Leaf extract from Vitis vinifera L. reduces high fat diet-induced obesity in mice.

Despite the health benefits of Vitis vinifera L. leaves, its anti-obesity potential has not been fully explored. In this work, we showed that Vitis vinifera L. leaf extract (VLE) inhibits the pancreatic lipase activity. Intragastric administration of VLE to mice led to a significant decrease in the body weight, tissue fat accumulation, levels of cholesterol, low-density lipoprotein and triglyceride compared to mice fed with high fat diet. We also found a lower level of neuropeptide-Y (NPY) in the serum and hypothalamus and a higher level of fibroblast growth factor 15 in mice supplemented with VLE. These results suggested that VLE regulates both the NPY-mediated pathway and the bile acid-FGF15 pathway to control energy metabolism and body weight gain. The composition of VLE was further investigated by a targeted metabolomics approach, which identified 21 compounds including phenolic acids, flavones, flavanols, flavanones, coumarins, and stilbenes. Taken together, we demonstrated the capacity of grape leaves in reducing obesity, which could be mediated by NPY and bile acids. Identification of putative active compounds in VLE also open the path for further studies to determine their effectiveness individually to treat obesity.

Intermittent fasting, adipokines, insulin sensitivity, and hypothalamic neuropeptides in a dietary overload with high-fat or high-fructose diet in mice.

The intermittent fasting (IF) might have benefits on metabolism and food intake. Twelve-week old C57BL/6 J mice were fed a control diet (C, 10% kcal fat), a high-fat diet (HF, 50% kcal fat) or a high-fructose diet (HFru, 50% kcal fructose) for 8 weeks, then half of the animals in each group underwent IF (24 h fed, 24 h fasting) for an additional 4 weeks. Although food intake on the fed day remained the same for all groups, all fasting groups showed a reduction in body mass compared to their counterparts. IF reduced total cholesterol, triacylglycerol, fasting glucose, fasting insulin resistance index, and plasma leptin, but increased plasma adiponectin. IF reduced Leptin gene expression in the HF-IF group, but increased proinflammatory markers in the hypothalamus, also in the C-IF group. Both groups HFru-IF and C-IF, showed alterations in the leptin signaling pathway (Leptin, OBRb, and SOCS3), mainly in the HFru-IF group, suggesting leptin resistance. NPY and POMC neuropeptides labeled the neurons of the hypothalamus by immunofluorescence, corroborating qualitatively other quantitative findings of the study. In conclusion, current results are convincing in demonstrating the IF effect on central regulation of food intake control, as shown by NPY and POMC neuropeptide expressions, resulting in a lower weight gain. Besides, IF improves glycemia, lipid metabolism, and consequently insulin and leptin resistance. However, there is increased expression of inflammatory markers in mouse hypothalamus challenged by the HF and HFru diets, which in the long term may induce adverse effects.

Effect of Transcutaneous Electrical Stimulation of Nerves on Blood Pressure and Blood Content of Neuropeptide CGRP and Nitric Oxide in Hypertensive Rats with Metabolic Disturbances.

The development of arterial hypertension in male Wistar rats with fructose-induced metabolic syndrome (12.5% of fructose solution as the only drinking source for 10 weeks) along with impaired glucose tolerance and increased serum concentration of triglycerides and LPO products caused a decrease in the content of serum blood calcitonin gene-related peptide (CGRP). Low-frequency transcutaneous electrical nerve stimulation (1 mA, 2 Hz, 10 min daily for 2 weeks) performed in 8 weeks after the beginning of fructose treatment reduced systolic BP and serum concentration of triglycerides and LPO produces and improved glucose tolerance. After stimulation, CGRP content in rats maintained on fructose diet returned to normal values and the content of nitric oxide metabolites increased. We hypothesize that CGRP and nitric oxide are involved in mechanisms mediating the therapeutic effect of low-frequency transcutaneous electrical nerve stimulation on arterial hypertension developing in metabolic syndrome.

Identification of Bioactive Chemical Markers in Zhi zhu xiang Improving Anxiety in Rat by Fingerprint-Efficacy Study.

