The role of syndecans in the regulation of body weight and synaptic plasticity

Body weight is tightly regulated by a feedback mechanism involving peripheral adiposity signals and multiple central nervous system neurotransmitter pathways. Despite the tight regulation of body weight there is an increase in the prevalence of obesity and overweight in Western society. Obesity and overweight are conditions of excess body weight stored as fat. Syndecan-3, a member of the syndecan family of type I transmembrane heparan sulfate proteoglycans is a novel a regulator of feeding behavior and body weight. Syndecans are extracellular matrix molecules (ECMs) that modulate cell adhesion, cell-cell interactions and ligand-receptor interactions. The finding that syndecan-3 can regulate body weight is novel and provides a unique link between the extracellular matrix and body weight regulatory mechanisms. Uniquely, hormones such as leptin previously thought only to regulate body weight by modulating neuropeptide levels, have now been demonstrated to regulate neuronal plasticity in the hypothalamus. ECMs and syndecans have long been recognized as regulators of plasticity. Therefore, this review will focus on highlighting the role of syndecans and in particular syndecan-3 in neuronal development and synaptic organization and how these processes may integrate body weight regulation. As part of this review, we will highlight how syndecan-3 can mediate the activity of adiposity signals, such as leptin, and facilitate changes in neuronal plasticity.     

Roles of pancreatic polypeptide in regulation of food intake

Pancreatic polypeptide (PP) is produced in pancreatic islets of Langerhans and released into the circulation after ingestion of a meal. Peripherally administered PP suppresses food intake and gastric emptying. On the other hand, central administration of PP elicits food intake and gastric emptying. Therefore, PP actions on food intake may be, in part, attributable to gastric emptying. PP transgenic mice exhibit decreases in both food intake and gastric emptying rate that were clearly reversed by anti-PP antiserum. PP is an anorexigenic signal in the periphery and an orexigenic signal in the central nervous system.     

A novel role for aminoacyl-tRNA synthetases in the regulation of polypeptide chain initiation

Exposure of the temperature-sensitive leucyl-tRNA synthetase mutant of Chinese hamster ovary cells, tsH1, to the non-permissive temperature of 39.5 degrees C results in a rapid inhibition of polypeptide chain initiation. This inhibition is caused by a reduced ability of the eukaryotic initiation factor eIF-2 to participate in the formation of eIF-2.GTP.Met-tRNAf ternary complexes and thus in the formation of 43S ribosomal pre-initiation complexes. Associated with this decreased eIF-2 activity is an increased phosphorylation of the eIF-2 alpha subunit. It has previously been shown in other systems that phosphorylation of eIF-2 alpha slows the rate of recycling of eIF-2.GDP to eIF-2.GTP catalysed by the guanine nucleotide exchange factor eIF-2B. We show here that phosphorylation of eIF-2 alpha by the reticulocyte haem-controlled repressor also inhibits eIF-2B activity in cell-free extracts derived from tsH1 cells. Thus the observed increased phosphorylation of eIF-2 alpha at the non-permissive temperature in this system is consistent with impaired recycling of eIF-2 in vivo. Using a single-step temperature revertant of tsH1 cells, TR-3 (which has normal leucyl-tRNA synthetase activity at 39.5 degrees C), we demonstrate here that all inhibition of eIF-2 function reverts together with the synthetase mutation. This establishes the close link between synthetase function and eIF-2 activity. In contrast, recharging tRNALeu in vivo in tsH1 cells at 39.5 degrees C by treatment with a low concentration of cycloheximide failed to reverse the inhibition of eIF-2 function. This indicates that tRNA charging per se is not involved in the regulatory mechanism. Our data indicate a novel role for aminoacyl-tRNA synthetases in the regulation of eIF-2 function mediated through phosphorylation of the alpha subunit of this factor. However, in spite of the fact that cell-free extracts from Chinese hamster ovary cells contain protein kinase and phosphatase activities active against either exogenous or endogenous eIF-2 alpha, we have been unable to show any activation of kinase or inactivation of phosphatase following incubation of the cells at 39.5 degrees C.     

Obesity: the role of hypothalamic AMP-activated protein kinase in body weight regulation

Obesity is rapidly increasing and is of great public health concern worldwide. Although there have been remarkable developments in obesity research over the past 10 years, the molecular mechanism of obesity is still not completely understood. Body weight results from the balance between food intake and energy expenditure. Recent studies have found that hypothalamic AMP-activated protein kinase plays a key role in regulating these processes. Leptin, insulin, glucose and alpha-lipoic acid have been shown to reduce food intake by lowering hypothalamic AMP-activated protein kinase activity, whereas ghrelin and glucose depletion increase food intake by increasing hypothalamic AMP-activated protein kinase activity. In addition, this enzyme plays a role in the central regulation of energy expenditure. These findings indicate that hypothalamic AMP-activated protein kinase is an important signal molecule, which integrates nutritional and hormonal signals and modulates feeding behavior and energy expenditure.     

Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance

Energy intake and expenditure is a highly conserved and well-controlled system with a bias toward energy intake. In times of abundant food supply, individuals tend to overeat and in consequence to increase body weight, sometimes to the point of clinical obesity. Obesity is a disease that is not only characterized by enormous body weight but also by rising morbidity for diabetes type II and cardiovascular complications. To better understand the critical factors contributing to obesity we performed the present study in which the effects of energy expenditure and energy intake were examined with respect to body weight, localization of fat and insulin resistance in normal Wistar rats. It was found that a diet rich in fat and carbohydrates similar to "fast food" (cafeteria diet) has pronounced implication in the development of obesity, leading to significant body weight gain, fat deposition and also insulin resistance. Furthermore, an irregularly presented cafeteria diet (yoyo diet) has similar effects on body weight and fat deposition. However, these rats were not resistant to insulin, but showed an increased insulin secretion in response to glucose. When rats were fed with a specified high fat/carbohydrate diet (10% fat, 56.7% carbohydrate) ad lib or at the beginning of their activity phase they were able to detect the energy content of the food and compensate this by a lower intake. They, however, failed to compensate when food was given in the resting phase and gained more body weight as controls. Exercise, even of short duration, was able to keep rats on lower body weight and reduced fat deposition. Thus, inappropriate food intake with different levels of energy content is able to induce obesity in normal rats with additional metabolic changes that can be also observed in humans.     

The role of PYY in feeding regulation

Peptide YY (PYY), a 36-amino-acid peptide, is secreted primarily from L-cells residing in the intestinal mucosa of the ileum and large intestine. PYY, which belongs to a family of peptides including neuropeptide Y (NPY) and pancreatic polypeptide, is released into the circulation as PYY(1-36) and PYY(3-36); the latter is the major form of PYY in gut mucosal endocrine cells and throughout the circulation. Plasma PYY levels begin to rise within 15 min after starting to eat and plateau within approximately 90 min, remaining elevated for up to 6 h. Exogenous administration of PYY(3-36) reduces energy intake and body weight in both humans and animals. Via Y2 receptors, the satiety signal mediated by PYY inhibits NPY neurons and activates pro-opiomelanocortin neurons within the hypothalamic arcuate nucleus. Peripheral PYY(3-36) binds Y2 receptors on vagal afferent terminals to transmit the satiety signal to the brain. PYY(3-36) may have therapeutic potential in human obesity.     

Leptin-induced adipose apoptosis: Implications for body weight regulation

Great strides have been made in understanding the genetics of body weight regulation, in part due to the study of rodent models of obesity that are characterized by mutations affecting leptin or its receptors. Leptin, produced in adipose tissue, acts both centrally and peripherally to orchestrate complex metabolic and behavioral changes that increase loss of adipose tissue, including suppressing food intake and increasing thermogenesis. In addition, recent evidence indicates that leptin acts centrally to trigger an apoptotic process resulting in adipocyte deletion. Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following leptin treatments. This review summarizes the major aspects of leptin-induced adipose tissue apoptosis, including some of the newest findings about possible mechanisms of action.     

Ghrelin and body weight regulation in the obese Zucker rat in relation to feeding state and dark/light cycle

Ghrelin is a new orexigenic peptide primarily produced by the stomach but also present in the hypothalamus. It has adipogenic effects when it is chronically injected in rodents but in obese humans, its plasma concentration is decreased. It can reverse the anorectic effects of leptin when it is co-injected with this peptide in the brain ventricles. The Zucker fa/fa rat is a genetic model of obesity related to a default in the leptin receptor. It is characterized by a large dysregulation of numerous hypothalamic peptides but the ghrelin status of this rat has not yet been determined. Through several experiments, we determine in lean and obese Zucker rats its circulating form in the plasma, its tissue levels and/or expression, and studied the influence of different feeding conditions and its light/dark variations. Ghrelin expression was higher in the obese stomach and hypothalamus (P < 0.05 and P < 0.02, respectively). The ratio of [Octanoyl-Ser3]-ghrelin (active form) to [Des-Octanoyl-Ser3]-ghrelin (inactive form) was approximately 1:1 in the stomach and 2:1 in the plasma in lean and obese rats (no differences). After fasting, plasma ghrelin concentrations increased significantly in lean (+ 64%; P < 0.001) and obese (+ 60%; P < 0.02) rats. After 24 hours of refeeding, they returned to their initial ad lib levels. Ghrelin concentrations were higher in obese rats by 69% (P < 0.005), 65% (P < 0.02), and 73% (P < 0.005) in the ad libitum, fast, and refed states respectively. These results indicate that the obese Zucker rat is characterized by increases in the stomach mRNA expression and in peptide release in the circulation. They clearly support a role for ghrelin in the development of obesity in the absence of leptin signaling.     

