Weight loss after bariatric surgery in morbidly obese adolescents with MC4R mutations.

OBJECTIVE: To determine the frequency of Melanocortin 4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations. DESIGN AND METHODS: In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12-month postoperative data available for analysis. RESULTS: MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although nonsignificant, %EWL compared to 52 nonmatched controls at 12 months postoperatively (48.6% vs. 23.4%; P < 0.37). When matched by age, sex, and race to 14 controls, there was no significant difference in %EWL (P < 0.31), BMI change (P < 0.27), or absolute weight loss (P < 0.20). CONCLUSION: The frequency of MC4R mutations is similar to prior studies, with affected patients showing beneficial weight loss outcomes.

Effects of reduced weight maintenance and leptin repletion on functional connectivity of the hypothalamus in obese humans.

Treating obesity has proven to be an intractable challenge, in part, due to the difficulty of maintaining reduced weight. In our previous studies of in-patient obese subjects, we have shown that leptin repletion following a 10% or greater weight loss reduces many of the metabolic (decreased energy expenditure, sympathetic nervous system tone, and bioactive thyroid hormones) and behavioral (delayed satiation) changes that favor regain of lost weight. FMRI studies of these same subjects have shown leptin-sensitive increases in activation of the right hypothalamus and reduced activation of the cingulate, medial frontal and parahippocampal gryi, following weight loss, in response to food stimuli. In the present study, we expanded our cohort of in-patient subjects and employed psychophysiological interaction (PPI) analysis to examine changes in the functional connectivity of the right hypothalamus. During reduced-weight maintenance with placebo injections, the functional connectivity of the hypothalamus increased with visual areas and the dorsal anterior cingulate (dorsal ACC) in response to food cues, consistent with higher sensitivity to food. During reduced-weight maintenance with leptin injections, however, the functional connectivity of the right hypothalamus increased with the mid-insula and the central and parietal operculae, suggesting increased coupling with the interoceptive system, and decreased with the orbital frontal cortex, frontal pole and the dorsal ACC, suggesting a down-regulated sensitivity to food. These findings reveal neural mechanisms that may underlie observed changes in sensitivity to food cues in the obese population during reduced-weight maintenance and leptin repletion.

Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons.

The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.