Zhi zhu xiang (ZZX for short) is the root and rhizome of Valeriana jatamansi Jones, which is a Traditional Chinese Medicine (TCM) used to treat various mood disorders for more than 2000 years, especially anxiety. The aim of the present work was to identify the bioactive chemical markers in Zhi zhu xiang improving anxiety in rats by a fingerprint-efficacy study. More specifically, the chemical fingerprint of ZZX samples collected from 10 different regions was determined by High Performance Liquid Chromatography (HPLC) and the similarity analyses were calculated based on 10 common characteristic peaks. The anti-anxiety effect of ZZX on empty bottle stimulated rats was examined through the Open Field Test (OFT) and the Elevated Plus Maze Test (EPM). Then we measured the concentration of CRF, ACTH, and CORT in rat's plasma by the enzyme-linked immune sorbent assay (ELISA) kit, while the concentration of monoamine and metabolites (NE, DA, DOPAC, HVA, 5-HT, 5-HIAA) in the rat's cerebral cortex and hippocampus was analysed by HPLC coupled with an Electrochemical Detector. At last, the fingerprint-efficacy study between chemical fingerprint and anti-anxiety effect of ZZX was accomplished by partial least squares regression (PLSR). As a result, we screened out four compounds (hesperidin, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C) as the bioactive chemical markers for the anti-anxiety effect of ZZX. The fingerprint-efficacy study we established might provide a feasible way and some elicitation for the identification of the bioactive chemical markers for TCM.

In renal hypertension, Cirsium japonicum strengthens cardiac function via the intermedin/nitric oxide pathway.

Cirsium japonicum, a constituent of traditional Chinese medicine, has been shown to exert inflammatory effects as well as to improve the circulation and thus to counteract hematologic stasis. Studies have demonstrated that intermedin (IMD) has protective effects on hypertension in rats by regulating the Ang/NO metabolic pathway. In this study, we investigated whether by regulating the expression of IMD, Cirsium japonicum could improve cardiac function in rats with 2k1c-induced renal hypertension. Renal hypertension was induced in Sprague-Dawley rats by occluding the renal artery. The rats were maintained on a normal diet and randomly divided into four groups: sham, 2k1c, 2k1c with Cirsium japonicum (1.8 g/kg per day) and 2k1c with IMD (n = 10 in each group). Cardiac function, plasma angiotensin II (Ang II), IMD, serum nitric oxide (NO) and nitric oxide synthase (NOS), as well as the expression of IMD and adrenomedullin (ADM) in the aorta and left ventricle were analyzed. Administration of Cirsium japonicum or IMD significantly strengthened cardiac function in 2k1c-induced rats, increased serum NO and NOS levels, reduced plasma Ang II, and upregulated IMD expression in the aorta and left ventricle. These results demonstrate that Cirsium japonicum has cardioprotective effects on 2k1c-induced renal hypertension in rats via the IMD/NO pathway.

Relationship between cerebrospinal fluid concentrations of orexin A/hypocretin-1 and body composition in humans.

The hypothalamic neuropeptide orexin A (hypocretin-1) is a key signal in sleep/wake regulation and promotes food intake. We investigated the relationship between cerebrospinal fluid orexin A concentrations and body composition in non-narcoleptic human subjects with a wide range of body weight to gain insight into the role of orexin A in human metabolism. We collected cerebrospinal fluid and blood samples and measured body composition by bioelectric impedance analysis in 36 subjects (16 women and 20 men) with body mass indices between 16.24 and 38.10 kg/m2 and an age range of 19-80 years. Bivariate Pearson correlations and stepwise multiple regressions were calculated to determine associations between orexin A and body composition as well as biometric variables. Concentrations of orexin A in cerebrospinal fluid averaged 315.6 ±â€¯6.0 pg/ml, were comparable between sexes (p > 0.15) and unrelated to age (p > 0.66); they appeared slightly reduced in overweight/obese compared to normal-weight subjects (p = .07). Orexin A concentrations decreased with body weight (r = -0.38, p = .0229) and fat-free mass (r = -0.39, p = .0173) but were not linked to body fat mass (p > 0.24). They were inversely related to total body water (r = -0.39, p = .0174) as well as intracellular (r = -0.41, p = .0139) and extracellular water (r = -0.35, p = .0341). Intracellular water was the only factor independently associated with cerebrospinal fluid orexin A concentrations (p = .0139). We conclude that cerebrospinal fluid orexin A concentrations do not display associations with body adiposity, but are inversely related to intracellular water content. These cross-sectional findings suggest a link between orexin A signaling and the regulation of water homeostasis in humans.

