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The discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic 'lean' mouse model, which has been selected for low adiposity over 60 generations, to identify mitochondrial thiosulfate sulfurtransferase (Tst; also known as rhodanese) as a candidate obesity-resistance gene with selectively increased expression in adipocytes. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst-deficient mice showed markedly exacerbated diabetes, whereas pharmacological activation of TST ameliorated diabetes in mice. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, TST mRNA expression in adipose tissue correlated positively with insulin sensitivity in adipose tissue and negatively with fat mass. Thus, the genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for individuals with type 2 diabetes N. Morton was supported by a Career Development Fellowship, Institutional Strategic Support Fund award and a New Investigator Award from the Wellcome Trust (100981/Z/13/Z), a Research Councils UK Fellowship and a British Heart Foundation Centre of Research Excellence exchange award. We thank the Slovenian Research Agency (core funding P4-0220, project N5-0003 Syntol and J4-6804 to S.H.); and a Young Scientist Fellowship to J. Beltram. We acknowledge support of the British Heart Foundation Research Excellence Award in support of the Bioinformatics Core contribution. T. Stulnig received funding from the Federal Ministry of Economy, Family and Youth and the Austrian National Foundation for Research, Technology and Development. G. Churchill was supported by the US National Institutes of Health grant R01GM 070683. J.M. Fernandez-Real acknowledges funding from FIS PI11/00214. A. Vidal-Puig was funded by the UK Medical Research Council (MRC) MDU, an MRC Programme grant, MRC DMC Core and MITIN (HEALTH-F4-2008-223450)

Decreased metabolic flexibility, i.e. a compromised ability to adjust fuel oxidation to fuel availability supports development of adverse consequences of obesity. The aims of this study were (i) to learn whether obesity-resistant A/J and obesity-prone C57BL/6J mice differ in their metabolic flexibility right after weaning; and (ii) to characterize possible differences in control of glucose homeostasis in these animals using glucose tolerance tests (GTT). A/J and C57BL/6J mice of both genders were maintained at 20 °C and weaned to standard low-fat diet at 30 days of age. During the first day after weaning, using several separate animal cohorts, (i) GTT was performed using 1 or 3 mg glucose/g body weight (BW), while glucose was administered either orally (OGTT) or intraperitoneally (IPGTT) at 20 °C; and (ii) indirect calorimetry (INCA) was performed, either in a combination with oral gavage of 1 or 7.5 mg glucose/g BW, or during a fasting/re-feeding transition. INCA was conducted either at 20 °C or 34 °C. Results of both OGTT and IPGTT using 1 mg glucose/g BW at 20 °C, and INCA using 7.5 mg glucose/g BW at 34 °C, indicated higher glucose tolerance and higher metabolic flexibility to glucose, respectively, and lower fasting glycemia in A/J mice as compared with C57BL/6J mice. Thus, control of whole body glucose metabolism between A/J and C57BL/6J mice represents a phenotypic feature differentiating between the strains right after weaning.

Background: Diet-induced obesity is frequently used to demonstrate cardiac dysfunction. However, some rats, like humans, are susceptible to developing an obesity phenotype, whereas others are resistant to that. Objective: To evaluate the association between obesity resistance and cardiac function, and the impact of obesity resistance on calcium handling. Methods: Thirty-day-old male Wistar rats were distributed into two groups, each with 54 animals: control (C; standard diet) and obese (four palatable high-fat diets) for 15 weeks. After the experimental protocol, rats consuming the high-fat diets were classified according to the adiposity index and subdivided into obesity-prone (OP) and obesity-resistant (OR). Nutritional profile, comorbidities, and cardiac remodeling were evaluated. Cardiac function was assessed by papillary muscle evaluation at baseline and after inotropic maneuvers. Results: The high-fat diets promoted increase in body fat and adiposity index in OP rats compared with C and OR rats. Glucose, lipid, and blood pressure profiles remained unchanged in OR rats. In addition, the total heart weight and the weight of the left and right ventricles in OR rats were lower than those in OP rats, but similar to those in C rats. Baseline cardiac muscle data were similar in all rats, but myocardial responsiveness to a post-rest contraction stimulus was compromised in OP and OR rats compared with C rats. Conclusion: Obesity resistance promoted specific changes in the contraction phase without changes in the relaxation phase. This mild abnormality may be related to intracellular Ca2+ handling. Resumo Fundamento: A obesidade induzida por dieta é frequentemente utilizada para demonstração de disfunção cardíaca. No entanto, alguns ratos, como humanos, são suscetíveis ao desenvolvimento de um fenótipo de obesidade, enquanto outros são resistentes. Objetivo: Avaliar a relação entre resistência à obesidade e função cardíaca e o impacto da resistência à obesidade no trânsito de cálcio. Métodos: Ratos Wistar machos com trinta dias de idade foram distribuídos em dois grupos com 54 animais cada: controle (C; dieta padrão) e obesos (quatro dietas palatáveis hiperlipídicas) por 15 semanas. Após o protocolo experimental, os ratos alimentados por dietas hiperlipídicas foram classificados de acordo com o índice de adiposidade e subdivididos em propensos à obesidade (PO) e resistentes à obesidade (RO). Foram avaliados o perfil nutricional, comorbidades e remodelação cardíaca. A função cardíaca foi avaliada pelo estudo do músculo papilar isolado em condições basais e após manobras inotrópicas. Resultados: As dietas hiperlipídicas promoveram aumento na gordura corporal e no índice de adiposidade em ratos PO comparados com ratos C e RO. Os perfis de glicose, lipídios e pressão arterial permaneceram inalterados em ratos RO. Além disso, os ratos RO apresentaram peso total do coração e dos ventrículos direito e esquerdo mais baixos do que ratos PO, mas semelhantes aos ratos C. Os músculos cardíacos de todos os ratos apresentaram dados semelhantes na condição basal, mas a resposta miocárdica a um estímulo de contração pós-pausa estava comprometida em ratos PO e RO em comparação aos ratos C. Conclusão: A resistência à obesidade promoveu alterações específicas na fase de contração, sem alterar a fase de relaxamento. Esta anormalidade leve pode estar relacionada com o trânsito intracelular de Ca+2.

Background Dietary polyunsaturated fatty acids (PUFA), in particular the long chain marine fatty acids docosahexaenoic (DHA) and eicosapentaenoic (EPA), are linked to many health benefits in humans and in animal models. Little is known of the molecular response to DHA and EPA of the small intestine, and the potential contribution of this organ to the beneficial effects of these fatty acids. Here, we assessed gene expression changes induced by DHA and EPA in the wildtype C57BL/6J murine small intestine using whole genome microarrays and functionally characterized the most prominent biological process. Results The main biological process affected based on gene expression analysis was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR, and -in a second animal experiment- intestinal fatty acid oxidation measurements confirmed significant gene expression differences and showed in a dose-dependent manner significant changes at biological functional level. Furthermore, no major changes in the expression of lipid metabolism genes were observed in the colon. Conclusion We show that marine n-3 fatty acids regulate small intestinal gene expression and increase fatty acid oxidation. Since this organ contributes significantly to whole organism energy use, this effect on the small intestine may well contribute to the beneficial physiological effects of marine PUFAs under conditions that will normally lead to development of obesity, insulin resistance and diabetes.