Y2Y4 Receptor Double Knockout Protects Against Obesity Due to a High-Fat Diet or Y1 Receptor Deficiency in Mice

Neuropeptide Y receptors are critical regulators of energy homeostasis, but the functional interactions and relative contributions of Y receptors and the environment in this process are unknown. We measured the effects of an ad libitum diet of normal or high-fat food on energy balance in mice with single, double, or triple deficiencies of Y1, Y2, or Y4 receptors. Whereas wild-type mice developed diet-induced obesity, Y2Y4 double knockouts did not. In contrast, Y1 knockout or Y1Y2 or Y1Y4 receptor double knockout mice developed an exacerbated diet-induced obesity syndrome. Remarkably, the antiobesity effect of Y2Y4 deficiency was stronger than the obesogenic effect of Y1 deficiency, since Y1Y2Y4 triple knockouts did not develop obesity on the high-fat diet. Resistance to diet-induced obesity in Y2Y4 knockouts was associated with reduced food intake and improved glucose tolerance in the absence of changes in total physical activity. Fecal concentration of free fatty acids was significantly increased in Y2Y4 knockouts in association with a significantly reduced bile acid pool and marked alterations in intestinal morphology. In addition, hypothalamic proopiomelanocortin expression was decreased in diet-induced obesity (in both wild-type and Y1 receptor knockout mice) but not in obesity-resistant Y2Y4 receptor knockout mice fed a high-fat diet. Therefore, deletion of Y2 and Y4 receptors synergistically protects against diet-induced obesity, at least partially via changes in food intake and hypothalamic proopiomelanocortin expression

Six-minute walking test in children with ESRD: discrimination validity and construct validity

The six-minute walking test (6MWT) may be a practical test for the evaluation functional exercise capacity in children with end-stage renal disease (ESRD). The aim of this study was to investigate the 6MWT performance in children with ESRD compared to reference values obtained in healthy children and, secondly, to study the relationship between 6MWT performance with anthropometric variables, clinical parameters, aerobic capacity and muscle strength. Twenty patients (13 boys and seven girls; mean age 14.1 ± 3.4 years) on dialysis participated in this study. Anthropometrics were taken in a standardized manner. The 6MWT was performed in a 20-m-long track in a straight hallway. Aerobic fitness was measured using a cycle ergometer test to determine peak oxygen uptake \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\left( {\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}} \right)$$\end{document}, peak rate (Wpeak) and ventilatory threshold (VT). Muscle strength was measured using hand-held myometry. Children with ESRD showed a reduced 6MWT performance (83% of predicted, p < 0.0001), irrespective of the reference values used. The strongest predictors of 6MWT performance were haematocrit and height. Regression models explained 59% (haematocrit and height) to 60% (haematocrit) of the variance in 6MWT performance. 6MWT performance was not associated with \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}}$$\end{document}, strength, or other anthropometric variables, but it was significantly associated with haematocrit and height. Children with ESRD scored lower on the 6MWT than healthy children. Based on these results, the 6MWT may be a useful instrument for monitoring clinical status in children with ESRD, however it cannot substitute for other fitness tests, such as a progressive exercise test to measure \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\mathop {\text{V}}\limits^\cdot {{\text{O}}_{\text{2peak}}}}$$\end{document} or muscle strength tests

Macrophage Inhibitory Cytokine 1 (MIC-1/GDF15) Decreases Food Intake, Body Weight and Improves Glucose Tolerance in Mice on Normal & Obesogenic Diets

Food intake and body weight are controlled by a variety of central and peripheral factors, but the exact mechanisms behind these processes are still not fully understood. Here we show that that macrophage inhibitory cytokine-1 (MIC-1/GDF15), known to have anorexigenic effects particularly in cancer, provides protection against the development of obesity. Both under a normal chow diet and an obesogenic diet, the transgenic overexpression of MIC-1/GDF15 in mice leads to decreased body weight and fat mass. This lean phenotype was associated with decreased spontaneous but not fasting-induced food intake, on a background of unaltered energy expenditure and reduced physical activity. Importantly, the overexpression of MIC-1/GDF15 improved glucose tolerance, both under normal and high fat-fed conditions. Altogether, this work shows that the molecule MIC-1/GDF15 might be beneficial for the treatment of obesity as well as perturbations in glucose homeostasis

