Hypothalamic Neuropeptide Gene Expression Research Articles

Phase-shifting the circadian glucocorticoid profile induces disordered feeding behaviour by dysregulating hypothalamic neuropeptide gene expression

Here we demonstrate, in rodents, how the timing of feeding behaviour becomes disordered when circulating glucocorticoid rhythms are dissociated from lighting cues; a phenomenon most commonly associated with shift-work and transmeridian travel ‘jetlag’. Adrenalectomized rats are infused with physiological patterns of corticosterone modelled on the endogenous adrenal secretory profile, either in-phase or out-of-phase with lighting cues. For the in-phase group, food intake is significantly greater during the rats’ active period compared to their inactive period; a feeding pattern similar to adrenal-intact control rats. In contrast, the feeding pattern of the out-of-phase group is significantly dysregulated. Consistent with a direct hypothalamic modulation of feeding behaviour, this altered timing is accompanied by dysregulated timing of anorexigenic and orexigenic neuropeptide gene expression. For Neuropeptide Y (Npy), we report a glucocorticoid-dependent direct transcriptional regulation mechanism mediated by the glucocorticoid receptor (GR). Taken together, our data highlight the adverse behavioural outcomes that can arise when two circadian systems have anti-phasic cues, in this case impacting on the glucocorticoid-regulation of a process as fundamental to health as feeding behaviour. Our findings further highlight the need for development of rational approaches in the prevention of metabolic dysfunction in circadian-disrupting activities such as transmeridian travel and shift-work.

Inhibition of adipose tissue angiogenesis prevents rebound weight gain after caloric restriction in mice fed a high-fat diet

AimsWe investigated whether modulation of white adipose tissue (WAT) vasculature regulates rebound weight gain (RWG) after caloric restriction (CR) in mice fed a high-fat diet (HFD). Main methodsWe compared changes in energy balance, hypothalamic neuropeptide gene expression, and characteristics of WAT by RT-qPCR, ELISA, immunohistochemistry, and adipose-derived stromal vascular fraction spheroid sprouting assay in obese mice fed a HFD ad libitum (HFD-AL), mice under 40 % CR for 3 or 4 weeks, mice fed HFD-AL for 3 days after CR (CRAL), and CRAL mice treated with TNP-470, an angiogenic inhibitor. Key findingsWAT angiogenic genes were expressed at low levels, but WAT vascular density was maintained in the CR group compared to that in the HFD-AL group. The CRAL group showed RWG, fat regain, and hyperphagia with higher expression of angiogenic genes and reduced pericyte coverage of the endothelium in WAT on day 3 after CR compared to the CR group, indicating rapidly increased angiogenic activity after CR. Administration of TNP-470 suppressed RWG, fat regain, and hyperphagia only after CR compared to the CRAL group. Changes in circulating leptin levels and hypothalamic neuropeptide gene expression were correlated with changes in weight and fat mass, suggesting that TNP-470 suppressed hyperphagia independently of the hypothalamic melanocortin system. Additionally, TNP-470 increased gene expression related to thermogenesis, fuel utilization, and browning in brown adipose tissue (BAT) and WAT, indicating TNP-470-induced increase in thermogenesis. SignificanceModulation of the WAT vasculature attenuates RWG after CR by suppressing hyperphagia and increasing BAT thermogenesis and WAT browning.

Roles of Ghrelin and Leptin in Body Mass Regulation under Food Restriction Based on the AMPK Pathway in the Red-Backed Vole, Eothenomys miletus, from Kunming and Dali Regions.

