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PubMed2002

Regulation of appetite in frail persons.

Aging is often accompanied by anorexia of aging, described as a decline in appetite resulting in a lower dietary intake, followed by unexplained weight loss and adverse effects on health. This article discusses the main causes of a lack of appetite in frail elderly people. It is clear that appreciation of hedonic qualities of foods declines with age, as does the ability to regulate food intake. Carefully controlled studies, however, have shown favorable results with interventions that stimulate appetite in, frail elderly people.

Aged↗

PubMed2001

Dysfunctional eating in the eating disorders.

Aberrant eating patterns in the eating disorders have been observed across various laboratory-based and clinical studies. It is now clear that problems in experiencing and expressing hunger, appetite, and satiety in anorexia and bulimia nervosa are likely to perpetuate the disorders once established. Whether problems in appetite regulation are primary or secondary to the development of the disorders is unknown. In studies examining indices of appetite regulation after treatment, there still remain significant levels of eating abnormality. This suggests that the main goals of treatment, including restoration of body weight in anorexia nervosa, abstaining from dieting in anorexia or bulimia nervosa, and reducing or abstaining from binge eating, do not correct some features of abnormal eating. The efficacy of nutritional counseling and specific nutritional management programs have been tested, and these seem to produce positive outcomes in improving eating behavior. Direct behavioral interventions to change eating patterns also have been examined, and these too seem to produce benefits that may be incorporated into CBT. Greater collaboration and cooperation between researchers and clinicians in addressing dysfunctional eating in the eating disorders will highlight improvements in treatment for identifiable eating abnormalities and will further the understanding of the human appetite system.

Cues↗

PubMed1989

Pantethine, a somatostatin depleting agent, increases food intake in rats.

During the course of studies of the effects of pantethine, a cysteamine precursor known to deplete tissue concentration of immunoreactive somatostatin, we observed that the subject rats continued to eat despite marked distension of the stomach. To determine whether this effect was caused by drug-altered food intake, we have measured food and water intake in pantethine-injected rats in the fed and fasting state. In three separate experiments, rats allowed free access to food until the morning of study showed significant increased food intake accompanied by an increased stomach content (at 4 hr) of both food and water following the IP injection of pantethine. In one experiment, intake at 3 hours was 0.60 g/100 g b.wt. (pantethine dose 0.74 g/kg b.wt.) and 0.64 g/100 g b.wt. (pantethine dose 1.47 g/kg b.wt.) compared with 0.24 g/100 g b.wt. in saline-treated animals (p less than 0.05). In contrast, pantethine, 1.47 g/kg b.wt., when administered to overnight-fasted rats, significantly inhibited food intake (3-hr intake 1.54 +/- 0.16 g/100 g b.wt. in rats injected with pantethine 1.47 g/kg b.wt. as compared with 3.3 +/- 0.21 g/100 g b.wt. in saline-injected controls). The intake-stimulating effect of pantethine in ad lib-fed rats was not demonstrable when the drug was administered shortly before the "lights out"-induced feeding at night. These findings indicate that pantethine, a cysteamine precursor, stimulates food intake in satiated rats, depending upon the stage of circadian rhythm, but is inhibitory to intake in fasted animals. We postulate that the effects are mediated directly or indirectly through the disinhibition of central appetite-regulating somatostatinergic pathways but, since cysteamine also inhibits dopamine-beta-hydroxylase, an effect on depletion of appetite-regulating central catecholamines cannot be excluded.

Animals↗

PubMed2004

Solution structure of human orexin-A: regulator of appetite and wakefulness.

Orexin-A and orexin-B (hypocretin-1 and hypocretin-2, respectively) are important hypothalamic neuro-peptides, which are encoded by a single mRNA transcript and stimulate food intake as well as regulate wakefulness. Here we determined the solution structure of orexin-A by NMR spectroscopy and by simulated-annealing calculation. The structural features of orexin-A involve two alpha-helices, with the hydrophobic residues disposed to on one side of helix, and hydrophilic residues to the other. A hydrophilic turn induced by two disulfide bonds provides the key difference between orexin-A and -B. With previous mutagenic studies, the derived structure of orexin-A provides us with a structure-functional view for novel drug design.

Appetite↗

PubMed2001

[Endocrinology 1999-2000].

Long-lasting problem on the differentiation of adenohypophyseal cell, which prepares them for their specific tasks (somatotropic, lactotropic ect.), becomes elucidated after recognition of the differentiational effect of transcription factor Pit-1. Expression of that factor in somatotrops results in STH secretion, contrary to lactotrops producing prolactin. Subclinical hypothyreosis (increased TSH with normal T3 and T4) endangers vessel not because of hypercholesterolemia, but because of changes in the dynamics of the blood flow. The idea of cardiotropic effect of thyroidal hormones is supported by the finding that administration of trijodthyronine to children after the surgical correction of heart malformations (cardiopulmonary bypass) improves myocardial function--it elevates cardiac output and decreases requirements on the intensive care. Receptors for hormones in tissues are flexible, they can be "heterooligomers" for dopamine and somatostatin. Mutations of mineralocorticoid receptor may cause hypertension in pregnancy and progesterone receptors have several isoforms. Receptors can be also activated by short exposition to a hormone. Glucocorticoids have probably also membrane receptors. Diabetes mellitus "type I" needn't to be immunogenic and DM type II not only results from down-regulation of receptors and subsequent insulin resistance, but it can be also caused by defects in insulin secretion. Insulin has receptors in the brain and participates in the appetite regulation. The attempt to use "desensibilisation" by peroraly administered insulin in patients with immunogenic DM had no effect. Stress affects memory mechanisms, heavy emotional stress during gravidity can bring congenital malformations. The decrease of mental functions in aged women depends on the level of free estradiol (the fraction, which is not bound to plasma proteins). Activation of dopaminergic neurons can be achieved by neurotropic growth factors. Nesiritide is a recombinant brain natriuretic hormone successfully tested in heart failure. The role of leptin in the appetite regulation in man is still not clear, other signalling molecules may have also an effect, e.g., ghrelin, which primarily stimulates STH secretion and brings about weight gain. Sildenafil influences nitrergic neurons elsewhere than in penis, for example it has positive effects in patients with oesophageal achalasia.

Endocrine System Diseases↗

PubMed2005

CRF-related peptides contribute to stress response and regulation of appetite in hypoxic rainbow trout.

Hypoxia stress suppresses appetite in a variety of fish species, but the mechanisms mediating this response are not known. Therefore, given their anorexigenic and hypophysiotropic properties, we investigated the contribution of forebrain corticotropin-releasing factor (CRF) and urotensin I (UI) to the regulation of food intake and the hypothalamic-pituitary-interrenal (HPI) stress axis in hypoxic rainbow trout. Exposure to 50 and 35% O(2) saturation for 24 h decreased food intake by 28 and 48%, respectively. The 35% O(2) treatment also increased forebrain CRF and UI mRNA levels, plasma cortisol, and lactate. Exposure for 72 h to the same conditions resulted in similar reductions in food intake, increases in plasma cortisol proportional to the hypoxia severity, and increases in forebrain CRF and UI mRNA levels in the 50% O(2) treatment. Relative to saline-infused fish, chronic intracranial infusion of the CRF receptor antagonist alpha-helical CRF((9-41)) reduced the appetite-suppressing effects of 24-h exposure to 35% O(2) and blocked the hypoxia-induced increase in plasma cortisol. Finally, forebrain microdissection revealed that 50 and 35% O(2) exposure for 24 h specifically increases preoptic area CRF and UI mRNA levels in proportion to the severity of the hypoxic challenge and either has no effect or elicits small decreases in other forebrain regions. These results show that CRF-related peptides play a physiological role in regulating the HPI axis and in mediating at least a portion of the reduction in food intake under hypoxic conditions in rainbow trout and demonstrate that the response of forebrain CRF and UI neurons to this stressor is region specific.

Adaptation, Physiological↗

PubMed2000

Effect of acute and subchronic subcutaneous urocortin on blood pressure and food consumption in ob/ob mice.

Corticotropin-releasing factor and urocortin belong to a hypothalamic peptide family thought to be important in appetite regulation. The present study compared the appetite-suppressant effect of subcutaneous urocortin in obese mice to its cardiovascular effects. Acutely, urocortin (100 nmol/kg iv) reduced blood pressure and increased heart rate in urethane anesthetized nonobese mice; effects similar to those produced by subcutaneous urocortin (10 and 100 nmol/kg sc) in nonobese and ob/ob mice. Over this same dose range (10-100 nmol/kg sc), urocortin dramatically inhibited food consumption in the ob/ob mouse. To determine if the acute hypotensive effect of urocortin (10 nmol/kg sc) in the ob/ob mouse persisted after repeated urocortin administration, animals were pretreated for 3 days with urocortin (10 nmol/kg sc) or vehicle. Following urocortin pretreatment, urocortin-induced hypotension was similar to the effect in vehicle pretreated mice. However, urocortin-induced appetite suppression was reduced following 3 days of pretreatment with urocortin (10 nmol/kg sc) to ob/ob mice. These data suggest that the hypotensive and appetite-suppressant effects of urocortin are mediated by different mechanisms and tolerance to the hypotension did not readily occur in obese animals.

Animals↗

PubMed2007

Brain activation in uremic anorexia.

This article reviews current knowledge about mechanisms responsible for uremic events, especially those that involve the central nervous system (CNS). Anorexia is a frequent complication of the uremic syndrome that contributes to malnutrition in patients on dialysis. Uremic anorexia has been associated with many factors. Traditionally, anorexia in dialysis patients has been regarded as a sign of uremic toxicity; therefore, 2 hypotheses have been proposed: the "middle molecule" and "peak concentration" hypotheses; both of these remain unproved. Recently, our group has proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino acid profile that may be acquired when the patient is in uremic status. It is characterized by low concentrations of large neutral and branched chain amino acids in the cerebrospinal fluid. This situation permits a high level of tryptophan transport across the blood-brain barrier and enhances the synthesis of serotonin (the final target responsible for inhibiting appetite). The role of inflammation in the genesis of anorexia-malnutrition is also emphasized. In summary, in the CNS, factors associated with uremic anorexia include high levels within the cerebrospinal fluid of proinflammatory cytokines, leptin, and free tryptophan and serotonin (hyperserotoninergic-like syndrome), along with deficiency of neural nitric oxide (nNO) and disorders in various receptors such as melanocortin receptor-4 (MC4-R). Uremic anorexia is a complex complication associated with malnutrition and high levels of morbidity and mortality. Several uremia-acquired disorders in the CNS such as high cerebrospinal fluid levels of anorexigen substances and disorders in appetite regulator receptors may explain the lack of appetite.

