Hypothalamic Appetite Regulation Research Articles

Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet

Maternal nutritional history predicts obesity in adult offspring independent of postnatal diet

Differential Responses of Orexigenic Neuropeptides to Fasting in Offspring of Obese Mothers

Maternal obesity due to long-term high-fat diet (HFD) consumption leads to faster growth in offspring during suckling, and increased adiposity at 20 days of age. Decreased expression of the orexigenic neuropeptide Y (NPY) and increased anorexigenic proopiomelanocortin (POMC) mRNA expression were observed in the fed state. However, hunger is the major drive to eat and hypothalamic appetite regulators change in response to meals. Therefore, it is important to compare both satiated and fasting states. Female Sprague-Dawley rats (8 weeks old) were fed a cafeteria-style HFD (15.33 kJ/g) or chow for 5 weeks before mating, with the same diet continuing throughout gestation and lactation. At postnatal day 20, male pups were killed either after overnight fasting or in the fed state. Pups from obese dams were hyperphagic during both pre- and postweaning periods. Pups from obese dams had higher hypothalamic mRNA expression of POMC and NPY Y1 receptor, but lower hypothalamic melanocortin-4 receptor (MC4R) and its downstream target single-minded gene 1 (Sim1), in the fed state. Overnight fasting reduced circulating glucose, insulin, and leptin and increased hypothalamic NPY Y1 receptor mRNA in pups from both lean and obese dams. Hypothalamic NPY and agouti-related protein (AgRP) were only increased by fasting in pups from obese dams; reductions in MC4R and Sim1 were only seen in pups from lean dams. At weaning, the suppressed orexigenic signals in offspring from obese dams were normalized after overnight fasting, although anorexigenic signaling appeared impaired in these animals. This may contribute to their hyperphagia and faster growth.

Cerebral activation by fasting induces lactate accumulation in the hypothalamus

Carbon-13 ((13)C) high-resolution magic angle spinning (HR-MAS) spectroscopy was used to investigate the neuroglial coupling mechanisms underlying appetite regulation in the brain of C57BL/6J mice metabolizing [1-(13)C]glucose. Control fed or overnight fasted mice received [1-(13)C]glucose (20 micromol/g intraperitoneally [i.p.]), 15 min prior to brain fixation by focused microwaves. The hypothalamic region was dissected from the rest of the brain and (13)C HR-MAS spectra were obtained from both biopsies. Fasting resulted in a significant increase in hypothalamic [3-(13)C]lactate and [2-(13)C]gamma-aminobutyric acid (GABA) relative to the remaining brain. Administration of the orexigenic peptide ghrelin (0.3 nmol/g i.p.) did not increase hypothalamic [3-(13)C]lactate or [2-(13)C]GABA, suggesting that ghrelin signaling is not sufficient to elicit all the metabolic consequences of hypothalamic activation by fasting. Our results indicate that the hypothalamic regulation of appetite involves, in addition to the well-known neuropeptide signaling, increased neuroglial lactate shuttling and augmented GABA concentrations.

Differential Effects of Restricted Versus Unlimited High‐Fat Feeding in Rats on Fat Mass, Plasma Hormones and Brain Appetite Regulators

The rapid rise in obesity has been linked to altered food consumption patterns. There is increasing evidence that, in addition to total energy intake, the macronutrient composition of the diet may influence the development of obesity. The present study aimed to examine the impact of high dietary fat content, under both isocaloric and hypercaloric conditions, compared with a low fat diet, on adiposity, glucose and lipid metabolism, and brain appetite regulators in rats. Male Sprague-Dawley rats were exposed to one of three diets: control (14% fat), ad lib high-fat palatable (HFD, 35% fat) or high-fat palatable restricted (HFD-R, matched to the energy intake of control) and were killed in the fasting state 11 weeks later. Body weight was increased by 28% in unrestricted HFD fed rats, with an almost tripling of caloric intake and fat mass (P < 0.001) and double the plasma triglycerides of controls. Glucose intolerance and increased insulin levels were observed. HFD-R animals calorie matched to control had double their fat mass, plasma insulin and triglycerides (P < 0.05). Only ad lib consumption of the HFD increased the hypothalamic mRNA expression of the appetite-regulating peptides, neuropeptide Y and pro-opiomelanocortin. Although restricted consumption of palatable HFD had no significant impact on hypothalamic appetite regulators or body weight, it increased adiposity and circulating triglycerides, suggesting that the proportion of dietary fat, independent of caloric intake, affects fat deposition and the metabolic profile.