Evidence For Genetic Heterogeneity Between Clinical Subtypes of Bipolar Disorder

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P = 3.28 × 10 − 8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia (SCZ) and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I h2 = 0.35; BD II h2 = 0.25; P = 0.02) with a genetic correlation between BD I and BD II of 0.78,compared with a genetic correlation of 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for SCZ and BD in patients with BD I compared with patients with BD II, and a greater load of SCZ risk alleles in the bipolar type of schizoaffective disorder (SAB) compared with both other BD subtypes. These results point to a partial difference in genetic architecture of BD subtypes, and are suggestive of a molecular correlate for the clinical division of BD into subtypes

Probiotic treatment reduces appetite and glucose level in the zebrafish model.

The gut microbiota regulates metabolic pathways that modulate the physiological state of hunger or satiety. Nutrients in the gut stimulate the release of several appetite modulators acting at central and peripheral levels to mediate appetite and glucose metabolism. After an eight-day exposure of zebrafish larvae to probiotic Lactobacillus rhamnosus, high-throughput sequence analysis evidenced the ability of the probiotic to modulate the microbial composition of the gastrointestinal tract. These changes were associated with a down-regulation and up-regulation of larval orexigenic and anorexigenic genes, respectively, an up-regulation of genes related to glucose level reduction and concomitantly reduced appetite and body glucose level. BODIPY-FL-pentanoic-acid staining revealed higher short chain fatty acids levels in the intestine of treated larvae. These results underline the capability of the probiotic to modulate the gut microbiota community and provides insight into how the probiotic interacts to regulate a novel gene network involved in glucose metabolism and appetite control, suggesting a possible role for L. rhamnosus in the treatment of impaired glucose tolerance and food intake disorders by gut microbiota manipulation

The role of leptin in the respiratory system: an overview

Since its cloning in 1994, leptin has emerged in the literature as a pleiotropic hormone whose actions extend from immune system homeostasis to reproduction and angiogenesis. Recent investigations have identified the lung as a leptin responsive and producing organ, while extensive research has been published concerning the role of leptin in the respiratory system. Animal studies have provided evidence indicating that leptin is a stimulant of ventilation, whereas researchers have proposed an important role for leptin in lung maturation and development. Studies further suggest a significant impact of leptin on specific respiratory diseases, including obstructive sleep apnoea-hypopnoea syndrome, asthma, COPD and lung cancer. However, as new investigations are under way, the picture is becoming more complex. The scope of this review is to decode the existing data concerning the actions of leptin in the lung and provide a detailed description of leptin's involvement in the most common disorders of the respiratory system

Mitochondrial respiratory states and rate

As the knowledge base and importance of mitochondrial physiology to human health expands, the necessity for harmonizing the terminologyconcerning mitochondrial respiratory states and rates has become increasingly apparent. Thechemiosmotic theoryestablishes the mechanism of energy transformationandcoupling in oxidative phosphorylation. Theunifying concept of the protonmotive force providestheframeworkfordeveloping a consistent theoretical foundation ofmitochondrial physiology and bioenergetics.We followguidelines of the International Union of Pure and Applied Chemistry(IUPAC)onterminology inphysical chemistry, extended by considerationsofopen systems and thermodynamicsof irreversible processes.Theconcept-driven constructive terminology incorporates the meaning of each quantity and alignsconcepts and symbols withthe nomenclature of classicalbioenergetics. We endeavour to provide a balanced view ofmitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes.Uniform standards for evaluation of respiratory states and rates will ultimatelycontribute to reproducibility between laboratories and thussupport the development of databases of mitochondrial respiratory function in species, tissues, and cells.Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery