Changes in Satiety Hormones in Response to Leptin Treatment in a Patient with Leptin Deficiency.

BACKGROUND: We tested whether leptin treatment affects secretion of satiety-related gut peptides and brain-derived neurotrophic factor (BDNF), which is a regulator of energy homeostasis downstream of hypothalamic leptin signaling. METHODS: We report the case of a morbidly obese 14.7-year-old girl with a novel previously reported homozygous leptin gene mutation, in whom hormone secretion was evaluated in 30-min intervals for 10 h (07.30-17.30) to assess BDNF, insulin, glucagon-like peptide-1 (GLP-1), ghrelin, and peptide YY (PYY) secretion before as well as 11 and 46 weeks after start of metreleptin treatment. RESULTS: Leptin substitution resulted in strong reductions of body fat and calorie intake. Insulin secretion increased by 58.9% after 11 weeks, but was reduced by -44.8% after 46 weeks compared to baseline. Similarly, GLP-1 increased after 11 weeks (+15.2%) and decreased after 46 weeks. PYY increased consistently (+5%/ +13.2%, after 11/46 weeks). Ghrelin decreased after 46 weeks (-11%). BDNF secretion was not affected by leptin treatment. CONCLUSION: The strong increase in insulin and GLP-1 secretion after 11 weeks of metreleptin treatment cannot be explained by reduced adiposity and might contribute to improved central satiety. Observed changes of PYY can lead to increased satiety as well. However, leptin replacement does not seem to affect circulating BDNF levels.

Sonographically Assessed Intra-Abdominal Fat And Cardiometabolic Risk Factors in Adolescents with Extreme Obesity.

OBJECTIVE: The metabolic and cardiovascular risk of obesity is predominantly defined through the amount of intra-abdominal fat (IAF). Regarding this risk and the benefits of weight reduction gender-specific differences have been described. The aim of this study was to examine the gender-specific relationship between IAF assessed via ultrasound and the cardiometabolic risk profile in extremely obese adolescents before and after weight loss. METHODS: In 107 consecutively admitted adolescents (n = 59 girls, mean age 15.4 ± 2.6 years boys and 15.1 ± 2.1 years girls, mean BMI z-score 3.2 ± 0.6 boys and 3.5 ± 0.6 girls) anthropometric and fasting laboratory chemical parameters were measured before and after an in-patient long-term therapy (mean durance 5.6 ± 2.3 months). IAF was determined by measuring the intra-abdominal depth (IAD) via ultrasound. RESULTS: IAD was higher in boys as compared to girls (58.0 ± 22.4 mm vs. 51.3 ± 16.0 mm). IAD values were positively associated with BMI-z scores, waist circumferences, HOMA-IR and serum levels of x03B3;GT, hs-CRP and IL-6 in both genders. In boys, but not in girls, IAD was significantly correlated with systolic and diastolic blood pressure, serum levels of triglycerides, ALT as well as adiponectin and HDL-cholesterol. After a marked mean weight loss of -27.1 ± 16.2 kg (-20.1 ± 7.9%) in boys and of -20.5 ± 11.5 kg (-17.3 ± 7.1%) in girls, IAD decreased by -20.7 ± 16.2 mm (--32.4 ± 16.9%) in boys and by -18.4 ± 12,7 mm (-34.3 ± 18.4%) in girls, resulting in more pronounced ameliorations of cardiovascular risk factors in boys than in girls. CONCLUSIONS: The present study indicates that IAF assessed by ultrasound is a good indicator for the cardiometabolic risk factor profile in extremely obese adolescents. Associations between IAF and risk factors are more pronounced in boys than in girls.

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.

Medical and psychosocial implications of adolescent extreme obesity - acceptance and effects of structured care, short: Youth with Extreme Obesity Study (YES).