060. OVER FEEDING EARLY IN LIFE AND RISK OF OBESITY: INSIGHT FROM THE RODENT

While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant disorders, mounting evidence suggests that programming of obesity may occur following over-nutrition during development. As hypothalamic control of appetite and energy expenditure is set early in life and can be perturbed by certain exposures such as under-nutrition and altered metabolic and hormonal signals, in utero exposure to maternal obesity related changes may contribute to programming of obesity in offspring. Data from animal studies indicate both intrauterine and postnatal environments are critical determinants of the development of pathways regulating energy homeostasis. Experimental evidence in rat studies from our laboratory points to an additive detrimental impact of high fat diet consumption after weaning in animals born of obese mothers. Deleterious effects of high fat diet during pregnancy on metabolic profile, adiposity and cardiac hypertrophy were enhanced by postnatal over consumption. Even modest early postnatal overfeeding induced by litter size reduction leads to increased adiposity. Studies are needed to determine to what extent the effect of maternal and early nutritional changes persist. This presentation summarizes recent evidence of the impact of maternal obesity on subsequent obesity risk, paying particular attention to the hypothalamic regulation of appetite, and markers of metabolic control. There is an urgent need to investigate the mechanisms underlying the trans-generational effects of maternal obesity due to an extraordinary rise in the rates of maternal obesity.

Established maternal obesity in the rat reprograms hypothalamic appetite regulators and leptin signaling at birth

Key appetite regulators and their receptors are already present in the fetal hypothalamus, and may respond to hormones such as leptin. Intrauterine food restriction or hyperglycemia can reprogram these circuits, possibly predisposing individuals to adverse health outcomes in adulthood. Given the global obesity epidemic, maternal overweight and obesity is becoming more prevalent. Earlier, we observed rapid growth of pups from obese dams during the suckling period. However, it is unclear whether this is because of alterations in leptin and hypothalamic appetite regulators at birth. Female Sprague-Dawley rats were fed palatable high-fat diet (HFD) or chow for 5 weeks to induce obesity before mating. The same diet continued during gestation. At day 1, after birth, plasma and hypothalamus were collected from male and female pups. Body weight and organ mass were recorded. Leptin and insulin levels were measured in the plasma by radioimmunoassay. Hypothalamic mRNA expression of neuropeptide-Y (NPY), pro-opiomelanocortin, leptin receptor and its downstream signal, STAT3 (signal transducer and activator of transcription 3), were measured using real-time PCR. Body and organ weights of pups from obese dams were similar to those from lean dams, across both genders. However, plasma leptin levels were significantly lower in offspring from obese dams (male: 0.53+/-0.13 vs 1.05+/-0.21 ng ml(-1); female: 0.33+/-0.09 vs 2.12+/-0.57 ng ml(-1), respectively; both P<0.05). Hypothalamic mRNA expression of NPY, pro-opiomelanocortin, leptin receptor and STAT3 were also significantly lower in pups from obese dams. Long-term maternal obesity, together with lower leptin levels in pups from obese dams may contribute to the lower expression of key appetite regulators on day 1 of life, suggesting altered intrauterine neuron development in response to intrauterine overnutrition, which may contribute to eating disorders later in life.

Hypothalamic regulation of appetite

The prevalence of obesity is steadily rising and has huge health and financial implications for society. Weight gain is due to an imbalance between dietary intake and energy expenditure and research has focused on trying to understand the complex pathways involved in controlling these aspects. This review highlights the key areas of research in the hypothalamic control of appetite. The hypothalamus consists of several nuclei that integrate peripheral signals, such as adiposity and caloric intake, to regulate important pathways within the CNS controlling food intake. The best characterized pathways are the orexigenic neuropeptide Y/Agouti-related protein and the anorexigenic pro-opiomelanocortin/cocaine- and amphetamine-related transcript neurons in the arcuate nucleus of the hypothalamus. These project from the arcuate nucleus to other key hypothalamic nuclei, such as the paraventricular, dorsomedial, ventromedial and lateral hypothalamic nuclei. There are also projections to and from the brainstem, cortical areas and reward pathways, all of which influence food intake. The challenge at present is to understand the complexity of these pathways and try to find ways of modulating them in order to find potential therapeutic targets.

Maternal and Postnatal Overnutrition Differentially Impact Appetite Regulators and Fuel Metabolism

Maternal obesity is increasing, and it is known that the intrauterine experience programs fetal and newborn metabolism. However, the relative contributions of pre- or postnatal factors are unknown. We hypothesized that maternal overnutrition caused by long-term maternal obesity would exert a stronger detrimental impact than postnatal overnutrition on offspring metabolic homeostasis, with additional postnatal overnutrition exaggerating these alterations. Female Sprague Dawley rats were exposed to chow or high-fat cafeteria diet for 5 wk before mating and throughout gestation and lactation. On postnatal d 1, litters were adjusted to three per litter to induce postnatal overnutrition (vs. 12 in control). Hypothalamic appetite regulators neuropeptide Y and proopiomelanocortin, glucose transporter 4, and lipid metabolic markers were measured. At postnatal d 20, male pups born of obese dams, or those overnourished postnatally, were 42% heavier than controls; combining both interventions led to 80% greater body weight. Maternal obesity increased pup adiposity and led to glucose intolerance in offspring; these were exaggerated by additional postnatal overnutrition during lactation. Maternal obesity was also linked to hyperlipidemia in offspring and reduced hypothalamic neuropeptide Y and increased proopiomelanocortin mRNA expression. Postnatal overnutrition of offspring from obese dams amplified these hypothalamic changes. Both maternal and postnatal overnutrition reduced muscle glucose transporter 4. Adipose carnitine palmitoyl-transferase-1 and adipose triglyceride lipase mRNA was up-regulated only by postnatal overnutrition. Maternal overnutrition appears to alter central appetite circuits and promotes early-onset obesity; postnatal overnutrition interacted to cause peripheral lipid and glucose metabolic disorders, supporting the critical message to reduce early-life adverse nutritional impact.

Factors Influencing Body Mass Index, Appetite Control, and the Role of Glutamate and Excess Nutritional Protein During Child Development: A Review

Obesity has become a major public health concern in this century. Yet, the widespread popularisation in managing overweight and obesity indicates that the problem of body weight maintenance has developed from an only medical into an interdisciplinary and already political problem. Current ideas about lifestyle and strategies to maintain health and weight have become dominated by increasingly popular beliefs that contrast scientific evidence. Particularly the relationship between physical activity, energy intake and body mass index (BMI) explains markedly less of the within-population variance of the BMI than commonly assumed. Instead, it has been noted that protein consumption significantly correlates with BMI explaining up to 13% of the BMI variance in young adolescents. Increasing evidence suggests that nutritional protein can stimulate food intake. Serum levels of most amino acids increase following a protein rich meal. Regions of the brain that are involved in the regulation of appetite accumulate glutamate and other small molecules. Free glutamate can be toxic for some of the essential neuronal structures of hypothalamic appetite regulation, may impair satiety and result in voracity. Protein toxicity in humans occurs at amounts beyond an intake of 200 g/d. Protein intake needs supplementation either by carbohydrate or fat in order to reduce its contribution to total energy intake to less than 40%, and the protein content of many popular high-protein weight loss diets must for the same reasons be regarded with great caution, and should particularly be avoided during pregnancy and childhood.