The phenotype plasticity of animals' physiological characteristics is an important survival strategy to cope with environmental changes, especially the change in climate factors. Small mammals that inhabit seasonally changing environments often face the stress of food shortage in winter. This study measured and compared the thermogenic characteristics and related physiological indicators in the adenosine-5'-monophosphate-activated protein kinase (AMPK) pathway in Eothenomys miletus between Kunming (KM, n = 18) and Dali (DL, n = 18) under food restriction and refeeding. The results showed that food restriction and the region have significant effects on body mass, the resting metabolic rate (RMR), hypothalamic neuropeptide gene expression, ghrelin levels in the stomach and serum, serum leptin level and the activity of AMPK, and malonyl CoA and carnitine palmitoyltransferase 1 (CPT-1) activity. Food restriction reduced the body mass, the gene expression of neuropeptide proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcription peptide (CART), and leptin level. However, the ghrelin concentration and AMPK activity increased. After refeeding, there was no difference in these physiological indexes between the food restriction and control groups. Moreover, the physiological indicators also showed regional differences, such as the body mass, POMC and CART gene expression, ghrelin concentration in the stomach and serum, and AMPK activity in DL changed more significantly. All these results showed that food restriction reduces energy metabolism in E. miletus. After refeeding, most of the relevant physiological indicators can return to the control level, indicating that E. miletus has strong phenotypic plasticity. Ghrelin, leptin, and the AMPK pathway play an important role in the energy metabolism of E. miletus under food restriction. Moreover, regional differences in physiological indicators under food restriction may be related to the different temperatures or food resources in different regions.

Role of Hypothalamic Transforming Growth Factor-β (TGF-β)/Smad Signaling in Feeding Regulation in Chickens.

Previous studies in mammalian obesity models have suggested that central transforming growth factor-β (TGF-β) controls the gene expression of appetite-regulating neuropeptides and peripheral energy metabolism. In the present study, we investigated the possible involvement of central TGF-β/Smad signaling in feeding regulation in chickens. Central administration of TGF-β1 resulted in phosphorylation of Smad2 in the hypothalamus of chicks and suppressed feed intake without changing the gene expression of hypothalamic appetite-regulating neuropeptides (neuropeptide Y, agouti-related protein, proopiomelanocortin, and corticotropin-releasing factor). However, neither fasting nor refeeding induced the phosphorylation of hypothalamic Smad2. These findings suggest that the activation of hypothalamic TGF-β/Smad signaling suppresses feed intake in chicks but it might not occur in response to feeding status.

BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet

ObjectivePancreatic β-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that β-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on β-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. MethodsBACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. β-cell proliferation was assessed by Ki67-positive nuclei, and β-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. ResultsAfter 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and β-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased β-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. ConclusionsCollectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.

The Ability to Dissipate Heat Is Likely to Be a More Important Limitation on Lactation in Striped Hamsters with Greater Reproductive Efforts under Warmer Conditions

The limitations on energy availability and outputs have been implied to have a profound effect on the evolution of many morphological and behavioral traits. It has been suggested that the reproductive performance of mammals is frequently constrained by intrinsic physiological factors, such as the capacity of the mammary glands to produce milk (the peripheral limitation [PL] hypothesis) or that of the body to dissipate heat (the heat dissipation limitation [HDL] hypothesis). Research on a variety of small mammals, however, has so far failed to provide unequivocal support for one hypothesis over the other. We tested the PL and HDL hypotheses in female striped hamsters (Cricetulus barabensis) with artificially manipulated litter sizes of two (three or four pups removed from natural litter size), five, eight (two or three pups added to natural litter size), and 12 (five to seven pups added to natural litter size) pups at ambient temperatures of 21° and 30°C. Energy intake and milk output of mothers, litter size, and litter mass were measured throughout lactation. Several markers indicating digestive enzyme activity and the gene expression of hypothalamic neuropeptides related to food intake were also measured. Food consumption and milk output increased with increasing litter size but reached a ceiling at 12 pups, causing 12-pup litters to have significantly lower litter mass and pup body mass than litters composed of fewer pups. Litter mass and maternal metabolic rate, milk output, maltase, sucrase, and aminopeptidase activity in the small intestine, and gene expression of hypothalamic orexigenic peptides were significantly lower at 30°C than at 21°C, and these differences were considerably more pronounced in 12-pup litters. These results suggest that PL and HDL can operate simultaneously but that the HDL hypothesis is probably more valid at warmer temperatures. Our results suggest that increased environmental temperatures in future climates may limit reproductive output through heat dissipation limits.

Body composition, biochemical, behavioral and molecular alterations in overfed rats after chronic exposure to SSRI

Serotonin (5-HT) plays a regulatory role in coordinating the neural circuits regulating energy balance, with differences in both 5-HT availability at the synapse and the activity of 5-HT receptors mediating anorectic (via POMC/CART activation) and orexigenic (via NPY/AgRP activation) responses. In conditions of overweight and obesity the control of energy balance is clearly deregulated, and serotonergic modulation appears to make a significant contribution to weight gain. Fluoxetine (FLX), a selective serotonin reuptake inhibitor (SSRI) that increases 5-HT availability in the synaptic cleft may thus have potential effects on energy balance. Our aim was to use an overfeeding model to investigate the effects of chronic FLX treatment on energy balance-related parameters regulated by hypothalamic neuropeptides. Nursing male Wistar rats were assigned to normofed (9 pups/dam) or overfed (3 pups/dam) groups beginning at 3 days of age and continuing until 21 days of age, when commercial chow and water were made available ad libitum until experimental treatments were begun. From 39 through 59 days of age groups were divided according to pharmacological treatment: 1) NV group, normofed + vehicle solution (NaCl 0.9%, 10 ml/kg b.w.), 2) NF group, normofed + FLX (10 mg/kg b.w., in vehicle solution, 10 ml/kg b.w.) 3), OV, overfed + vehicle solution and 4) OF, overfed + FLX. At 60 days of age, body weight, white and brown adipose tissue content, and food intake were determined, and serum biochemical parameters and hypothalamic neuropeptide gene expression were measured. Results showed that FLX induced reductions in several murinometric indices, improvement of adipose profile, hypophagic behavior, reduction in serum parameters, and positive modulation of hypophagia-related genes. These data suggest that the beneficial effects of FLX-treatment on overfeeding-induced physical and behavioral effects in rats was due to hypothalamic alterations that led to improvement in energy balance in animals with a compromised metabolism.

Strategies of behavior, energetic and thermogenesis of striped hamsters in response to food deprivation.

The life history of many animals includes periods of food shortage. Two behavioral strategies are involved in small mammals in response to food shortage: an increase in activity behavior, representing the increased foraging or migratory behavior, and a decrease in activity level, serving as a mechanism for conserving energy. However, it is uncertain whether animals adopt both strategies in response to food shortage, and whether hormone and neuroendocrine mechanisms are involved in both strategies. In the present study, changes in behavior and metabolic rate were examined in food-deprived striped hamsters (Cricetulus barabensis). The effects of leptin supplement on activity behavior, metabolic rate and hypothalamic neuropeptide gene expression were also examined. The behavior of food-deprived hamsters significantly changed with photoperiod phases: with increasing activity during the dark phase compared to those fed ad libitum, whereas decreasing activity and simultaneously increasing resting behavior during the light phase. Resting metabolic rate, body mass, and masses of fat depots and digestive tracts significantly decreased in food-deprived hamsters compared with ad libitum controls. Leptin supplement tended to attenuate the increased activity in the dark phase. Gene expression of hypothalamic neuropeptide Y (NPY) was significantly upregulated in food-deprived hamsters, while was significantly attenuated by exogenous leptin. These findings suggest that both behavior strategies are important behavioral adjustments in free-living animals to cope with food shortage. Leptin and hypothalamic NPY gene expression may be involved in the adjustments of physiology and behavior in animals demonstrating a hyperactivity strategy in response to food shortage.

Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression

We tested the hypothesis that dietary whey protein isolate (WPI) affects the intestinal mechanisms related to energy absorption and that the resulting energy deficit is compensated by changes in energy balance to support growth. C57BL/6 mice were provided a diet enriched with WPI with varied sucrose content, and the impact on energy balance-related parameters was investigated. As part of a high-sucrose diet, WPI reduced the hypothalamic expression of pro-opiomelanocortin gene expression and increased energy intake. The energy expenditure was unaffected, but epididymal weight was reduced, indicating an energy loss. Notably, there was a reduction in the ileum gene expression for amino acid transporter SLC6a19, glucose transporter 2, and fatty acid transporter 4. The composition of the gut microbiota also changed, where Firmicutes were reduced. The above changes indicated reduced energy absorption through the intestine. We propose that this mobilized energy in the adipose tissue and caused hypothalamic changes that increased energy intake, acting to counteract the energy deficit arising in the intestine. Lowering the sucrose content in the WPI diet increased energy expenditure. This further reduced epididymal weight and plasma leptin, whereupon hypothalamic ghrelin gene expression and the intestinal weight were both increased. These data suggest that when the intestine-adipose-hypothalamic pathway is subjected to an additional energy loss (now in the adipose tissue), compensatory changes attempt to assimilate more energy. Notably, WPI and sucrose content interact to enable the component mechanisms of this pathway.

