Background: Glutaredoxin-2 (Grx2) modulates reversible glutathionylation of mitochondrial proteins. Results: Grx2 glutathionylates and inhibits UCP3-mediated proton leak. Conclusion: Grx2 modulates UCP3 activity. Significance: Grx2 is required to control proton leak through UCP3 and mitochondrial metabolism.

Obesity is reaching epidemic proportions in developed countries and represents a signifi cant risk factor for cardiovascular disease, diabetes, and cancer ( 1 ). Enrolment in clinical and nonclinical obesity treatment programs is unprecedented. Success in obesity treatment programs is highly variable, related in part to compliance and program characteristics (e.g., type and duration of hypocaloric diets, educational components, and/or exercise-associated energy expenditure). While it is generally well accepted that there is substantial inter-individual variability in the susceptibility to weight gain in response to overfeeding ( 2, 3 ), less well understood is the impact of biological factors on weight loss success. However, studies of monozygotic twins have shown greater inter-pair than intra-pair variation in weight loss ( 4 ), consistent with the idea that there are important genetic determinants of weight loss success. We have studied the molecular and cellular determinants of variable weight loss in highly compliant subjects in an intensively supervised and interactive hypocaloric clinical obesity treatment program at the Ottawa Hospital. We previously reported differences in muscle mitochondrial energy ineffi ciencies between program participants exhibiting high versus low weight loss success ( 5 ). Here, we extend these fi ndings by demonstrating distinct differences in skeletal muscle gene expression profi les and in structural and metabolic characteristics between individuals who Abstract Inter-individual variability in weight gain and loss under energy surfeit and defi cit conditions, respectively, are well recognized but poorly understood phenomena. We documented weight loss variability in an intensively supervised clinical weight loss program and assessed skeletal muscle gene expression and phenotypic characteristics related to variable response to a 900 kcal regimen. Matched pairs of healthy, diet-compliant, obese diet-sensitive (ODS) and dietresistant (ODR) subjects were defi ned as those in the highest and lowest quintiles for weight loss rate. Physical activity energy expenditure was minimal and comparable. Following program completion and weight stabilization, skeletal muscle biopsies were obtained. Gene expression analysis of rectus femoris and vastus lateralis indicated upregulation of genes and gene sets involved in oxidative phosphorylation and glucose and fatty acid metabolism in ODS compared with ODR. In vastus lateralis , there was a higher proportion of oxidative (type I) fi bers in ODS compared with ODR women and lean controls, fi ber hypertrophy in ODS compared with ODR women and lean controls, and lower succinate dehydrogenase in oxidative and oxidative-glycolytic fi bers in all obese compared with lean subjects. Intramuscular lipid content was generally higher in obese versus lean, and specifi cally higher in ODS vs. lean women. Altogether, our fi ndings demonstrate differences in muscle gene expression and fi ber composition related to clinical weight loss success. Abbreviations: B...

BackgroundIn utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice.MethodsWe used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum fed dams (C). Weight loss of 10 wk old offspring on a 4 wk 40% calorie restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level.ResultsU have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber type muscle U had decreased mitochondrial content and decreased adenylate free leak respiration, fatty acid oxidative capacity, and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction.ConclusionsOur results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle energetics and blunts response to a hypocaloric diet in adulthood. We propose that mitochondrial dysfunction links undernutrition in utero with metabolic disease in adulthood.

We show that in utero undernutrition is associated with impaired cardiac muscle energetics and increased plasma short-chain acylcarnitines in adult mice. Findings suggest that in utero undernutrition is associated with maladaptive programming processes that have negative effects on the heart.

BackgroundSignificant knowledge gaps exist related to evaluating health product risk communication effectiveness in a regulatory setting. To this end, Health Canada is assessing methods to evaluate the effectiveness of their health product risk communications in an attempt to identify best practices.ObjectiveWe examined the health literacy burden of Public Advisories (PAs) before and after implementation of a new template. We also compared two methods for their usefulness and applicability in a regulatory setting.MethodsSuitability assessment of materials (SAM) and readability tests were run by three independent evaluators on 46 PAs (14 “Pre-format change” and 32 “Post-format change”). These tests provided adequacy scores for various health literacy elements and corresponding scholastic grades.ResultsPAs using the new template scored better, with an average increase of 18 percentage points (p < 0.001), on the SAM test. All of the 46 PAs evaluated were rated as “requiring a college/university education comprehension level” using readability tests. Results among readability tests were comparable.ConclusionImprovements made to Health Canada’s PA template had a measurable, positive effect on reducing the health literacy burden, based on the SAM results. A greater focus on the use of plain language would likely add to this effect. The SAM test emerged as a robust, reliable, and informative health literacy tool to assess risk messages and identify further improvement efforts. Regulators, industry, and public sector organizations involved in communicating health product risk information should consider the use of this test as a best practice to evaluate health literacy burden.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-013-0117-8) contains supplementary material, which is available to authorized users.