The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa.

Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa.

Increased Hypothalamic Levels of Endozepines, Endogenous Ligands of Benzodiazepine Receptors, in a Rat Model of Sepsis.

BACKGROUND: The mechanisms involved in septic anorexia are mainly related to the secretion of inflammatory cytokines. The term endozepines designates a family of neuropeptides, including the octadecaneuropeptide (ODN), originally isolated as endogenous ligands of benzodiazepine receptors. Previous data showed that ODN, produced and released by astrocytes, is a potent anorexigenic peptide. We have studied the effect of sepsis by means of a model of cecal ligation and puncture (CLP) on the hypothalamic expression of endozepines (DBI mRNA and protein levels), as well as on the level of neuropeptides controlling energy homeostasis mRNAs: pro-opiomelanocortin, neuropeptide Y, and corticotropin-releasing hormone. In addition, we have investigated the effects of two inflammatory cytokines, TNF-α and IL-1ß, on DBI mRNA levels in cultured rat astrocytes. METHODS: Studies were performed on Sprague-Dawley male rats and on cultures of rat cortical astrocytes. Sepsis was induced using the CLP method. Sham-operated control animals underwent the same procedure, but the cecum was neither ligated nor incised. RESULTS: Sepsis caused by CLP evoked an increase of DBI mRNA levels in ependymal cells bordering the third ventricle and in tanycytes of the median eminence. CLP-induced sepsis was also associated with stimulated ODN-like immunoreactivity (ODN-LI) in the hypothalamus. In addition, TNF-α, but not IL-1ß, induced a dose-dependent increase in DBI mRNA in cultured rat astrocytes. An increase in the mRNA encoding the precursor of the anorexigenic peptide α-melanocyte stimulating hormone, the pro-opiomelanocortin, and the corticotropin-releasing hormone was observed in the hypothalamus. CONCLUSION: These results suggest that during sepsis, hypothalamic mRNA encoding endozepines, anorexigenic peptide as well as stress hormone could play a role in the anorexia/cachexia associated with inflammation due to sepsis and we suggest that this hypothalamic mRNA expression could involve TNF-α.

The absence of GH signaling affects the susceptibility to high-fat diet-induced hypothalamic inflammation in male mice.

GH is important in metabolic control, and mice with disruption of the gene encoding the GH receptor (GHR) and GH binding protein (GHR-/- mice) are dwarf with low serum IGF-1 and insulin levels, high GH levels, and increased longevity, despite their obesity and altered lipid and metabolic profiles. Secondary complications of high-fat diet (HFD)-induced obesity are reported to be associated with hypothalamic inflammation and gliosis. Because GH and IGF-1 can modulate inflammatory processes, our objective was to evaluate the effect of HFD on hypothalamic inflammation/gliosis in the absence of GH signaling and determine how this correlates with changes in systemic metabolism. On normal chow, GHR-/- mice had a higher percentage of fat mass and increased circulating nonesterified free fatty acids levels compared with wild type (WT), and this was associated with increased hypothalamic TNF-α and phospho-JNK levels. After 7 weeks on a HFD, both WT and GHR-/- mice had increased weight gain, with GHR-/- mice having a greater rise in their percentage of body fat. In WT mice, HFD-induced weight gain was associated with increased hypothalamic levels of phospho-JNK and the microglial marker Iba-1 (ionized calcium-binding adapter molecule 1) but decreased cytokine production. Moreover, in GHR-/- mice, the HFD decreased hypothalamic inflammatory markers to WT levels with no indication of gliosis. Thus, the GH/IGF-1 axis is important in determining not only adipose tissue accrual but also the inflammatory response to HFD. However, how hypothalamic inflammation/gliosis is defined will determine whether it can be considered a common feature of HFD-induced obesity.