Geomagnetic field absence reduces adult body weight of a migratory insect by disrupting feeding behavior and appetite regulation

The geomagnetic field(GMF)is well documented for its essential role as a cue used in animal orientation or navigation.Recent evidence indicates that the absence...     

Opioid regulation of food intake and body weight in humans

Relatively few studies of humans have evaluated the effects of opioids on food intake and body weight. Most have focused on the potential role of opioids in the etiology of obesity. Measurements of endogenous opioids in plasma or spinal fluid of humans reveal higher levels, particularly of beta-endorphin, in obese subjects. Opioid agonists such as methadone and butorphanol tartrate stimulate food intake, and all studies with naloxone, an opioid antagonist, demonstrate a reduction of short-term food intake in obese or lean humans. Long-term studies with naltrexone, an antagonist similar to naloxone, show no effect on food intake or body weight. Opioid agonists or antagonists have little effect on nutrient selection in humans. The effects on feeding-related hormones is equivocal. Further studies with more specific opioid receptor activities are needed.     

Role of set-point theory in regulation of body weight

In adult individuals body weight is maintained at a relatively stable level for long periods. The set-point theory suggests that body weight is regulated at a predetermined, or preferred, level by a feedback control mechanism. Information from the periphery is carried by an affector to a central controller located in the hypothalamus. The controller integrates and transduces the information into an effector signal that modulates food intake or energy expenditure to correct any deviations in body weight from set-point. Evidence for involvement of various factors and physiological systems in the control of food intake and regulation of body weight and fat are reviewed within the context of a control model. Current working hypotheses include roles for nutrients, dietary composition and organoleptic properties, hormones, neural pathways, various brain nuclei, and many neurotransmitters in the regulation of food intake. It is concluded that regulation of body weight in relation to one specific parameter related to energy balance is unrealistic. It seems appropriate to assume that the level at which body weight and body fat content are maintained represents the equilibria achieved by regulation of many parameters.     

Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control

Interleukin (IL)-15 is a cytokine which is highly expressed in skeletal muscle. Cell culture studies have indicated that IL-15 may have an important role in muscle fiber growth and anabolism. However, data concerning the metabolic effects of this cytokine in vivo are lacking. In the present study, IL-15 was administered to adult rats for 7 days. While IL-15 did not cause changes in either muscle mass or muscle protein content, it induced significant changes in the fractional rates of both muscle protein synthesis and degradation, with no net changes in protein accumulation. Additionally, IL-15 administration resulted in a 33% decrease in white adipose tissue mass and a 20% decrease in circulating triacylglycerols; this was associated with a 47% lower hepatic lipogenic rate and a 36% lower plasma VLDL triacylglycerol content. The decrease in white fat induced by IL-15 was in adipose tissue. No changes were observed in the rate of lipolysis as a result of cytokine administration. These findings indicate that IL-15 has significant effects on both protein and lipid metabolism, and suggest that this cytokine may participate in reciprocal regulation of muscle and adipose tissue mass.     

A cDNA encoding a small common precursor for human pancreatic polypeptide and pancreatic icosapeptide.

A cDNA for the hormone, human pancreatic polypeptide (PP), was isolated by oligodeoxynucleotide screening from a cDNA library constructed from normal human pancreatic mRNA. The primary structure of the precursor protein as deduced from the cDNA sequence is 95 amino acids long and is composed of a typical, but rather long signal peptide of 29 residues, followed by the sequence of the 36 amino acid human pancreatic polypeptide, which again is separated from the human pancreatic icosapeptide sequence by a classic cleavage and amidation site, Gly-Lys-Arg. The precursor terminates in a heptapeptide which is cleaved from the icosapeptide at a monobasic processing site. Both the size and the structure of the PP precursor was supported by the results of peptide analysis of biosynthetically labeled pro-PP isolated from canine PP cells in which processing was prevented by the arginine analogue canavanine. It is concluded that the precursor for mammalian PP gives rise to two peptide products, the well preserved, carboxyamidated PP and an icosapeptide which is preserved only in its COOH-terminal end, plus a small highly variable COOH-terminal oligopeptide.     