Malabsorption and intestinal adaptation after one anastomosis gastric bypass compared with Roux-en-Y gastric bypass in rats.

The technically easier one-anastomosis (mini) gastric bypass (MGB) is associated with similar metabolic improvements and weight loss as the Roux-en-Y gastric bypass (RYGB). However, MGB is controversial and suspected to result in greater malabsorption than RYGB. In this study, we compared macronutrient absorption and intestinal adaptation after MGB or RYGB in rats. Body weight and food intake were monitored and glucose tolerance tests were performed in rats subjected to MGB, RYGB, or sham surgery. Carbohydrate, protein, and lipid absorption was determined by fecal analyses. Intestinal remodeling was evaluated by histology and immunohistochemistry. Peptide and amino acid transporter mRNA levels were measured in the remodeled intestinal mucosa and those of anorexigenic and orexigenic peptides in the hypothalamus. The MGB and RYGB surgeries both resulted in a reduction of body weight and an improvement of glucose tolerance relative to sham rats. Hypothalamic orexigenic neuropeptide gene expression was higher in MGB rats than in RYGB or sham rats. Fecal losses of calories and proteins were greater after MGB than RYGB or sham surgery. Intestinal hyperplasia occurred after MGB and RYGB with increased jejunum diameter, higher villi, and deeper crypts than in sham rats. Peptidase and peptide or amino acid transporter genes were overexpressed in jejunal mucosa from MGB rats but not RYGB rats. In rats, MGB led to greater protein malabsorption and energy loss than RYGB. This malabsorption was not compensated by intestinal overgrowth and increased expression of peptide transporters in the jejunum.

Association analysis between feed efficiency studies and expression of hypothalamic neuropeptide genes in laying ducks.

Residual feed intake (RFI) is now considered a more reasonable metric to evaluate animal feed efficiency. In this study, the correlation between RFI and other feed efficiency traits was investigated and gene expression within the hypothalamus was determined in low RFI (LRFI) and high RFI (HRFI) ducks. Further, several hypothalamic neuropeptide genes were measured using quantitative real-time PCR. The mean feed intake value was 160g/day, whereas the egg mass laid (EML) and body weight were approximately 62.4g/day and 1.46kg respectively. Estimates for heritability of RFI, feed conversion ratio (FCR) and feed intake were 0.26, 0.18 and 0.23 respectively. RFI is phenotypically positively correlated with feed intake and FCR (P<0.01). The expression of neuropeptide Y (NPY) and neuropeptide Y receptor Y5 (NPY5R) mRNA was higher in HRFI ducks compared with LRFI ducks (P<0.05), whereas that of proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R) and cholecystokinin (CCK) was lower (P<0.05). The mRNA expression of gonadotropin-releasing hormone 1 (luteinizing-releasing hormone) (GNRH1) and prolactin receptor (PRLR) was unchanged between LRFI and HRFI ducks. The results indicate that selection for LRFI could reduce feed intake without significant changes in EML, whereas selection on FCR will increase EML.

Diet-induced obesity and prenatal undernutrition lead to differential neuroendocrine gene expression in the hypothalamic arcuate nuclei.