Dietary fat alters the expression of cortistatin and ghrelin systems in the PBMCs of elderly subjects: putative implications in the postprandial inflammatory response.

SCOPE: Dietary fat influences systemic inflammatory status, which determines the progression of age-associated diseases. Since somatostatin (SST), cortistatin (CORT), and ghrelin systems modulate inflammatory response, we aim to comprehensively characterize the presence and regulation of the components of these systems in the peripheral blood mononuclear cells (PMBCs), a subset of white blood cells placed at the crossroad between diet and inflammation, in response to diets with different fat composition, and during the postprandial phase in elderly subjects. METHODS AND RESULTS: The applied nutrigenomic, inflammation-related PBMC-based approach revealed that the majority of components of SST/CORT and ghrelin systems are present in the human PBMCs. Particularly, CORT, SST/CORT receptors (sst2, sst3, sst5, and sst5TMD4), ghrelin, its acylating enzyme (GOAT), In1-ghrelin variant, and GHSR1b were detected in PBMCs. Their expression was altered in the long-term by diet composition, and in the short-term, during the postprandial phase. Of particular relevance is the postprandial elevation of CORT, sst2, and sst5 expression in PBMCs of subjects under n-3 PUFAs-enriched diet. CONCLUSION: Our results suggest a potential relevant role of CORT/ssts and ghrelin systems in regulating PBMCs response to nutrient intake, which could help to explain the positive effects of n-3 PUFAs-enriched diets in reducing the inflammatory response.

Reduced orexin-A levels in frontotemporal dementia: possible association with sleep disturbance.

Sleep disturbances including excessive daytime sleepiness (EDS) are encountered in frontotemporal dementia (FTD). To investigate the relationship between the plasma orexin-A levels and sleep disturbance patterns, we measured the plasma orexin-A levels and performed sleep studies in patients with FTD. The orexin-A levels were measured in 10 consecutive patients with FTD and controls by enzyme-linked immunosorbent assay. Nocturnal polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) were performed in 2 patients with FTD. The orexin-A levels were significantly lower in patients with FTD compared to controls. The PSG revealed increased rapid eye movement (REM) latency in patients, whether or not they reported EDS. Mean sleep latency in MSLT was less than 10 minutes in both the patients, being shorter in patient without EDS, but none of them had REM sleep onset. Some patients with FTD may develop narcolepsy-like involuntary sleep attacks, even without complaining of EDS. Involvement of hypothalamus and a subsequent alteration in the orexin levels might be one of the determining factors in this sleep disturbance.

The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: olanzapine monotherapy.

The mechanism underlying the weight gain due to treatment with olanzapine and other second generation antipsychotics has not been fully understood. To examine olanzapine's weight gain effects, we accepted first attack psychotic patients with no medication (pre-treatment) (n=22) and the healthy control group (n=26) in this study. After patients diagnosis, they were hospitalized and then treated for four weeks with olanzapine (post-treatment). We used case-control association design to test body mass index (BMI) and biochemical changes in each group. We also investigated peripheral leptin and neuropeptides/hormones namely, pro-opiomelanocortin (POMC), cocaine and amphetaime regulated transcript (CART), and neuropeptide Y (NPY) levels. These neuropeptides which are synthesized/secreted from arcuate nucleus of hypothalamus affect food intake and therefore, body weight. After 4 weeks of olanzapine treatment; BMI (body mass index), waist circumference, blood triglyceride, total cholesterol, and very low density lipoprotein (VLDL) levels were increased significantly in patients compared to their pre-treatment baseline. In pre-treatment, patients' NPY levels were significantly lower while α-MSH, the anorexigenic product of POMC levels were significantly higher vs. control. Both leptin and NPY levels were significantly increased in patients after the treatment but the NPY levels were also significantly lower in post-treatment vs. the control group. The CART levels did not change after the treatment. We may presume that the antagonist effect of olanzapine on the serotonin (5HT2CR and 5HT1BR) receptors of the arcuate hypothalamic neurons may be a basis for a deregulation of the neurohormones secretion.

