The CPT1C 5′UTR Contains a Repressing Upstream Open Reading Frame That Is Regulated by Cellular Energy Availability and AMPK

BACKGROUND: Translational control is utilized as a means of regulating gene expression in many species. In most cases, posttranscriptional regulatory mechanisms play an important role in stress response pathways and can lead to dysfunctional physiology if blocked by mutations. Carnitine Palmitoyltransferase 1 C (CPT1C), the brain-specific member of the CPT 1 family, has previously been shown to be involved in regulating metabolism in situations of energy surplus. PRINCIPAL FINDINGS: Sequence analysis of the CPT1C mRNA revealed that it contains an upstream open reading frame (uORF) in the 5' UTR of its mRNA. Using CPT1C 5' UTR/luciferase constructs, we investigated the role of the uORF in translational regulation. The results presented here show that translation from the CPT1C main open reading frame (mORF) is repressed by the presence of the uORF, that this repression is relieved in response to specific stress stimuli, namely glucose deprivation and palmitate-BSA treatment, and that AMPK inhibition can relieve this uORF-dependent repression. SIGNIFICANCE: The fact that the mORF regulation is relieved in response to a specific set of stress stimuli rather than general stress response, hints at an involvement of CPT1C in cellular energy-sensing pathways and provides further evidence for a role of CPT1C in hypothalamic regulation of energy homeostasis

Successful Weight Loss Surgery Improves Eating Control and Energy Metabolism: A Review of the Evidence

Eating behavior is determined by a balance of memories in terms of reward and punishment to satisfy the urge to consume food. Refilling empty energy stores and hedonistic motivation are rewarding aspects of eating. Overfeeding, associated adverse GI effects, and obesity implicate punishment. In the current review, evidence is given for the hypothesis that bariatric surgery affects control over eating behavior.Moreover, any caloric overload will reduce the feeling of satiety. Durable weight loss after bariatric surgery is probably the result of a new equilibrium between reward and punishment, together with a better signaling of satiation due to beneficial metabolic changes.We propose to introduce three main treatment goals for bariatric surgery: 1) acceptable weight loss, 2) improvement of eating control, and 3) metabolic benefit. To achieve this goal, loss of 50% to 70% of excess weight will be appropriate (i.e. 30% to 40% loss of initial weight), depending on the degree of obesity prior to operation

Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis

The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus

Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle

Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation/inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine/palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for β oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor α (PPARα), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an α-adrenergic blocking agent, prevents the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced decrease of skeletal muscle malonyl-CoA. Thus, the sympathetic nervous system is implicated in the transmission of the “malonyl-CoA signal” from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPARα is the concomitant increase in the expression of PGC1α, transcriptional coactivator of the UCP3 and PPARα-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure

AL Amyloidosis Associated with IgM Monoclonal Protein: A Distinct Clinical Entity

IgM-associated AL amyloidosis is rare and may represent a distinct entity. Sixty (7%) of 868 consecutive AL patients referred to our center had an IgM monoclonal protein. They were significantly older than non-IgM patients (median, 67 years vs. 62 years), had a higher frequency of lymph-node involvement (25% vs. 2%) and significantly lower median proteinuria (1.2 g/24h vs. 3.4 g/24h), N-terminal pro-natriuretic peptide type-B (1177 ng/L vs. 2135 ng/L) and troponin 1 (0.02 ng/mL vs. 0.05 ng/mL). In IgM patients, K light-chains were more frequent (42% vs. 23%) and the involved free light-chain concentration was lower (median 63 mg/L vs. 182 mg/L). Serum albumin and NT-proBNP were independent prognostic determinants. Response to treatment improved survival. The 14 patients who received melphalan/dexamethasone showed a 64% hematologic (complete remissions, 29%) and a 43% organ response rate. IgM-associated AL amyloidosis is a distinct entity, with less advanced organ dysfunction. Treatment with melphalan/dexamethasone might be effective in these patients

Rapid progression of familial amyloidotic polyneuropathy: a multinational natural history study

https://www.ncbi.nlm.nih.gov/pubmed/2620895

Changes in the Expression of Hypothalamic Lipid Sensing Genes in Rat Model of Intrauterine Growth Retardation (IUGR).