Previously we reported that prenatal undernutrition (UN) leads to a dysregulation of appetite suppression through alterations in hypothalamic neuropeptide gene expression. In the current study, we expand our observations and investigate neuroendocrine transcriptional responses and central leptin sensitivity within the arcuate nucleus of rats exposed to prenatal UN or a postnatal high-fat diet (HF). Pregnant Wistar rats were fed a standard chow diet either ad libitum (AD) or at 30% of AD intake throughout gestation (UN) resulting in either control or intrauterine growth-restricted female offspring. At weaning, AD offspring were fed either a chow (C) or a HF (30% fat wt/wt) diet ad libitum for the remainder of the study, whereas UN offspring were fed a chow diet only. At ~142days, AD and UN offspring received either recombinant rat leptin (L) or saline (S) subcutaneously for 14days. Prenatal UN had a significant effect on hypothalamic NPY (P<0.0001), AgRP (P<0.01) and ObRb (P<0.02) mRNA expression compared to AD chow-fed offspring. A postnatal HF diet had a significant effect on AgRP mRNA expression (P<0.001), compared to AD chow-fed offspring, but no effect on NPY and ObRb expression. Leptin treatment, in both UN and HF offspring, was ineffective in reducing NPY and AgRP mRNA expression, and had no effect on ObRb expression. These findings suggest that prenatal UN and a postnatal HF diet lead to differential neuroendocrine gene expression in the hypothalamic arcuate nuclei and reduced sensitivity to leptin's anorexigenic effects.

Alterations in hypothalamic gene expression following Roux-en-Y gastric bypass.

ObjectiveThe role of the central nervous system in mediating metabolic effects of Roux-en-Y gastric bypass (RYGB) surgery is poorly understood. Using a rat model of RYGB, we aimed to identify changes in gene expression of key hypothalamic neuropeptides known to be involved in the regulation of energy balance.MethodsLean male Sprague-Dawley rats underwent either RYGB or sham surgery. Body weight and food intake were monitored bi-weekly for 60 days post-surgery. In situ hybridization mRNA analysis of hypothalamic AgRP, NPY, CART, POMC and MCH was applied to RYGB and sham animals and compared with ad libitum fed and food-restricted rats. Furthermore, in situ hybridization mRNA analysis of dopaminergic transmission markers (TH and DAT) was applied in the midbrain.ResultsRYGB surgery significantly reduced body weight and intake of a highly palatable diet but increased chow consumption compared with sham operated controls. In the arcuate nucleus, RYGB surgery increased mRNA levels of orexigenic AgRP and NPY, whereas no change was observed in anorexigenic CART and POMC mRNA levels. A similar pattern was seen in food-restricted versus ad libitum fed rats. In contrast to a significant increase of orexigenic MCH mRNA levels in food-restricted animals, RYGB did not change MCH expression in the lateral hypothalamus. In the VTA, RYGB surgery induced a reduction in mRNA levels of TH and DAT, whereas no changes were observed in the substantia nigra relative to sham surgery.ConclusionRYGB surgery increases the mRNA levels of hunger-associated signaling markers in the rat arcuate nucleus without concomitantly increasing downstream MCH expression in the lateral hypothalamus, suggesting that RYGB surgery puts a brake on orexigenic hypothalamic output signals. In addition, down-regulation of midbrain TH and DAT expression suggests that altered dopaminergic activity also contributes to the reduced intake of palatable food in RYGB rats.

Transgenic n-3 PUFAs enrichment leads to weight loss via modulating neuropeptides in hypothalamus

Body weight is related to fat mass, which is associated with obesity. Our study explored the effect of fat-1 gene on body weight in fat-1 transgenic mice. In present study, we observed that the weight/length ratio of fat-1 transgenic mice was lower than that of wild-type mice. The serum levels of triglycerides (TG), cholesterol (CT), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and blood glucose (BG) in fat-1 transgenic mice were all decreased. The weights of peri-bowels fat, perirenal fat and peri-testicular fat in fat-1 transgenic mice were reduced. We hypothesized that increase of n-3 PUFAs might alter the expression of hypothalamic neuropeptide genes and lead to loss of body weight in fat-1 transgenic mice. Therefore, we measured mRNA levels of appetite neuropeptides, Neuropeptide Y (NPY), Agouti-related peptides (AgRP), Proopiomelanocortin (POMC), Cocaine and amphetamine regulated transcript (CART), ghrelin and nesfatin-1 in hypothalamus by real-time PCR. Compared with wild-type mice, the mRNA levels of CART, POMC and ghrelin were higher, while the mRNA levels of NPY, AgRP and nesfatin-1 were lower in fat-1 transgenic mice. The results indicate that fat-1 gene or n-3 PUFAs participates in regulation of body weight, and the mechanism of this phenomenon involves the expression of appetite neuropeptides and lipoproteins in fat-1 transgenic mice.