Geomagnetic field absenee reduces adult body weight of a migratory insect by disrupt!ng feeding behavior and appetite regulation

The geomagnetic field(GMF)is well documented for its essential role as a cue used in animal orientation or navigation.Recent evidence indicates that the absence of GMF(mimicked by the near-zero magnetic field,NZMF)can trigger stress-like responses such as reduced body weight,as we have previously shown in the brown planthopper,Nilaparvata lugens.In this study,we found that consistent with the significantly decreased body weight of newly emerged female(—14.67%)and male(—13.17%)adult N.lugens,the duration of the phloem ingestion feeding waveform was significantly reduced by 32.02%in 5th instar nymphs reared under the NZMF versus GMF.Interestingly,5th instar nymphs that exhibited reduced feeding had significantly higher glucose levels(+16.98%and+20.05%;24 h and 48 h after molting),which are associated with food aversion,and expression patterns of their appetite-related neuropeptide genes(neuropeptide F,dow regulated overall;short neuropeptide F,dowregulated overall;adipokinetic hormone up-regulated overall;and adipokinetic hormone receptor,down-regulated overall)were also altered under the absence of GMF in a manner consistent with diminishing appetite.Moreover,the expressions of the potential magnetosensor croptochromes(Crys)were found significantly altered under the absence of GMF,indicating the likely upstream signaling of the Cry-mediated magnetoreception mechanisms.These findings support the hypothesis that strong changes in GMF intensity can reduce adult body weight through affecting insect feeding behavior and underlying regulatory processes including appetite regulation.Our results highlight that GMF could be necessary for the maintenanee of energy homeostasis in insects.     

Estrogenic regulation of body weight in the female rat.

For a period of weeks subsequent to bilateral ovariectomy, female rats given unlimited access to food increased their food intakes and the rates at which they gained body weight; this resulted in elevated levels of body weight. Restricting ovariectomized (ovx) rats to their preoperative level of food intake (restricted diet), prevented this excessive gain in body weight. Estradiol benzoate (EB) treatments of 0.5 μg per day for 15 consecutive days partially reversed pre-occurring weight gain in obese ovx rats; this was accompanied by a reduction in food intake. In contrast, identical EB treatment for nonobese ovx rats (restricted diet) did not result in any loss of body weight or change in food intake. Oil-treated nonobese ovx rats gained a small amount of weight relative to their EB-treated counterparts, despite the similarity in their food intakes. Thus, part of the increased weight gain observed after ovariectomy may be independent of changes in food consumption, and related to removal of estrogenic influences from metabolic and behavioral processes involved in energy balance. The weight limiting actions of estradiol were far more pronounced in animals already obese or facing impending obesity than in animals in which excessive weight gain was prevented. The data also suggest that estradiol is more effective in preventing than in reversing the weight gain associated with ovariectomy, and that estrogenic influences on the body weight set point are manifested with very short latencies. These findings support earlier conclusions that estradiol does not regulate food intake directly, but secondarily controls consumption as a means of weight regulation.     

Glucocorticoids and melanocortins in the regulation of body weight in humans.

The last decade witnessed a dramatic increase in knowledge concerning regulation of body weight and obesity. According to recent concepts constancy of body weight is a side product of regulatory events which ensure constant glucose fluxes to the brain. Within these control systems glucocorticoids and melanocortins play a fundamental role at several sites. The melanocortin neurons in the arcuate nucleus are important mediators of the feedback effects of leptin and insulin. Glucocorticoid and mineralocorticoid receptors in hippocampal neurons are crucial as they define the balance between glucose allocation processes and food intake. Thereby, the hippocampal structures determine the setpoint for bodyweight regulation. Novel approaches to treatment of obesity must aim at manipulating these brain structures.     

A new in vitro model for studies of pancreatic polypeptide secretion and biochemistry

A new model tissue (pseudoislet) is described for studies of pancreatic polypeptide (PP) secretion and biochemistry. It consists of islet-like aggregates of canine pancreatic endocrine cells which are formed and maintained on tissue culture. Immunocytochemical staining revealed that pseudoislets prepared from the duodenal end of the pancreas contained a predominance (40-60%) of F cells (the PP secreting cell). Also present were 10-25% exocrine cells and an equal proportion of A, B and D cells. Several studies were conducted to characterize the pseudoislets' capacity to secrete PP. Basal rates of PP release and the concentration of PP per pseudoislet remained constant during four weeks of culture. Stimulation at weekly intervals by carbachol (0.1 mM) resulted in a stable secretory rate for 2 weeks, that declined progressively at weeks 3 and 4. When studied in a perfusion system, carbachol-stimulated PP release occurred in a biphasic pattern, similar to the well-recognized biphasic release of insulin from perifused rat islets. Dose-response curves of four cholinergic agonists revealed clear differences in secretagogue activity. Acetylcholine and methacholine were found to be equipotent, followed in order of potency by carbachol and bethanechol. These histologic and secretory data show that canine pseudoislets are healthy tissues composed of a high proportion of F cells which secrete PP in response to cholinergic stimulation. The data suggest that the cultured canine pseudoislet model provides an excellent system useful in studies of PP secretion and biosynthesis.