During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a ...prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.
The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy ...expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg·d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.
Bariatric surgery reduces cancer risk in populations with obesity. It is unclear if weight loss alone or metabolic changes related to bariatric surgery cause this effect.
We evaluated the ...relationship between surgical weight loss and serum biomarker changes with incident cancer in a bariatric surgery cohort.
Ten U.S. clinical facilities.
The Longitudinal Assessment of Bariatric Surgery 2 (LABS-2) is a prospective multicenter cohort (n = 2458, 79% female, mean age = 46). We evaluated weight and serum biomarkers, measured preoperatively and 1 year postoperatively, as predictors for incident cancer. Associations were determined using Cox proportional hazards models adjusting for weight loss, age, sex, education, and smoking history.
Over 8759 person-years of follow-up, 82 patients reported new cancer diagnosis (936 per 100,000 person-years, 95% confidence interval CI: 749-1156). Cancer risk was decreased by approximately 50% in participants with 20% to 34.9% total weight loss (TWL) compared with <20% TWL (hazard ratio HR = .49, 95%CI: .29-.83). Reduced cancer risk was observed with percent decrease from baseline for glucose (per 10%, HR = .94, 95%CI: .90-.99), proinsulin (per 20%, HR = .95, 95%CI: .93-.98), insulin (per 30%, HR = .97, 95%CI: .96-.99), and leptin (per 20%, HR = .81, 95%CI: .68-.97), and per 15% percent increase in ghrelin (HR = .94, 95%CI: .29-.83).
After bariatric surgery, cancer risk is reduced >50% when weight loss exceeds 20% TWL compared with patients with <20% TWL. Weight loss alone may not explain the observed risk reduction, as improvements in diabetes, leptin, and ghrelin were associated with decreased cancer risk.
Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is ...a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5–15) and body mass index (BMI) of 31.3 kg/m2 (range, 22–46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean ± sd; 429 ± 374 vs. 270 ± 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean ± sd; 429 ± 374 vs. 139 ± 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.
Background:
The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and Prader-Willi Syndrome (PWS) are poorly understood.
Objective:
We compared effects of ...high-carbohydrate (HC) and high-fat (HF) meals and GH therapy on ghrelin, insulin, peptide YY (PYY), and insulin sensitivity in children with PWS and body mass index (BMI) –matched obese controls (OCs).
Methods:
In a randomized, crossover study, 14 PWS (median, 11.35 y; BMI z score BMI-z, 2.15) and 14 OCs (median, 11.97 y; BMI-z, 2.35) received isocaloric breakfast meals (HC or HF) on separate days. Blood samples were drawn at baseline and every 30 minutes for 4 hours. Mixed linear models were adjusted for age, sex, and BMI-z.
Results:
Relative to OCs, children with PWS had lower fasting insulin and higher fasting ghrelin and ghrelin/PYY. Ghrelin levels were higher in PWS across all postprandial time points (P < .0001). Carbohydrate was more potent than fat in suppressing ghrelin levels in PWS (P = .028); HC and HF were equipotent in OCs but less potent than in PWS (P = .011). The increase in PYY following HF was attenuated in PWS (P = .037); thus, postprandial ghrelin/PYY remained higher throughout. A lesser increase in insulin and lesser decrease in ghrelin were observed in GH-treated PWS patients than in untreated patients; PYY responses were comparable.
Conclusion:
Children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ghrelin/PYY ratio. GH therapy in PWS is associated with increased insulin sensitivity and lesser postprandial suppression of ghrelin. The ratio Ghrelin/PYY may be a novel marker of orexigenic drive.
Summary
Background Prader–Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with ...hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear.
Objective To determine if high ghrelin levels precede the onset of obesity in young PWS children.
Design and methods A cross‐sectional study of 33 infants with PWS and 28 healthy control subjects (C). Fasting ghrelin and other satiety hormones were measured.
Results Median total serum ghrelin in young children with PWS trended higher, but did not differ significantly from those in C of similar age, weight‐for‐age z‐score and sex. However, there was more variability in ghrelin concentrations of young PWS. Eleven of 33 PWS subjects had ghrelin levels greater than the 95th percentile for ghrelin values in the C subjects (> 2871 pg/ml). Six of the PWS subjects with high ghrelin levels had weight‐for‐age z‐scores < 0. Ghrelin concentrations in PWS and C infants exceeded those in older children. In youngsters with PWS, leptin was higher, suggesting a relative excess of fat to lean body mass and plasma adiponectin was increased.
Conclusions Young infants with PWS who have not yet developed hyperphagia or obesity have median fasting ghrelin levels similar to controls. However, a subset (33%) of young PWS is hyperghrelinaemic; approximately one‐half of those with hyperghrelinaemia have BMI z‐score < 0. The age‐related decline in ghrelin is blunted in PWS.
Contents:
Ghrelin is implicated in meal initiation because circulating levels increase before and fall after meal consumption. In rodents, ghrelin stimulates food intake via hypothalamic circuits ...expressing the melanocortin 4 receptor (MC4R).
Objective:
The aim of the study was to investigate the impact of central melanocortinergic tone on ghrelin secretion in humans.
Design/Setting/Patients/Main Outcome Measure:
We measured plasma total ghrelin before and after 3 standardized meals in patients with MC4R mutations and obese and lean controls. Fasting total ghrelin, area under the curve, and early (30-min) and intermeal postprandial total ghrelin suppression (the percentage difference between the premeal and the 30-min postprandial or intermeal nadir total ghrelin concentration) were calculated.
Results:
Fasting total ghrelin concentrations and area under the curve for total ghrelin concentrations were significantly decreased in both obese groups compared to lean controls (fasting total ghrelin: lean controls, 1083 ± 203 pg/ml; and obese controls, 696 ± 81 pg/ml; MC4R: 609 ± 99 pg/ml, P < .05). Early and intermeal postprandial total ghrelin suppression was attenuated in MC4R-deficient patients compared to lean controls (P < .05); a similar pattern was observed for early postprandial suppression in comparison with obese controls, but this difference did not reach statistical significance (P = .09).
Conclusions:
These findings are consistent with a role for central melanocortinergic signaling in modulating meal-related total ghrelin suppression.
Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin ...concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 μg/kg·d) for 5–7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (−35%; P < 0.001) was still present after intervention but was blunted (−11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject’s parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population.
Summary
Objective Prader–Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized ...that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.
Design, patients and measurements We measured total adiponectin and its isoforms high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin and satiety hormones in 14 children with PWS median age 11·35 years, body mass index (BMI) Z‐score 2·15 and 14 BMI‐matched controls (median age 11·97 years, BMI Z‐score 2·34).
Results Despite comparable BMI Z‐scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA‐IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z‐score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0·05), HOMA‐IR (P < 0·01), BMI Z‐score (P < 0·05), insulin (P < 0·01) and leptin (P < 0·05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls.
Conclusions Relative to controls of similar age and BMI Z‐score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI‐matched controls.
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