Chronic Mild Cold Conditioning Modulates the Expression of Hypothalamic Neuropeptide and Intermediary Metabolic-Related Genes and Improves Growth Performances in Young Chicks.

BackgroundLow environmental temperatures are among the most challenging stressors in poultry industries. Although landmark studies using acute severe cold exposure have been conducted, still the molecular mechanisms underlying cold-stress responses in birds are not completely defined. In the present study we determine the effect of chronic mild cold conditioning (CMCC) on growth performances and on the expression of key metabolic-related genes in three metabolically important tissues: brain (main site for feed intake control), liver (main site for lipogenesis) and muscle (main site for thermogenesis).Methods80 one-day old male broiler chicks were divided into two weight-matched groups and maintained in two different temperature floor pen rooms (40 birds/room). The temperature of control room was 32°C, while the cold room temperature started at 26.7°C and gradually reduced every day (1°C/day) to reach 19.7°C at the seventh day of the experiment. At day 7, growth performances were recorded (from all birds) and blood samples and tissues were collected (n = 10). The rest of birds were maintained at the same standard environmental condition for two more weeks and growth performances were measured.ResultsAlthough feed intake remained unchanged, body weight gain was significantly increased in CMCC compared to the control chicks resulting in a significant low feed conversion ratio (FCR). Circulating cholesterol and creatine kinase levels were higher in CMCC chicks compared to the control group (P<0.05). CMCC significantly decreased the expression of both the hypothalamic orexigenic neuropeptide Y (NPY) and anorexigenic cocaine and amphetamine regulated transcript (CART) in chick brain which may explain the similar feed intake between the two groups. Compared to the control condition, CMCC increased the mRNA abundance of AMPKα1/α2 and decreased mTOR gene expression (P<0.05), the master energy and nutrient sensors, respectively. It also significantly decreased the expression of fatty acid synthase (FAS) gene in chick brain compared to the control. Although their roles are still unknown in avian species, adiponectin (Adpn) and its related receptors (AdipoR1 and 2) were down regulated in the brain of CMCC compared to control chicks (P<0.05). In the liver, CMCC significantly down regulated the expression of lipogenic genes namely FAS, acetyl-CoA carboxylase alpha (ACCα) and malic enzyme (ME) and their related transcription factors sterol regulatory element binding protein 1/2 (SREBP-1 and 2). Hepatic mTOR mRNA levels and phosphorylated mTOR at Ser2448 were down regulated (P<0.05), however phosphorylated ACCαSer79 (inactivation) was up regulated (P<0.05) in CMCC compared to control chicks, indicating that CMCC switch hepatic catabolism on and inhibits hepatic lipogenesis. In the muscle however, CMCC significantly up regulated the expression of carnitine palmitoyltransferase 1 (CPT-1) gene and the mRNA and phosphorylated protein levels of mTOR compared to the control chicks, indicating that CMCC enhanced muscle fatty acid β-oxidation.ConclusionsIn conclusion, this is the first report indicating that CMCC may regulate AMPK-mTOR expression in a tissue specific manner and identifying AMPK-mTOR as a potential molecular signature that controls cellular fatty acid utilization (inhibition of hepatic lipogenesis and induction of muscle fatty acid β-oxidation) to enhance growth performance during mild cold acclimation.