Involvement of neuropeptide Y signaling in the antidepressant-like effect and hippocampal cell proliferation induced by kososan, a Kampo medicine, in the stress-induced depression-like model mice.

Neuropeptide Y (NPY) and Orexin-A (OX-A), well-known neuropeptides associated with feeding and arousal, show antidepressant-like properties via hippocampal cell proliferation. Previous studies have revealed that kososan, a Kampo (Japanese herbal) medicine, has an antidepressant-like effect in behavioral animal models of depression; the mechanisms underlying this effect may involve the orexinergic system and subsequent upregulation of hippocampal cell proliferation. However, the roles of NPY in kososan's antidepressant-like effect remain unclear. Here we investigated whether the regulation of the NPY system could play crucial roles in this effect in the stress-induced depression-like model mice. The antidepressant-like effect of kososan administered orally (1.0 g/kg) for 28 d was abolished by a continuous intracerebroventricular injection of BIBO3304, a neuropeptide Y1 receptor antagonist, for 7 d. Likewise, BIBO3304 injection blocked the kososan-induced increases in hippocampal cell proliferation and cluster formation of neural progenitor cells. On the other hand, BIBO3304 injection did not affect kososan-induced increases in hypothalamic OX-A-producing cells or in serum OX-A levels. These results suggest that the control of the NPY system in the brain plays an essential role in kososan's antidepressant-like effect and facilitates hippocampal cell proliferation, both of which could be attributed, at least in part, to the control of the NPY system subsequent to the control of the OX-A system.

Orexin-A facilitates emergence from propofol anesthesia in the rat.

BACKGROUND: Hypothalamic orexinergic neurons play a critical role in the promotion and maintenance of wakefulness in mammals. Previous studies have demonstrated that activities of orexinergic neurons were inhibited by isoflurane and sevoflurane, and microinjection of orexin facilitated the emergence from volatile anesthesia. In this study we first examined the hypothesis that the activity of orexin neurons is inhibited by propofol anesthesia. Moreover, the role of the orexinergic signals in basal forebrain in regulating the anesthesia-arousal cycle of propofol anesthesia is also elucidated. METHODS: Rats were killed at 0, 30, 60, and 120 minutes of propofol infusion as well as at the time the righting reflex returned after the termination of anesthesia. Activated orexinergic neurons were detected by c-Fos expression. The plasma concentrations of orexin-A were measured by radioimmunoassay. Orexin-A (30 or 100 pmol) or the orexin-1 receptor antagonist, SB-334867A (5 or 20 µg), was microinjected into the basal forebrain 15 minutes before propofol infusion, or 15 minutes before the termination of propofol infusion. The loss and the return of the righting reflex time were recorded as the induction and the emergence time. RESULTS: Propofol anesthesia resulted in an inhibition of orexinergic neuron activity as demonstrated by the reduced numbers of c-Fos-immunoreactive orexinergic neurons. The activities of orexinergic neurons were restored when rats emerged from anesthesia. Propofol anesthesia decreased plasma orexin-A concentrations. Intrabasalis microinjection of orexin-A had no effect on the induction time but facilitated the emergence from propofol anesthesia. Inversely, intrabasalis microinjection of the orexin-1 receptor antagonist SB-334867A delayed the emergence from propofol anesthesia. CONCLUSIONS: Our findings indicate that activity of orexinergic neurons is inhibited by propofol anesthesia, and the orexin signals in basal forebrain are involved in anesthesia-arousal regulation from propofol anesthesia.

Effect of heat exposure on gene expression of feed intake regulatory peptides in laying hens.