BACKGROUND: Prevalence rates of overweight and obesity have increased in German children and adolescents in the last three decades. Adolescents with extreme obesity represent a distinct risk group. On the basis of data obtained by the German Child and Youth Survey (KiGGS) and the German district military offices we estimate that the group of extremely obese adolescents (BMI ≥ 35 kg/m2) currently encompasses approximately 200.000 adolescents aged 14 to 21 yrs. Conventional approaches focusing on weight reduction have largely proven futile for them. In addition, only a small percentage of adolescents with extreme obesity seek actively treatment for obesity while contributing disproportionately strong to health care costs. Because of somatic and psychiatric co-morbidities and social problems adolescents with extreme obesity require special attention within the medical care system. We have initiated the project "Medical and psychosocial implications of adolescents with extreme obesity--acceptance and effects of structured care, short: 'Youths with Extreme Obesity Study (YES)'", which aims at improving the medical care and social support structures for youths with extreme obesity in Germany. METHODS/DESIGN: We focus on identification of these subjects (baseline examination) and their acceptance of diagnostic and subsequent treatment procedures. In a randomized controlled trial (RCT) we will investigate the effectiveness of a low key group intervention not focusing on weight loss but aimed at the provision of obesity related information, alleviation of social isolation, school and vocational integration and improvement of self-esteem in comparison to a control group treated in a conventional way with focus on weight loss. Interested individuals who fulfill current recommended criteria for weight loss surgery will be provided with a structured preparation and follow-up programs. All subjects will be monitored within a long-term observational study to elucidate medical and psychosocial outcomes. Our aim is to evaluate realistic treatment options. Therefore inclusion and exclusion criteria are minimized. We will recruit adolescents (age range 14-21 years) with extreme obesity (BMI ≥ 35 kg/m2) (extreme group) within 24 months (120 per centre, 5 centres) as well as obese adolescents being at risk for developing extreme obesity (BMI ≥ 30-34.9 kg/m2) (at risk group). Follow-up evalutations will be performed biannually after inclusion for several years depending on additional funding. In sum, we aim at establishing evaluated health care structures for extremely obese adolescents. DISCUSSION: The results of YES will be of importance for a frequently neglected group of individuals, for whom current medicine has little to offer in terms of structured access to empirically evaluated therapeutic programs. Thus, the results will be both a help for the adolescents within the study and for others in the future given that the trial will lead to a positive finding. Moreover, it will help practitioners and therapists to deal with this neglected group of individuals. TRIAL REGISTRATION: Project registration numbers for each subproject: 1.) ClinicalTrials.gov: NCT01625325, NCT01703273, NCT01662271, NCT01632098; 2.) Germanctr.de: DRKS00004172, DRKS00004195, DRKS00004198, DRKS00004197.

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

OBJECTIVE: 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). DESIGN AND METHODS: HDL function in obese adolescents and the impact of LI or Roux-en-Y gastric bypass surgery (RYGB) was assessed. HDL was isolated from 14 adolescents with normal body mass index (HDLcontrol ), 10 obese (HDLobese ) before and after 6 month LI, and five severe obese adolescents before and one year after RYGB. HDL-mediated phosphorylation of endothelial nitric oxide synthase (eNOS)-Ser(1177) , eNOS-Thr(495) , and PKC-ßII was evaluated. In addition the HDL proteome was analyzed. RESULTS: HDLobese -mediated eNOS-Ser(1177) phosphorylation was reduced, whereas eNOS-Thr(495) phosphorylation increased significantly when compared to HDLcontrol . No impact of obesity was observed on PKC-ßII phosphorylation. LI and RYGB had no impact on HDL-mediated phosphorylation of eNOS and PKC-ßII. A principle component plot analysis of the HDL particle separated controls and severe obese, whereas the interventions did not trigger sufficient differences to the HDL proteome to permit distinction. CONCLUSION: These results demonstrated that HDL-function is impaired in obese adolescents, and that LI or RYGB did not correct this dysfunction. This might be an argument for developing earlier prevention strategies in obese adolescents to avoid HDL dysfunction.

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.