Long term ingestion of a preload containing fructo-oligosaccharide or guar gum decreases fat mass but not food intake in mice

Fermentable dietary fibre such as fructo-oligosaccharide and viscous dietary fibers such as guar gum and alginate affect energy homeostasis. The goal of this study was to compare the impact of long term intake of these three dietary fibers on food intake, meal pattern, body weight and fat accumulation in mice. Over a period of 3weeks, the mice were fed daily with a preload containing 32mg of fructo-oligosaccharide or alginate or 13mg of guar gum. Food intake and body weight were monitored weekly, while meal patterns, adiposity and the expression of hypothalamic neuropeptide genes were evaluated at the end of the study period. The 3 dietary fibers produced a similar decrease in total daily food intake (14 to 22%) at the end of the first week, and this effect disappeared over time. The 3 dietary fibers induced a slight variation in satiation parameters. Body weight and expression of hypothalamic neuropeptide genes were not affected by any of the treatment. Preload of fructo-oligosaccharide and guar gum induced a similar and substantial decrease in the development of adiposity (17% and 14%, respectively), while alginate had no effect. Our results demonstrate mainly that the inhibitory effect of dietary fiber on food intake is lost over time, and that guar gum limits fat storage.

Seasonal changes in body mass, serum leptin levels and hypothalamic neuropeptide gene expression in male Eothenomys olitor

The present study examined seasonal changes in body mass and energy metabolism in the Chaotung vole (Eothenomys olitor) and the physiological mechanisms underpinning these changes. Seasonal changes in the following parameters were measured in male E. olitor, body mass, food intake, thermogenesis, enzyme activity, masses of tissues and organs, hormone concentrations and expression of hypothalamic arcuate nucleus energy balance genes including neuropeptide Y (NPY), agouti-related protein (AgRP), pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART). Body mass was constant over the year, but the masses of tissues and organs differed significantly between seasons. There were significant changes in body fat mass and serum leptin levels over the four seasons. E. olitor showed significant seasonal changes in food intake and thermogenesis, uncoupling protein 1 (UCP1) content, enzyme activity, and serum tri-iodothyronine (T3) and thyroxine (T4) levels. Moreover, mRNA expression in the hypothalamus showed significant seasonal changes. All of our results suggested that E. olitor had constant body mass over the year, which was inconsistent with the prediction of the ‘set-point’ hypothesis. However, body fat mass and serum leptin levels were significantly different among the four seasons, providing support for the ‘set-point’ hypothesis. The changes in leptin, NPY, AgRP, POMC, and CART mRNA levels may play a role in the regulation of energy intake in E. olitor. Furthermore, the role of leptin and hypothalamic neuropeptide gene in the regulation of energy metabolism and body mass may be different in animals that are acclimated to different seasons.

Decreased circulating leptin and increased neuropeptide Y gene expression are implicated in food deprivation-induced hyperactivity in striped hamsters, Cricetulus barabensis

Physiological and behavioral adjustments of small mammals are important strategies in response to variations in food availability. Although numerous of studies have been carried out in rodents, behavioral patterns in response to food deprivation and re-feeding (FD–RF) are still inconsistent. Here we examined effects of a 24h FD followed by RF on general activity, serum leptin concentrations and gene expression of orexigenic and anorexigenic hypothalamic neuropeptides in striped hamsters (Cricetulus barabensis) with/without leptin supplements. The time spent on activity was increased by 2.5 fold in FD hamsters compared with controls fed ad libitum (P<0.01). Body mass, fat mass as well as serum leptin concentrations were significantly decreased in FD hamsters in comparison with ad libitum controls, which were in parallel with hyperactivity. During re-feeding, leptin concentrations increased rapidly to pre-deprivation levels by 12h, but locomotor activity decreased gradually and did not return to pre-deprivation levels until 5days after re-feeding. Leptin administration to FD hamsters significantly attenuated the increased activity. Gene expression of hypothalamic neuropeptide Y (NPY) was upregulated in FD hamsters and fell down to control levels when hamsters were re-fed ad libitum, similar to that observed in activity behavior. Leptin supplement induced increases in serum leptin concentrations (184.1%, P<0.05) in FD hamsters and simultaneously attenuated the increase in activity (45.8%, P<0.05) and NPY gene expression (35%, P<0.05). This may allow us to draw a more generalized conclusion that decreased leptin concentrations function as a starvation signal in animals under food shortage; to induce an increase in activity levels, leading animals to forage and/or migrate, and consequently increasing the chance of survival. Decreased concentrations of serum leptin in animals subjected to food shortage may induce an upregulation of gene expression of hypothalamus NPY, consequently driving a significant increase in foraging behavior.