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. Recent data suggest that some of the molecular defects underlying type 2 diabetes reside in the CNS. The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where LCFA undergo -oxidation. Hypothalamic inhibition of CPT1 decreases food intake and suppresses endogenous glucose production. Our aim was to investigate the effects of uterine artery ligation, a procedure that mimics uteroplacental insufficiency, on the CNS expression of CPT1 and other key enzymes of LCFA metabolism. Bilateral uterine artery ligation was performed on d 19 of gestation in the pregnant rat; sham-operated pregnant rats served as controls. Hypothalamus, cerebellum, hippocampus, and cortex were dissected and analyzed at birth by real-time PCR. Nonesterified fatty acid (NEFA) serum levels were significantly higher in IUGR pups (p 0.0001). In IUGR rats, the hypothalamic expression of CPT1 isoform C (p 0.005) and acetyl-CoA carboxylase (ACC) isoforms alpha (p 0.05) and beta (p 0.005) were significantly decreased. The data presented here support the hypothesis that an abnormal intrauterine milieu can induce changes in hypothalamic lipid sensing

Evaluation of mechanical properties of Z250 composite resin light-cured by different methods Avaliação de propriedades mecânicas da resina composta Z250 fotoativada com diferentes métodos

This study evaluated some mechanical parameters of Z250 composite resin using different light-curing methods. Ten specimens were prepared for each mechanical test group with different dimensions according to the test. Light-curing was performed by: a). continuous light (800mW/cm²-40s); b). exponential light (0-800mW/cm²-40s); c). intermittent light (2s-600mW/cm²; 2s without light-80s); d). stepped light (10s-150mW/cm²; 30s-650mW/cm²); e). PAC (1320mW/cm²-3s); f). LED (350mW/cm²-40s). After 24 &plusmn; 1 h, the specimens were loaded at a crosshead speed of 0.5 mm/min until fracture. The mechanical properties were calculated and analyzed by ANOVA and Tukey test (5%). The results showed that the highest compressive strength values were found for the continuous, exponential, intermittent and stepped light methods, whereas PAC and LED obtained the lowest values. LED, stepped light, PAC, exponential and continuous light presented the highest values for diametral tensile strength. The intermittent light showed the lowest value, which was significantly lower than the value obtained for LED only. Flexural strength results were not significantly different between all light-curing methods. Finally, the highest modulus of elasticity values were obtained for LED, exponential, continuous and intermittent light, whereas PAC and stepped light showed the lowest values. The mechanical properties were affected by light-curing methods employed.<br>Este estudo avaliou algumas propriedades mecânicas da resina composta Z250 usando diferentes métodos de fotoativação. Dez amostras foram preparadas para cada grupo, com diferentes dimensões de acordo com o ensaio. Os métodos de fotoativação foram: a) luz contínua (800mW/cm²-40s); b) luz exponencial (0-800mW/cm²-40s); c) luz intermitente (2s-600mW/cm²; 2s sem luz-80s); d) dupla intensidade (10s-150mW/cm²; 30s-650mW/cm²); e) PAC (1320mW/cm²-3s); f) LED (350mW/cm²-40s). Após 24 &plusmn; 1 h, as amostras foram carregadas até fraturar (v=0,5 mm/min.). As propriedades mecânicas foram calculadas e os dados analisados estatisticamente (ANOVA e teste de Tukey 5%). Os resultados mostraram que, para resistência à compressão, os maiores valores foram encontrados com os métodos luz contínua, intermitente, exponencial e dupla intensidade, enquanto que PAC e LED obtiveram os menores valores. Os métodos LED, PAC, luz contínua, exponencial e dupla intensidade, mostraram os maiores valores para resistência à tração diametral, enquanto luz intermitente mostrou os menores valores, que diferiram apenas do LED. Para a resistência flexural, não houve diferença entre os métodos. Já, para o módulo de elasticidade, os maiores valores foram obtidos com LED, luz exponencial, contínua e intermitente, enquanto que PAC e dupla intensidade mostraram os menores valores. As propriedades mecânicas podem ser afetadas pelo método de fotativação utilizado