Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.

DNA Damage and the Activation of the p53 Pathway Mediate Alterations in Metabolic and Secretory Functions of Adipocytes.

Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the effect on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of mice fed a high-fat diet and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, injection of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by proinflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased the expression of chemokines and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased, and lipolysis was increased. These events were prevented by p53 inhibition, whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocytes could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction, and insulin resistance.

Registered dietitians' roles in decision-making processes for PEG placement in the elderly.

PURPOSE: The role of registered dietitians (RDs) in decision-making for percutaneous endoscopic gastrostomy (PEG) placement was explored. The ethical climate in their workplace and the relationship between decision-making and the ethical climate were examined. METHODS: The survey included 67 RDs in complex continuing care and long-term care settings in Ontario. Descriptive statistics were used to describe roles, ethical climate, and professional characteristics. Pearson's and nonparametric correlations were used to examine relationships between roles, ethical climate, and professional characteristics. RESULTS: Among the respondents, 97% thought RDs had a role in decision-making processes. The majority of RDs were usually or always involved in two roles: identifying relevant nutrition issues (91.2%) and discussing feeding options and alternatives (80.7%). Dietitians' roles in decision-making processes were more extensive when their relationship with physicians was positive (r=0.321, P=0.016), they had adequate knowledge (r=0.465, P<0.001) and adequate skills (r=0.520, P<0.001), and they were more satisfied with their role (r=0.554, P<0.001). CONCLUSIONS: Registered dietitians performed a variety of roles in decision-making processes concerning PEG placement in the elderly. A positive working relationship with physicians, knowledge, skills, and role satisfaction significantly increase RDs' involvement with patients and families.

Functions performed by level of practice of registered dietitian members of the diabetes care and education dietetic practice group.

The purpose of this study was to examine current professional practices of registered dietitians (RDs) in the Diabetes Care and Education dietetic practice group (DPG), analyzed by levels of practice: entry-level, specialty-practice, or advanced-level. The results of the Diabetes Care and Education DPG 2002-2003 membership survey were used for this study. The study was limited to RD members of the Diabetes Care and Education DPG who completed the membership survey in its entirety. Frequency distributions, chi2, Fisher exact test, and cluster analysis were performed with a prior alpha set at .10. Sixty-one (5.0%) RDs were functioning as an entry-level practitioner, 851 (69.1%) were functioning as a specialty-practice practitioner, and 320 (25.1%) as an advanced-level practitioner. Significantly more advanced-level practitioners were performing more tasks compared with entry-level practitioners. Entry-level RDs performed a mean of 2.4 functions, specialty-practice practitioners performed 7.7, and advanced-level practitioners performed 11.6 functions. The results of this survey further delineated that RDs function at various levels of practice and that credentials for RDs increased as level of practice advanced.