The aim of this paper was to investigate the effect of heat stress on the regulation of appetite-associated genes in laying hens. Forty eight laying hens were randomly divided into two circumstances: high (31 ± 1.5°C; relative humidity, 82.0 ± 2.2%) or normal (20 ± 2°C, control; relative humidity, 60.1 ± 4.5%) ambient environment. Heat stress decreased body weight gain (P < 0.01), feed intake (P < 0.01), laying rate (P < 0.05), average egg mass (P < 0.01), egg production (P < 0.01), shell thickness (P < 0.01), and feed efficiency (P < 0.05). High ambient temperature decreased plasma uric acid (P < 0.05). Heat stress significantly increased mRNA levels of ghrelin and cocaine- and amphetamine-regulated transcript (P < 0.05) and decreased mRNA levels of cholecystokinin (P < 0.05) in the hypothalamus. Heat stress significantly increased (P < 0.05) mRNA levels of ghrelin in the glandular stomach and jejunum but significantly decreased (P < 0.05) mRNA levels of cholecystokinin in the duodenum and jejunum. In conclusion, heat stress plays a unique role in some special neuropeptides (e.g., ghrelin, cocaine- and amphetamine-regulated transcript, and cholecystokinin), which might participate in the regulation of feed intake in laying hens under high ambient temperature.

Role of growth hormone-releasing hormone in sleep and growth impairments induced by upper airway obstruction in rats.

Upper airway obstruction (UAO) can lead to abnormal growth hormone (GH) homeostasis and growth retardation but the mechanisms are unclear. We explored the effect of UAO on hypothalamic GH-releasing hormone (GHRH), which has a role in both sleep and GH regulation. The tracheae of 22-day-old rats were narrowed; UAO and sham-operated animals were sacrificed 16 days post-surgery. To stimulate slow-wave sleep (SWS) and GH secretion, rats were treated with ritanserin (5-HT(2) receptor antagonist). Sleep was measured with a telemetric system. Hypothalamic GHRH, hypothalamic GHRH receptor (GHRHR) and GH receptor, and orexin were analysed using ELISA, real-time PCR and Western blot. UAO decreased hypothalamic GHRH, GHRHR and GH receptor levels, while orexin mRNA increased (p<0.01). In UAO rats, the duration of wakefulness was elevated and the duration of SWS, paradoxical sleep and slow-wave activity was reduced (p<0.001). Ritanserin alleviated these effects, i.e. normalised hypothalamic GHRH content, decreased wake duration, increased duration and depth of SWS, and attenuated growth impairment (p<0.001). Here, we present evidence that growth retardation in UAO is associated with a reduction in hypothalamic GHRH content. Our findings show that abnormalities in the GHRH/GH axis underlie both growth retardation and SWS-disorder UAO.

Migraine preventive drug-induced weight gain may be mediated by effects on hypothalamic peptides: the results of a pilot study.

AIMS: This study was aimed to verify changes in the levels of hypothalamic neuropeptides in migraineurs under preventive treatment with amitryptiline and flunarizine. Thirty-nine migraine patients with a body mass index <25 kg/m(2) and without endocrinological or metabolic diseases were assigned to two treatment groups, one receiving amitryptiline, the other flunarizine, for 3 months. Orexin-A, orexin-B and neuropeptide-Y plasma levels were measured at the basal time, at the 1st, 2nd and 3rd months of preventive treatment. RESULTS: A statistically significant reduction in plasma orexin-A and orexin-B levels emerged in both groups. Conversely, plasma neuropeptide-Y levels were markedly increased, with the highest levels at the 2nd and 3rd months, in both patient groups. Orexin-A levels were also negatively correlated to weight gain in both groups during the treatment period. CONCLUSIONS: These results suggest that changes in the levels of hypothalamic orexinergic peptides may contribute to body weight increase occurring in migraineurs during amitryptiline or flunarizine prophylactic treatment.

Obesity of TallyHO/JngJ mouse is due to increased food intake with early development of leptin resistance.

