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Introduction/Aim: Regular exercise may have beneficial effects on high blood-pressure, as shown in different types of experimental hypertension models in rats. The present study aims to investigate...

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.

Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin’s ability to inhibit feeding but did not counter leptin’s ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin’s effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin’s anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1 loxP/loxP or AgRP-Cre; LRP1 loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin’s anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.

Hypothalamic and extra-hypothalamic neuronal populations play important roles in the regulation of energy balance and glucose homeostasis. However, the underlying mechanisms of this control remain unclear. We have recently reported that inhibition of hypothalamic pro-opiomelanocortin (POMC) neuronal activity leads to a reduction in blood glucose levels of normoglycemic POMC-cre mice. This effect is independent of energy intake. Since hypothalamic POMC neurons project to the paraventricular nucleus of the hypothalamus (PVH) and regulate energy metabolism via melanocortin-4 receptor (MC4R), we hypothesized that changes in the activity of MC4R-expressing neurons in the PVH could alter glycemic levels. To address this, we stereotaxically injected designer receptors exclusively activated by designer drug (DREADD) viruses into the PVH of MC4R-cre mice to chemogenetically and selectively activate or inhibit these neurons. We continuously activated or inhibited these neurons by injecting clozapine-N-oxide (CNO) every 8 hours for 5 days and monitored daily blood glucose levels and energy intake. Interestingly, inhibition of MC4R-expressing neurons in the PVH leads to a significant reduction (∼ 30%) in blood glucose levels despite of increased food intake. On the other hand, blood glucose levels are significantly increased, but food intake is greatly decreased when MC4R-expressing neurons are activated. We further determined the peripheral insulin response via MC4R-expressing neurons in the PVH. We found that CNO-induced inhibition or activation of MC4R-expressing neurons did not affect serum insulin levels. These data suggest that MC4R-expressing neurons in the PVH can regulate blood glucose levels and food intake via divergent cellular mechanisms, which is independent of circulating insulin. Thus, the inhibition of MC4R-expressing neurons may be a promising target for novel antidiabetic medicines. Disclosure A.G. Uner: None. H. Lee: None. J. Han: None. R.M. Pereira: None. X. Sun: None. H. Kim: None. Y. Kim: None.

Insulin signaling is essential for the maintenance of glucose homeostasis. ROCK2 has been shown to participate in insulin signaling and glucose metabolism in cultured cell lines. However, the in vivo function of ROCK2 in muscle remains to be elucidated. To explore the physiological role of muscle ROCK2 in the regulation of whole-body glucose homeostasis and insulin sensitivity in vivo, mice lacking ROCK2 in skeletal muscle selectively (myogenic-Cre; ROCK2lox/lox) were studied. Here we show that muscle-specific ROCK1-deficient mice displayed insulin resistance, as revealed by the failure of blood glucose levels to decrease after insulin injection. However, glucose tolerance was normal in the absence of muscle-specific ROCK2. These effects were independent of changes in adiposity. To determine the mechanism(s) by which muscle-specific deletion of ROCK2 causes insulin resistance, we measured the ability of insulin to activate downstream distal pathways in skeletal muscle. Insulin-stimulated IRS-1 tyrosine phosphorylation in skeletal muscle was markedly reduced by ∼80% in myogenic-Cre; ROCK2lox/lox mice compared with control (ROCK2lox/lox) mice. Concurrently, impaired insulin-induced phosphorylation of Akt, AS160, GSK, and S6K was found when ROCK2 was specifically deleted in muscle. Of pathological significance, ROCK2 activity in skeletal muscle was markedly decreased in obese type 2 diabetic mice in response to insulin, along with an impairment of IRS-1 phosphorylation. These data suggest that ROCK2 deficiency results in systemic insulin resistance by impairing insulin signaling in skeletal muscle, at the level of IRS-1. Thus, our results identify ROCK2 as a novel regulator of glucose homeostasis and insulin sensitivity in vivo, which could lead to new treatment approaches for obesity and type 2 diabetes. Disclosure H. Kim: None. R.M. Pereira: None. A.G. Uner: None. H. Lee: None. Y. Kim: None.

