Proximate causes for diet-induced obesity in laboratory mice: a case study.

BACKGROUND/OBJECTIVES: Detailed protocols and recommendations for the assessment of energy balance have been provided to address the problems associated with different body mass and body composition as apparent for mouse models in obesity research. Here, we applied these guidelines to investigate energy balance in two inbred mouse strains with contrasting susceptibilities for diet-induced obesity (DIO). Mice of the AKR/J strain are highly susceptible, whereas the SWR/J mice are almost completely resistant. The proximate mechanisms responsible for this striking phenotypic difference are only partially understood. SUBJECTS/METHODS: Body mass and body composition, metabolizable energy, energy expenditure (EE), body temperature and spontaneous physical activity behavior were first assessed in a cohort of male AKR/J (N=29) and SWR/J (N=30) mice fed on a low-fat control diet (CD) to identify metabolic adaptations determining resistance to DIO. Thereafter, the immediate metabolic responses to high-fat diet (HFD) feeding for 3 days were investigated. Groups of weight-matched AKR/J (N=8) and SWR/J (N=8) mice were selected from the initial cohort for this intervention. RESULTS: Strain differences in body mass, fat mass and lean mass were adjusted by body mass as this was the only covariate significantly correlated with metabolizable energy and EE. On the CD, EE and fat oxidation was higher in SWR/J than in AKR/J mice, whereas no difference was found for metabolizable energy. In response to HFD feeding, both strains increased metabolizable energy intake, but also increased EE, body temperature, and fat oxidation. The catabolic adaptations to HFD feeding opposed the development of positive energy balance. Increased EE was not due to increased spontaneous physical activity. A significant strain difference was found when balancing metabolizable energy and daily energy expenditure (DEE). CONCLUSIONS: The guidelines were applicable with some limitations related to the adjustment of differences in body composition. Metabolic phenotyping revealed that metabolizable energy, DEE and metabolic fuel selection all contribute to the development of DIO. Therefore, assessing both sides of the energy balance equation is essential to identify the proximate mechanisms.

The gap between coverage and care-what can Canadian paediatricians do about access to health services for refugee claimant children?

INTRODUCTION: In June 2012, the government of Canada severely restricted the scope of the Interim Federal Health Program that had hitherto provided coverage for the health care needs of refugee claimants. The Quebec government decided to supplement coverage via the provincial health program. Despite this, we hypothesized that refugee claimant children in Montreal would continue to experience significant difficulties in accessing basic health care. OBJECTIVES: (1) Report the narrative experiences of refugee claimant families who were denied health care services in Montreal following June 2012, (2) describe the predominant barriers to accessing health care services and understanding their impact using thematic analysis and (3) derive concrete recommendations for child health care providers to improve access to care for refugee claimant children. METHODS: Eleven parents recruited from two sites in Montreal participated in semi-structured interviews designed to elicit a narrative account of their experiences seeking health care. Interviews were recorded, transcribed, coded using NVivo software and subjected to thematic analysis. RESULTS: Thematic analysis of the data revealed five themes concerning barriers to health care access: lack of continuous health coverage, health care administrators/providers' lack of understanding of Interim Federal Health Program coverage, refusal of services or fees charged, refugee claimants' lack of understanding about health care rights and services and language barriers, and four themes concerning the impact of denial of care episodes: potential for adverse health outcomes, psychological distress, financial burden and social stigma. CONCLUSION: We propose eight action points for advocacy by Canadian paediatricians to improve access to health care for refugee claimant children in their communities and institutions.

Characterization of the melanocortin-4-receptor nonsense mutation W16X in vitro and in vivo.

Several genetic diseases are triggered by nonsense mutations leading to the formation of truncated and defective proteins. Aminoglycosides have the capability to mediate a bypass of stop mutations during translation thus resulting in a rescue of protein expression. So far no attention has been directed to obesity-associated stop mutations as targets for nonsense suppression. Herein, we focus on the characterization of the melanocortin-4-receptor (MC4R) nonsense allele W16X identified in obese subjects. Cell culture assays revealed a loss-of-function of Mc4r(X16) characterized by impaired surface expression and defect signaling. The aminoglycoside G-418 restored Mc4r(X16) function in vitro demonstrating that Mc4r(X16) is susceptible to nonsense suppression. For the evaluation of nonsense suppression in vivo, we generated a Mc4r(X16) knock-in mouse line by gene targeting. Mc4r(X16) knock-in mice developed hyperphagia, impaired glucose tolerance, severe obesity and an increased body length demonstrating that this new mouse model resembles typical characteristics of Mc4r deficiency. In a first therapeutic trial, the aminoglycosides gentamicin and amikacin induced no amelioration of obesity. Further experiments with Mc4r(X16) knock-in mice will be instrumental to establish nonsense suppression for Mc4r as an obesity-associated target gene expressed in the central nervous system.