Dietary restriction and induced tumorigenesis in mice with altered hypothalamic appetite regulation

Dietary restriction (DR), the reduction of calorie intake or meal frequency, profoundly effects the health of laboratory animals including cancer incidence. One recurring theme among DR manipulations is the induction of hunger, which may play a critical role in mediating the neuroendocrine response and driving beneficial systemic effects like reduced tumorigenesis. We examined the effects of DR on tumorigenesis under appetite suppression in two mouse models: Neuropeptide‐Y knockout mice (NPY, a major orexigenic peptide) and monosodium glutamate‐injected mice (MSG damages the arcuate nucleus, the ‘satiety center’ of the hypothalamus that coordinates feeding behavior). Calorie restriction (CR) at 30% was compared with every‐other‐day (EOD) feeding, a high‐fiber, low‐calorie chow (LC), and ad libitum (AL) feeding. A two‐stage skin tumor induction model was employed to assess tumorigenesis in the groups. While CR lowered blood leptin levels in both the NPY‐knockout and MSG‐injected mice, tumor latency was not increased by CR in the MSG mice. The LC diet lowered blood leptin in both models and reduced tumor incidence in the MSG mice but not the NPY mice. The EOD diet alone was protective in both models. These data suggest DR's anticancer effects involve both hypothalamus‐dependent and hypothalamus‐independent mechanisms. Funded by the NIH/NIA Intramural Research Program.

Impact of Resistant Starch on Body Fat Patterning and Central Appetite Regulation

BackgroundAdipose tissue patterning has a major influence on the risk of developing chronic disease. Environmental influences on both body fat patterning and appetite regulation are not fully understood. This study was performed to investigate the impact of resistant starch (RS) on adipose tissue deposition and central regulation of appetite in mice.Methodology and Principle FindingsForty mice were randomised to a diet supplemented with either the high resistant starch (HRS), or the readily digestible starch (LRS). Using 1H magnetic resonance (MR) methods, whole body adiposity, intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) were measured. Manganese-enhanced MRI (MEMRI) was used to investigate neuronal activity in hypothalamic regions involved in appetite control when fed ad libitum. At the end of the interventional period, adipocytes were isolated from epididymal adipose tissue and fasting plasma collected for hormonal and adipokine measurement. Mice on the HRS and LRS diet had similar body weights although total body adiposity, subcutaneous and visceral fat, IHCL, plasma leptin, plasma adiponectin plasma insulin/glucose ratios was significantly greater in the latter group. Adipocytes isolated from the LRS group were significantly larger and had lower insulin-stimulated glucose uptake. MEMRI data obtained from the ventromedial and paraventricular hypothalamic nuclei suggests a satiating effect of the HRS diet despite a lower energy intake.Conclusion and SignificanceDietary RS significantly impacts on adipose tissue patterning, adipocyte morphology and metabolism, glucose and insulin metabolism, as well as affecting appetite regulation, supported by changes in neuronal activity in hypothalamic appetite regulation centres which are suggestive of satiation.

Continuous positive airway pressure for asthma: not a big stretch?

Obesity increases the risk of both asthma and obstructive sleep apnoea (OSA). By compromising upper airway anatomy, obesity contributes to compromised pharyngeal mechanics and the development of OSA. The mechanisms for how obesity contributes to the development of asthma are less well understood. The association between obesity and asthma, however, is undeniable and to date over 30 articles have shown a relationship between the two 1, 2. Obesity has effects on both inflammation and airway mechanics, which may be important in asthma. For example, obesity has been associated with increased inflammatory cytokines and adipokines 3. The role of leptin, a hormone that decreases appetite and increases metabolism, has been of particular interest in obesity and asthma. Obese subjects have increased levels of leptin, suggesting leptin resistance, at least at the level of hypothalamic appetite regulation. Leptin has been found to be pro-inflammatory and in animal models it may increase airway hyperresponsiveness 4, 5. However, the pro-inflammatory effects of obesity are not the only way in which obesity contributes to the development of asthma. The effect of obesity on lung mechanics may be just as or even more important. With obesity, lung volumes (especially functional residual capacity; FRC) decrease as a result of increased abdominal and chest wall pressure. Since airway calibre is a function of lung volume 6, 7, obesity contributes to smaller airway calibre. Smaller airway calibre is likely to unload the airway smooth muscle, increase actin–myosin cross-bridging and allow for increased shortening when activated 8, 9. Deep breathing has been found to be a potent bronchodilator by periodically stretching the airway smooth muscle and disturbing actin–myosin attachments, making contractions less forceful …

Role of neuropeptides in appetite regulation and obesity – A review

Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.

Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12-16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.

Obesity, voracity, and short stature: the impact of glutamate on the regulation of appetite

World-wide obesity has risen to alarming levels. We present experimental support for a new and very challenging hypothesis linking obesity, voracity, and growth hormone (GH) deficiency, to the consumption of elevated amounts of the amino-acid glutamate (GLU). Supraphysiological doses of GLU are toxic for neuronal cells. Human data were obtained from 807,592 German conscripts born between 1974 and 1978, and from 1,432,368 women of the German birth statistics (deutsche Perinatalerhebung) 1995-1997. The effects of orally administered monosodium glutamate (MSG) were investigated in 30 pregnant Wistar rats and their offspring. Pregnant animals either received no extra MSG, or 2.5 g MSG, or 5 g MSG per day, up to the end of the weaning period. In all, 2.5 g, respectively 5 g, MSG accounted for some 10%, respectively 20%, of dry weight of the average daily food ration. After weaning, MSG feeding was continued in the offspring. Morbid obesity associates with short stature. Average stature of conscripts progressively declines when body mass index increases above 38 kg/m2. Also morbidly obese young women are shorter than average though to a lesser extent than conscripts. Oral administration of MSG to pregnant rats affects birth weight of the offspring. Maternal feeding with 5 g MSG per day results in severe birth weight reduction (P<0.01). Weight increments remain subnormal when MSG feeding to the mothers is maintained during weaning (P < 0.01). GH serum levels are affected in animals that received MSG during prenatal life via maternal feeding. Animals that are kept on high MSG diet (5 g MSG per day) continue to show serum GH levels that are as low or even lower than those of MSG injected animals (P < 0.05), both at day 30 and at day 90 of life. Animals that were kept on medium MSG diet (2.5 g MSG per day) showed low serum GH levels at day 30 of life (P < 0.01), but seemed to partially recover before day 90. Almost identical results were observed in IGF-1 serum levels. Oral MSG resulted in dose dependent voracity. The animals fed 5 g MSG per day increased water uptake by threefold (P < 0.01), and food uptake by almost two-fold (P < 0.01). The influence of MSG is in general more marked in males than in females. GLU is a widely used nutritional substance that potentially exhibits significant neuronal toxicity. Voracity, and impaired GH secretion are the two major characteristics of parenterally administered GLU-induced neuronal damage. GLU maintains its toxicity in animals even when administered orally. Males appear to be more sensitive than females. The present study for the first time demonstrates, that a widely used nutritional monosubstance--the flavouring agent MSG--at concentrations that only slightly surpass those found in everyday human food, exhibits significant potential for damaging the hypothalamic regulation of appetite, and thereby determines the propensity of world-wide obesity. We suggest to reconsider the recommended daily allowances of amino acids and nutritional protein, and to abstain from the popular protein-rich diets, and particularly from adding the flavouring agents MSG.

Cachexia in chronic kidney disease: a link to defective central nervous system control of appetite

Anorexia is one of several abnormalities characterizing chronic kidney disease (CKD) that cause cachexia, the loss of muscle and adipose stores. It has been attributed to mechanisms ranging from accumulation of toxic "middle molecules" to psychological problems. In this issue of the JCI, Cheung and coworkers used elegant techniques to demonstrate that CKD-associated anorexia is caused by defective hypothalamic regulation of appetite. They attributed the defect to an alteration in the hypothalamus's response to leptin and inflammation. Since similar hypothalamic defects suppress appetite in inflammatory states and in cancer, it is possible that anorexia in several cachexia-inducing conditions results from a common set of hypothalamic abnormalities. The development of small molecules capable of preventing these regulatory abnormalities holds the promise of eliminating the contribution of anorexia to the development of cachexia.

The Hypothalamus and Obesity

Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling "full-up" (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY(3-36)) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential "drugable" targets by which to treat obesity.

Obesity in patients with craniopharyngioma: assessment of food intake and movement counts indicating physical activity.