WOS: 000431511000003, PubMed ID: 29624513, Classical risk factors such as cholesterol and lipoproteins are currently not sufficient to explain all physiopathological processes of obesity-related vascular dysfunction as well as atherosclerosis and arteriosclerosis. Therefore, the discovery of potential markers involved in vascular dysfunction in the obese state is still needed. Disturbances in hemostatic factors may be involved in the developmental processes associated with obesity-related cardiovascular disorders. We hypothesized that alterations of several hemostatic factors in the obese state could correlate with the function and morphology of the aorta and it could play an important role in the development of vascular dysfunction. To test this, we fed mice with a high-fat diet for 18 weeks and investigated the relationships between selected hemostatic factors (in either plasma or in the liver), metabolic hormones and morphology, and ex-vivo function of the aorta. Here, we show that 18-week exposure to a high-fat diet results in a higher plasma fibrinogen and prolonged prothrombin time in diet-induced obese mice compared to the controls. In addition, liver levels or activities of FII, FX, activated protein C, AT-III, and protein S are significantly different in diet-induced obese mice as compared to the controls. Curiously, FII, FVIII, FX, activated protein C, PTT, and protein S are correlated with both the aorta histology (aortic thickness and diameter) and ex-vivo aortic function. Notably, ex-vivo studies revealed that diet-induced obese mice show a marked attenuation in the functions of the aorta. Taken together, aforementioned hemostatic factors may be considered as critical markers for obesity-related vascular dysfunction and they could play important roles in diagnosing of the dysfunction., Adnan Menderes University [VTF-12006, VTF-14027], A.G.U. and M.B. designed research; C.U., A.G.U., H.U., M.A.E., E.K., M.E., H.A., F.B., and L.T. performed research; C.U., A.G.U., M.B., and L.T. analyzed data; C.U. and A.G.U. wrote the paper with comments from all of the authors. This study was supported by the grants (VTF-12006 and VTF-14027 to AGU and MB, respectively) of Adnan Menderes University. We thank Dr Murat Boyacioglu, Dr Hande Sultan Yalinkilic, Dr Omer Sevim, and Biologist Necati Gunay for technical assistance. We also gratefully thank Ms. Tze-Min Lin for correcting the English grammar mistakes of the manuscript.

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity., Hepatokines are proteins secreted by the liver that can regulate whole body metabolism. Here the authors identify apolipoprotein J as a hepatokine that regulates muscle glucose metabolism and insulin resistance through a low-density lipoprotein receptor-related protein−2 mediated mechanism in mice.

Objective Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. Methods We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. Results We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lepob/ob mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lepob/ob mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. Conclusions GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action., Highlights • Glutamate action via GluN2B in AgRP neurons is required for normal body weight. • Genetic loss of GluN2B selectively in AgRP neurons reduces food intake. • Deletion of GluN2B from AgRP neurons prevents diabetes in ob/ob mice. • Glutamate action via GluN2B-NMDARs in AgRP neurons regulates neuronal survival and dendritic plasticity. • GluN2B-NMDARs in AgRP neurons are novel anti-obesity and anti-diabetes drug targets.

Day length-related alterations of several metabolic factors (glucose, leptin, insulin, and insulin-like growth factor-1 [IGF-1]), cytokines (interleukin-2 [IL-2], IL-4, IL-6, tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], and lymphocyte subpopulations [CD2, CD3, CD4, CD8, CD19, natural killer (NK) cells) were evaluated in Arabian and Thoroughbred horses. Plasma glucose, leptin, IGF-1, insulin, and cytokines levels were measured on the longest day of the breeding season and on the shortest day of the nonbreeding season. Determination of lymphocyte subpopulations was performed by flow cytometry. Glucose and IL-2 levels, CD4:CD8 ratio, and NK cells showed variations that depended on the day length. Mean concentrations of plasma leptin were higher in Arabian horses than in Thoroughbred horses, whereas mean concentrations of IGF-1 and IL-2 were lower in Arabian horses. Day length-by-breed-by-gender interaction was found for insulin, IFN-gamma, and IL-4 levels. An interaction was also found between day length and gender for the expressions of CD2, CD3, CD8, and CD19. Correlations were detected between expression of CD8(+) cells and levels of TNF-alpha and IFN-gamma and between percentages of NK cells and levels of IGF-1, insulin, and glucose. Results suggested that day length and, therefore, season are important determinants or factors in modulating the immune system and could affect lymphocyte subpopulations depending on the sex of the horse. Additionally, it seems that a complex relationship in horses, as in humans and mice, exists between the immune and metabolic system, which changes according to day length, breed, and gender. (C) 2013 Elsevier Inc. All rights reserved.

