Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

Aims/hypothesis: A hallmark feature of the metabolic syndrome is abnormal glucose metabolism which can be improved by exercise. Recently the orphan nuclear receptor subfamily 4, group A, member 1 (NUR77) was found to be induced by exercise in muscle and was linked to transcriptional control of genes involved in lipid and glucose metabolism. Here we investigated if overexpression of Nur77 (also known as Nr4a1) in skeletal muscle has functional consequences for lipid and/or glucose metabolism. Methods: L6 rat skeletal muscle myotubes were infected with a Nur77-coding adenovirus and lipid and glucose oxidation was measured. Nur77 was also overexpressed in skeletal muscle of chow- and fat-fed rats and the effects on glucose and lipid metabolism evaluated. Results: Nur77 overexpression had no effect on lipid oxidation in L6 cells or rat muscle, but did increase glucose oxidation and glycogen synthesis in L6 cells. In chow- and high-fat-fed rats, Nur77 overexpression by electrotransfer significantly increased basal glucose uptake and glycogen synthesis, but no increase in insulin-stimulated glucose metabolism was observed. Nur77 electrotransfer was associated with increased production of GLUT4 and glycogenin and increased hexokinase and phosphofructokinase activity. Interestingly, Nur77 expression in muscle biopsies from obese men was significantly lower than in those from lean men and was closely correlated with body-fat content and insulin sensitivity. Conclusions/interpretation: Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism.T. Kanzleiter, E. Preston, D. Wilks, B. Ho, A. Benrick, J. Reznick, L. K. Heilbronn, N. Turner, G. J. Coone

Massive intestinal resection in rats fed up on glutamine: hepatic glycogen content valuation Ressecção intestinal extensa em ratos tratados com oferta oral de glutamina: avaliação do conteúdo hepático de glicogênio

BACKGROUND: Glutamine has been widely used in treatment of small bowel syndrome and its metabolic effects on the small intestine are well known, however, it has been little studied its effects on hepatic metabolism under this condition. AIM: To verify through experimental model, a glutamine based supplemental diet, administered via oral to rats submitted to massive intestinal resection, evaluating weight evolution and hepatic glycogen content. MATERIAL AND METHODS: Male rats, Wistar, were allocated into three groups to undergo enterectomy. Following diets were applied: with glutamine (G group), without glutamine (NG group), and standard diet from the laboratory (R group). All animals had massive small intestine resection including ileocecal valve removal. After 20 days, all animals were sacrificed. The liver was removed to histological analysis by light microscopy. Slides were stained by periodic acid of Schiff with diastasis. RESULTS: All animals lost weight from the beginning to the end of experiment. Comparing weight loss average expressed in percentage, there was no difference statistically significant on this variance. In analyzed groups, the hepatic glycogen content did not differ statistically, in the histological method evaluated. CONCLUSION: Glutamine feeding via oral did not influence weight loss reduction of animal submitted to massive intestinal resection and did not stimulate glycogen synthesis and storage into hepatocytes.<br>RACIONAL: A glutamina tem sido utilizada amplamente no tratamento da síndrome do intestino curto e seus efeitos metabólicos são bem conhecidos no intestino delgado, porém pouco se tem relatado sobre seus efeitos no metabolismo hepático nessa condição. OBJETIVO: Verificar em modelo experimental, o efeito de dieta suplementada com glutamina administrada por via oral, em ratos submetidos a ressecção intestinal extensa, na evolução ponderal e no conteúdo de glicogênio hepático. MATERIAL E MÉTODOS: Ratos Wistar machos foram distribuídos em três grupos enterectomizados. As seguintes dietas foram utilizadas: com glutamina (grupo G), sem glutamina (grupo NG) e a dieta padrão do laboratório (grupo R). Em todos os animais a ressecção extensa do intestino delgado incluiu a válvula íleo-cecal. Após 20 dias os animais foram sacrificados. O fígado foi retirado para estudo histológico por microscopia ótica. As lâminas foram coradas pelo ácido periódico com base de Schiff com diastase. RESULTADOS: Todos os animais perderam peso entre o inicio e o final da pesquisa. Na comparação da perda média de peso expressa em percentagem, não houve diferença estatística em relação a essa variável. Nos grupos estudados o conteúdo de glicogênio no hepatócito, avaliado por método histológico, não diferiu estatisticamente. CONCLUSÕES: A oferta de glutamina por via oral não contribuiu para redução da perda de peso dos animais submetidos a ressecção intestinal extensa e não estimulou a síntese e armazenamento de glicogênio nos hepatócitos