Patients with childhood-onset craniopharyngioma (CP) often suffer from obesity. We evaluated two important etiological factors of obesity development, energy intake and physical activity. Energy intake was supposed to be high due to a disturbed hypothalamic regulation of appetite. We used a validated nutritional diary to determine the 1-wk food intake in 27 CP patients (12 with intrasellar tumors and 15 with hypothalamic tumors) and 1027 controls who were a representative sample of the 7- to 16-yr-old German population. In 2 accelerometry settings, we determined movement counts indicating physical activity. Nineteen CP patients were comparable to 26 controls for age and body mass index. One setting was a clinical one during weight reduction; the other was an out-patient setting. Daily energy intake was 1916 +/- 677 kcal (mean +/- SD) in intrasellar CP patients, 2075 +/- 877 kcal in hypothalamic CP patients, and 2476 +/- 815 kcal in non-CP controls. Patients suffering from CP showed fewer movement registrations [clinical setting, 228 vs. 298 cpm for obese controls (P = 0.01); out-patient setting, 228 vs. 282 cpm for controls (P = 0.08)]. Differences were most pronounced during leisure time (382 cpm in CP patients vs. 546 cpm in obese controls; P = 0.002; clinical setting). Our findings suggest that reduced physical activity, rather than increased energy intake, in CP patients is responsible for the obesity development noted in these subjects.

Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats.

A number of neuropeptides implicated in the hypothalamic regulation of appetite are synthesized in the arcuate nucleus (Arc). Neuropeptide Y (NPY) and agouti-related protein (Agrp) are orexigenic. The pro-opiomelanocortin (POMC) product alpha-melanocyte-stimulating hormone (alpha-MSH) is anorectic. Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) decreases food intake. However, recent results show that CART is orexigenic when injected into discrete hypothalamic nuclei. There is almost complete coexpression of NPY and Agrp mRNA in Arc neurones, and the majority of CART-containing neurones in the Arc also contain POMC mRNA. We investigated possible interactions between these neuropeptides in vitro using a rat hypothalamic explant system. Administration of 1, 10 and 100 nm of NPY to hypothalamic explants significantly increased release of Agrp(83-132)-immunoreactivity (IR). NPY (10 and 100 nm) significantly increased the release of CART(55-102)-IR and alpha-MSH-IR from hypothalamic explants. Agrp(83-132) (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. Agrp(83-132) (10 and 100 nm) significantly decreased the release of CART(55-102)-IR from hypothalamic explants. Administration of 1, 10 and 100 nm CART(55-102) to hypothalamic explants resulted in a significant increase in NPY-IR release. Administration of 10 nm CART(55-102) to hypothalamic explants significantly increased the release of Agrp(83-132)-IR. NDP-MSH (10 nm) administered to hypothalamic explants significantly increased the release of NPY-IR. NDP-MSH (10 and 100 nm) significantly increased the release of Agrp(83-132)-IR from hypothalamic explants. These data suggest that orexigenic neuropeptides in the arcuate nucleus stimulate the release of each other, perhaps reinforcing orexigenic behaviour via a positive-feedback loop. Our results are also in keeping with the possibility that the melanocortin-3 receptor in the arcuate nucleus may influence the release of arcuate neuropeptides.

Inappropriately high plasma leptin levels in obese haemodialysis patients can be reduced by high flux haemodialysis and haemodiafiltration.

1. Blood leptin levels are increased in obese subjects and seem to play a major role in the hypothalamic regulation of appetite and energy expenditure. 2. We measured plasma leptin levels in a cohort of 46 patients on maintenance haemodialysis treatment and 26 control subjects. 3. Higher body mass indices were associated with higher plasma leptin levels in both groups. 4. The increase was more pronounced in the dialysis group than in the control group (P = 0.001), leading to inappropriately high plasma levels. 5. Haemodialysis with low flux cellulosic dialysers did not result in a decrease in plasma levels, while dialysis with high flux dialysers and haemodiafiltration led to a substantial reduction of the initial value to 76.95 +/- 14.89% (P = 0.013) and 62.90 +/- 24.94% (P = 0.001) respectively. 6. Our data suggest that high flux dialysis membranes can decrease plasma leptin levels and that inappropriately high plasma leptin levels may play a role in the nutrition of haemodialysis patients.