A trial was conducted to investigate the effects of a dietary organic acid blend for a period of 35 days on the growth performance, intestinal histomorphology and microflora of male broiler chicks with delayed access to feed. One hundred and ninety two one day old broiler chicks (ROSS 308) were randomly distributed into 4 groups housed in four replicate pens with 12 birds in each. A 2 × 2 factorial design was implemented. Four experimental groups were formed by two levels of dietary organic acid blend supplementation (Control and Fysal Dry ® ) and two periods of delayed feed access (0 and 36 h). At 36 h after hatching body weight and body weight change of chicks were significantly (P < 0.001) lower than groups fed immediately after hatching. Delayed feed access had an adverse impact (P < 0.001) on the body weight and feed consumption of broiler chickens on days 14 and 28. Between the days 28 and 35 of the feeding period, these differences disappeared. The relative weight of gizzard (P < 0.05), pancreas (P < 0.01) on day 6 and intestine (P < 0.05) on day 10, and gizzard (P < 0.01) on day 10 were reduced in birds subjected to delayed feed access. Dietary organic acid blend inclusion increased villus length (P < 0.001), whereas delayed feed access decreased villus length (P < 0.05) and increased the incidence of epithelial degeneration and basal membrane separation of the propria mucosa of villus in the jejenum. A significant decrease in Enterobacteriaceae count (P < 0.01) was noted in organic acid blend supplemented groups on day 25. Pectoral muscle malondialdehyde levels were decreased (P < 0.01) with dietary organic acid blend supplementation at

Summary: The objective of this study was to characterize seasonal variations in serum concentrations of melatonin, testosterone, and progesterone in Arabian horses under natural photoperiodic conditions. Peripheral blood samples were collected during breeding and non-breeding seasons from mares and stallions. Serum concentrations of melatonin, testosterone, and progesterone were determined by radioimmunoassay. Serum concentrations of melatonin were greater in the non-breeding season (42.41±1.59 and 37.68±1.55 pg/ml) when compared to breeding season (23.52±1.24 and 17.22±2.10 pg/ml) in both mares and stallions, respectively. Melatonin concentrations were low but not different between the luteal and follicular phases during breeding season in cyclic mares. Mares had greater concentrations of melatonin than stallions in both breeding and non-breeding season. Mean concentrations of testosterone were greater during breeding season (6.58±0.50 ng/ml) than non-breeding season (3.64±0.48 ng/ml) in stallions. There was a negative correlation (r=-0.658, p

Moderate exercise stimulates immune system whereas intensive exercise may display immune-suppressive effect associated with the disruption of intestinal barrier. With this study, we tested the effects of moderate and intensive swimming exercises on some cytokines and oxidant variables and zonulin, an intestinal barrier marker, in rats. We also tested possible ameliorative effects of probiotic VSL#3 in both moderate and intensive exercise regimens. Twenty eight rats were randomly divided into 4 equal groups: Control-C, Probiotic-P, Exercise-E, Probiotic+Exercise-PE. The rats in group E and PE underwent moderate swimming exercise for 5 weeks. Following this period, intensive swimming exercise was performed for 5 days. The rats in group C and group P were sedentary. Probiotic VSL#3 was given to group P and PE in the water. At the end of the experiments, serum zonulin, TNF-α, IL-6, IL-10, TGF-β, MDA, and protein carbonyl levels were determined. Evidences obtained from present study indicate that moderate swimming exercise improves barrier integrity of intestine and decreases oxidative stress. During the moderate swimming experiment, probiotic VSL#3 supplementation may also improve inflammatory response. On the other hand, intensive exercise does not led changes in the inflammatory response and oxidative stress, but beneficial responses of moderate exercise on the selected parameters probably disappear due to the intense exercise-induced mild stress.