Residual feed intake studies in Angus-sired cattle reveal a potential role for hypothalamic gene expression in regulating feed efficiency1,2

Mechanisms underlying variation in residual feed intake (RFI), a heritable feed efficiency measure, are poorly understood while the relationship between RFI and meat quality is uncertain. To address these issues, 2 divergent cohorts consisting of High (HRFI) and Low (LRFI) RFI individuals were created by assessing RFI in 48 Angus-sired steers during a 70 d feeding trial to identify steers with divergent RFI. The association of RFI with indices of meat quality and expression of genes within hypothalamic and adipose tissue was then determined in LRFI and HRFI steers. While on test, feed intake was recorded daily with BW and hip heights recorded at 14 d intervals. Ultrasound measurements of rib eye area (REA) and backfat (BF) were recorded initially and before harvest. Carcass and growth data were analyzed using a mixed model with RFI level (LRFI, HRFI) as the independent variable. The least-square means (lsmeans) for RFI were -1.25 and 1.51 for the LRFI and HRFI cohorts (P < .0001). Dry matter intake was higher for the HRFI individuals versus the LRFI steers (P < .0001) while on test BW gain was not different between the 2 groups (P < 0.73). There were no differences detected in marbling score (P < 0.93), BF (P < 0.61), REA (P < 0.15), yield grade (P < 0.85) or objective Hunter color measures between LRFI and HRFI steers indicating that there was no relationship between RFI and meat quality. Neuropeptide-Y (NPY), relaxin-3 (RLN3), melanocortin 4 receptor (MC4R), and GnRH mRNA expression was 64%, 59%, 58%, 86% lower (P < 0.05), respectively, while gonadotropin inhibiting hormone (GnIH) and pro-opiomelanocortin (POMC) mRNA expression was 198% and 350% higher (P < 0.01) in the arcuate nucleus of LRFI steers. Expression of agouti-related protein (AGRP), relaxin/insulin-like family peptide receptor 1 (RXFP1), and melanocortin 3 receptor mRNA was similar between LRFI and HRFI animals. Pituitary expression of FSHβ (P < 0.03) and LHβ (P < 0.01) was correlated to hypothalamic GnRH levels suggesting that changes in gene expression within the arcuate nucleus had functional consequences. Leptin mRNA expression was 245% higher in the adipose tissue of LRFI steers consistent with lower levels of NPY and higher expression of POMC in their hypothalami. These data support the hypothesis that differences in hypothalamic neuropeptide gene expression underlie variation in feed efficiency in steers while the gonadotropin axis may also influence feed efficiency.

Orexigenic effects of endomorphin-2 (EM-2) related to decreased CRH gene expression and increased dopamine and norepinephrine activity in the hypothalamus

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are opioid peptides which are selective partial agonists of μ-opioid receptor. We studied the effects of EM-2 injected into the arcuate nucleus (ARC) of the hypothalamus on feeding behavior and gene expression of orexigenic [agouti-related peptide (AgRP), neuropeptide Y (NPY) and orexin-A] and anorexigenic [cocaine and amphetamine-regulated transcript (CART), corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC)] peptides in male Wistar rats fed a standard laboratory diet. Furthermore, we evaluated the effects of EM-2 on dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) steady state concentrations, in the hypothalamus. 64 rats (16 for each group of treatment) were injected into the ARC, at 9.00am, with either vehicle or EM-2 (0.50–0.75μmol/kg) or EM-2 (0.50μmol/kg) plus β-funaltrexamine (0.20μmol/kg). Food intake was recorded through 24h following injection, and hypothalamic DA, NE, 5-HT levels and neuropeptide gene expression were evaluated 24h after EM-2 administration. Compared to vehicle, EM-2 significantly increased food intake, throughout 24h post-injection. Furthermore, EM-2 treatment led to a significant increase of DA and NE concentrations and a decrease of CRH mRNA levels. On the other hand, β-funaltrexamine administration reverted both feeding stimulatory and neuromodulatory effects induced by EM-2. We can conclude that the orexigenic effect of μ-opioid receptor activation by EM-2 could be related to both inhibition of CRH and stimulation of dopamine and norepinephrine levels, in the hypothalamus.