initiated. After 76 weeks of therapy, menstruation occurred at the age of 16.3 years. Pulsatile nocturnal growth hormone secretion, stimulated growth hormone secretion and IGF1 values also normalized. Conclusion: We describe here the first adolescent with hypogonadotropic hypogonadism due to connatal leptin deficiency. Leptin substitution led to a rapid induction of gonadotropin secretion and menarche. These data are further proof of the concept that leptin is needed for a timely maturation of the hypothalamic/pituitary/gonadal axis.

Weight loss in children and adolescents.

BACKGROUND 15% of children and adolescents in Germany are overweight, including 6.3% who are affected by obesity. The efficacy of conservative weight-loss treatments has been demonstrated, but there has not yet been a detailed analysis of their efficacy in terms of the amount of weight loss that can be expected. We re-evaluated the available evidence on this question, with particular attention to the methodological quality of clinical trials, in order to derive information that might be a useful guide for treatment. METHODS We conducted a systematic literature search of Medline for the period May 2008 (final inclusion date for a 2009 Cochrane Review) to December 2013. The identified studies were analyzed qualitatively. RESULTS 48 randomized controlled clinical trials with a total of 5025 participants met the predefined inclusion criteria for this analysis. In the ones that met predefined criteria for methodological quality, conservative weight-loss treatments led to weight loss in amounts ranging from 0.05 to 0.42 BMI z score (standard deviation score of the body mass index) over a period of 12-24 months. Information on trial dropout rates was available for 41 of the 48 trials; the dropout rate was 10% or higher in 27 of these (66% ), and 25% or higher in 9 (22% ). CONCLUSION The available evidence consistently shows that only a modest degree of weight loss can be expected from conservative treatment. Families seeking treatment should be informed of this fact. Future research should focus on determining predictive factors for therapeutic benefit, and on the evaluation of additional types of psychological intervention to promote coping with obesity.

Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene.

Context: Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone. Case Description: We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss. Conclusions: Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin.

Long-term stabilization effects of leptin on brain functions in a leptin-deficient patient.

Context Congenital leptin deficiency, caused by a very rare mutation in the gene encoding leptin, leads to severe obesity, hyperphagia and impaired satiety. The only systemic treatment is the substitution with metreleptin leading to weight reduction based on hormonal changes. Several studies have also shown alterations in brain function after metreleptin therapy. In a previous study, we were able to show changes in homeostatic (hypothalamus) and reward-related brain areas (striatum, orbitofrontal cortex (OFC), substantia nigra/ventral tegmental area, amygdala) 3 days and 6 months after therapy start in a leptin-deficient adolescent girl. To further access the time course of functional brain activation changes, we followed the patient for 2 years after initiation of the therapy. Design, Patient Functional magnetic resonance imaging during visual stimulation with food (high- and low-caloric) and non-food pictures was performed 1 and 2 years after therapy start in the previously described patient. Results The comparison of ‘food vs. non-food’ pictures showed a stabilization of the long-term effects in the amygdala and in the OFC. Therefore, no significant differences were observed between 6 months compared to 12 and 24 months in these regions. Additionally, a reduction of the frontopolar cortex activity over the whole time span was observed. For the comparison of high- and low-caloric pictures, long-term effects in the hypothalamus showed an assimilating pattern for the response to the food categories whereas only acute effects after 3 months were observed in hedonic brain regions. Conclusion This follow-up study shows that the long lasting benefit of metreleptin therapy is also associated with activation changes in homeostatic, hedonic and frontal control regions in congenital leptin deficiency.

Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girl

Background: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. Subject and Methods: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. Results: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. Conclusion: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.

Impaired HDL function in obese adolescents: Impact of lifestyle intervention and bariatric surgery

HDL regulates endothelial function via stimulation of nitric oxide production. It is documented that endothelial function is impaired in obese adolescents, and improved by lifestyle interventions (LI).

Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency

Context and aims Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency. Methods An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents. Results In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80–1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48–0.55) being distinct from normal was observed. Conclusions The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.

Evidence of inappropriate cardiovascular risk assessment in middle-age women based on recommended cut-points for waist circumference

BACKGROUND AND AIMS Diverse waist circumference thresholds for assessment of metabolic and cardiovascular risk in Caucasians are recommended by different health professional organizations. We aimed to determine optimal sex-specific thresholds for anthropometric measures showing the strongest association with cardiovascular risk factors in a cohort of middle-aged Germans. METHODS AND RESULTS Statistical analyses are based on data from 426 mothers and 267 fathers of participants of the Ulm Birth Cohort Study undergoing a clinical follow-up examination in 2008 (median age 41 years) using logistic regression analyses. The prevalence of many cardiometabolic risk factors was significantly higher in men than in women; hypertension: 45%/17% (p < 0.0001), apolipoprotein ratio B/A1 > 0.72: 35%/9% (<0.0001), hyperglycemia: 11%/14% (p = 0.3), which is in contrast to the predicted cardiovascular risk of 52%/70% and 24%/36% based on thresholds for waist circumference proposed by International Diabetes Federation and American Heart Association, respectively. We determined optimal thresholds for waist circumference between 90 and 95 cm for men and women. Using a threshold of 92 cm the prevalence of abdominal obesity was 59% in men and 24% in women, which was in agreement with the higher prevalence of overweight and obesity in men than in women (Body Mass Index (BMI) > 25: 64%/35%). The prediction of cardiometabolic risk factors by waist circumference and waist-to-height ratio did not outperform the prediction by BMI. In contrast to BMI, waist circumference was correlated with body height independent of sex. CONCLUSION Currently proposed thresholds for waist circumference spuriously overestimate the cardiovascular risk in women, but not in men in a German population.

Restrained and External-Emotional Eating Patterns in Young Overweight Children-Results of the Ulm Birth Cohort Study

Childhood obesity is one of the greatest public health challenges in Western countries. Abnormal eating behavior is thought to be a developmental trajectory to obesity. The Eating Pattern Inventory for Children (EPI-C) has not been used for children as young as eight years, and possible associations with body weight have not yet been established. Five hundred and twenty-one children of the Ulm Birth Cohort Study (UBCS; age eight) filled out the EPI-C and BMI was assessed. Adequacy of the scales was tested with confirmatory factor analysis and a MANOVA and cluster analysis established associations between eating patterns and BMI. The factor structure of the EPI-C was confirmed (GFI = .968) and abnormal eating behavior was associated with overweight (χ2(8) = 79.29, p<.001). The EPI-C is a valid assessment tool in this young age group. Overweight children consciously restrain their eating.