Purpose: The current study aimed to reveal the therapeutic effects of a pulsed electromagnetic field and swimming exercises on rats with experimental sciatic nerve injury, which was induced with crush-type neuropathy model damage, using electrophysiological methods. Subjects: In the current study, the sample consisted of 28 adult male Wistar albino rats. Methods: The rats were randomized into four groups (n=7). Swimming exercise and PEMF (2 Hz and 0.3 MT) were applied one hour a day, five days a week, for four weeks. Electroneuromyographic (ENMG) measurements were taken on day 7. Results: When the data were evaluated, it was found that the 4 weeks of PEMF and swimming exercises led to an increase in motor conduction rates and a decrease in latency values, but the changes were not significant in comparison with the control and injury groups. The compound muscle action potential (CMAP) values of the left leg were lower in weeks 2, 3, and 4 in the swimming exercise group in comparison with the control group, although for the PEMF group, the CMAP values of the left leg reached the level observed in the control group beginning in week 3. Conclusion: PEMF and swimming exercise made positive contributions to nerve regeneration after week 1, and regeneration was enhanced. © 2014 The Society of Physical Therapy Science. Published by IPEC Inc.

Leptin, a hormone-cytokine mainly produced by the adipose tissue, has pleitropic effects on many biological system including metabolic, endocrine, and immune system. Although it is well known that leptin controls food intake on hypothalamic regions of brain, the role of leptin in hematopoietic and immune processes has been mainly investigated with in vitro and transgenic mouse studies. The aim of this study was to investigate the effects of peripheral leptin on lymphocyte subpopulation. Initially forty male Swiss albino mice were divided into five groups. Mice in group I (Control) were given serum physiologic (SP) and group L100, group L250, group L500, and group L1000 were given 100, 250, 500 and 1000 μg/kg/day recombinant mouse leptin, respectively. Leptin or SP was injected subcutaneously for the next 6 days. Daily food/water intake was recorded for each group. At the end of the study, whole blood samples (500 μl) were obtained via intracardiac punction in anesthetized mice. Leptin levels and lymphocyte subpopulations in blood samples were analyzed. We show that no in vivo dose-dependent effect of leptin is existed on lymphocyte subpopulations count in mice. Treatment of mice with high-dose leptin led to increase only CD4+ cells (P0.05). In addition, high-dose leptin slightly increased CD3+ cells but this was not statistically confirmed (P=0.08). Notably, it was found that leptin caused insignificant changes on body weight and food intake in normal body weight mice. The data support that high-dose leptin has proliferative effect on CD4+ cells in vivo. However, more in vivo study needs to be examined to clarify how leptin affect lymphocyte subpopulations.

A five-year-old female dog was presented with a four-week history of inappetence, weight loss, and skin and gait abnormalities. Physical examination revealed weakness, depression, incoordination of the posterior limbs, emaciation, skin and hair coat alterations, peripheral lymphadenopathy, pale mucous membranes and fever. Laboratory analysis of samples revealed abnormalities which included anaemia, neutrophilic leucocytosis, thrombocytopenia, low serum glucose and albumin concentrations, and increased serum alkaline phosphatase activity. The diagnosis was confirmed microscopically, by demonstrating the presence of Hepatozoon canis gametocytes within neutrophils in Giemsa-stained peripheral blood smears. Treatment consisting of toltrazuril and a trimethoprim-sulfamethoxazole combination was effective in relieving the clinical signs and clearing the blood of H. canis gametocytes. To the authors' knowledge, this is the first detailed clinical description of H. canis infection in a dog in Turkey.