TALLYHO/JngJ (TallyHo) mouse is a recently established animal model for type 2 diabetes mellitus (T2DM) with phenotypes of mild obesity and male-limited hyperglycemia. In this study, we investigated how obesity develops in TallyHo mice by measuring parameters of food intake and energy expenditure. At 4 weeks of age, TallyHo mice were heavier than control C57BL/6 mice with increased food intake but comparable energy expenditure parameters, such as body temperature, cold-induced thermogenesis, oxygen consumption rate (VO(2)) and spontaneous locomotor activity. Furthermore, pair-fed TallyHo mice, which were fed the same amount of food as C57BL/6 mice, showed similar patterns of body weight gain to C57BL/6 mice at all ages, implying that obesity in TallyHo mice may develop by increased food intake but not by decreased energy consumption. TallyHo mice appear to have hypothalamic leptin resistance at 4 weeks of age, as indicated by the increased expression of orexigenic neuropeptides in the hypothalamus and no alteration of food intake and neuropeptide expression upon intravenous leptin treatment. Leptin injection to TallyHo mice, however, increased the phosphorylation of STAT3 and Akt, an important signaling mediator of leptin, in a pattern similar to that in C57BL/6 mice. In conclusion, increased food intake is a crucial component in the development of obesity in TallyHo mice, in which central leptin resistance, possibly caused by uncoupling between activation of leptin signaling and neuropeptide expression, might be involved.

Specially processed cereals diet increases plasma levels of active antisecretory factor and up-regulates rat hepatic glutathione S-transferase mu.

OBJECTIVE: Antisecretory factor (AF) inhibits pathologic fluid secretion and inflammation. AF is expressed in most tissues and is secreted into the blood. Challenge with bacterial enterotoxins increases AF activity. The plasma level of active AF is also increased after intake of certain food constituents, such as specially processed cereals, SPC. The exact molecular events that mediate these responses have remained obscure. The objective of this study was to investigate changes in protein expression in liver after SPC diet. METHODS: Rats were fed SPC or standard rodent diet for 18 d. The induction of AF in plasma was tested by ELISA. Changes in the liver proteome were analyzed by using 2D DIGE and LC-MS/MS. Further characterizations were done with Western blot and immunohistochemistry studies. RESULTS: The AF activity was increased after intake of SPC. Equivalent to recombinant AF, 6.6 ± 1.09 ng/well could be detected in control plasma compared to 26 ± 5.73 ng/well in plasma after SPC treatment. We found that the protein level of glutathione S-transferase mu (GST mu) was significantly up-regulated 1.2-fold in rat liver after stimulation with SPC (wheat). The result was further confirmed by Western blot analysis. Immunohistochemistry showed staining for GST mu1 and AF preferentially in the central parts of the liver lobuli. CONCLUSION: Given the known role of GST mu1 in inducing defense, our results suggest that SPC-induced GST mu1 up-regulation can contribute to the positive clinical effects seen by SPC treatment.

The relative impact of chronic food restriction and acute food deprivation on plasma hormone levels and hypothalamic neuropeptide expression.

Our understanding of the central regulation of food intake and body weight has increased tremendously through implication of a high number of neuropeptides. However, lack of all-embracing studies have made comparison difficult in the past. The objective of this study was to demonstrate the relative importance of the different neuropeptides in terms of involvement in appetite regulatory mechanisms. We quantified expression levels of 21 hypothalamic neuropeptides and circulating levels of leptin, insulin, corticosterone, adrenocorticotropic hormone, ghrelin and adiponectin in rats after acute food deprivation and chronic food restriction using validated quantitative real-time PCR and hormone measurements. Body weight, insulin and leptin were reduced whereas corticosterone was increased by both acute food deprivation and chronic food restriction. Our results confirmed the relative importance in body weight homeostasis of neuropeptide Y and proopiomelanocortin, which were increased and decreased as predicted. The expression of other neuropeptides previously attributed central roles in body weight homeostasis, e.g. melanin-concentrating hormone and orexin, appeared to be less affected by the treatments. Moreover, the expression of dynorphin, galanin-like peptide and neuropeptide B was dramatically reduced after both treatments. This suggests that the latter neuropeptides--although previously known to be involved in body weight homeostasis--may be of unexpected importance in states of negative energy balance.