Amino Acids↗

PubMed2006

Leptin induces cyclooxygenase-2 via an interaction with interleukin-1beta in the rat brain.

In addition to its central effects on appetite regulation, leptin has been implicated in immune function and inflammation. Previous data suggested that leptin acts as an inflammatory signal within the brain, as exogenously administered leptin induced fever, a typical brain-regulated inflammatory response. The present study aimed to delineate the inflammatory actions and cellular targets of leptin in the brain by examining its effects on the expression of interleukin (IL)-1beta and cyclooxygenase (COX)-2, two important inflammatory components of the fever response. Intracerebroventricular injection of leptin (5 microg/rat) induced IL-1beta and COX-2 mRNA and protein in the hypothalamus between 1 and 3 h after treatment as determined by reverse transcription-polymerase chain reaction and immunohistochemistry. Coinjection of IL-1 receptor antagonist (100 microg/rat, intracerebroventricular) attenuated leptin-induced COX-2, whereas IL-1 receptor antagonist had no effect on endogenous IL-1beta levels, suggesting that leptin induces COX-2 via, at least partly, IL-1beta action. IL-1beta protein expression was induced in macrophages in the meningis and perivascular space after leptin treatment, whereas COX-2 induction was observed in endothelial cells, indicating the roles for these non-neuronal cells in mediating inflammatory actions of leptin. In addition, neutralization of endogenous circulating leptin with anti-leptin antiserum attenuated intraperitoneal lipopolysaccharide (100 microg/kg)-induced brain IL-1beta and COX-2 upregulation, suggesting that leptin indeed acts as an inflammatory signal to the brain during systemic inflammation. These findings are in contrast to the effects of leptin on appetite regulation where it is believed to act primarily on neurons, thus presenting a distinct anatomical basis for the inflammatory and appetite regulatory actions of leptin in the brain.

Animals↗

PubMed2006

Ghrelin and the short- and long-term regulation of appetite and body weight.

Ghrelin, an acylated upper gastrointestinal peptide, is the only known orexigenic hormone. Considerable evidence implicates ghrelin in mealtime hunger and meal initiation. Circulating levels decrease with feeding and increase before meals, achieving concentrations sufficient to stimulate hunger and food intake. Preprandial ghrelin surges occur before every meal on various fixed feeding schedules and also among individuals initiating meals voluntarily without time- or food-related cues. Ghrelin injections stimulate food intake rapidly and transiently, primarily by increasing appetitive feeding behaviors and the number of meals. Preprandial ghrelin surges are probably triggered by sympathetic nervous output. Postprandial suppression is not mediated by nutrients in the stomach or duodenum, where most ghrelin is produced. Rather, it results from post-ingestive increases in lower intestinal osmolarity (information probably relayed to the foregut via enteric nervous signaling), as well as from insulin surges. Consequently, ingested lipids suppress ghrelin poorly compared with other macronutrients. Beyond a probable role in meal initiation, ghrelin also fulfills established criteria for an adiposity-related hormone involved in long-term body-weight regulation. Ghrelin levels circulate in relation to energy stores and manifest compensatory changes in response to body-weight alterations. Ghrelin crosses the blood-brain barrier and stimulates food intake by acting on several classical body-weight regulatory centers, including the hypothalamus, hindbrain, and mesolimbic reward system. Chronic ghrelin administration increases body weight via diverse, concerted actions on food intake, energy expenditure, and fuel utilization. Congenital ablation of the ghrelin or ghrelin-receptor gene causes resistance to diet-induced obesity, and pharmacologic ghrelin blockade reduces food intake and body weight. Ghrelin levels are high in Prader-Willi syndrome and low after gastric bypass surgery, possibly contributing to body-weight alterations in these settings. Extant evidence favors roles for ghrelin in both short-term meal initiation and long-term energy homeostasis, making it an attractive target for drugs to treat obesity and/or wasting disorders.

Animals↗

PubMed1998

Cerebrospinal fluid levels of oxytocin in Prader-Willi syndrome: a preliminary report.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder characterized by mental retardation, appetite dysregulation, and a high risk for obsessive-compulsive disorder (OCD). Microscopic abnormalities of the hypothalamus have been described in PWS, and oxytocin has been implicated in both appetite regulation and OCD. METHODS: Oxytocin and arginine vasopressin (AVP) were measured in the cerebrospinal fluid of 5 subjects with PWS (2 male, 3 female) and in 6 normal control subjects (all female). RESULTS: CSF oxytocin was elevated in PWS (9.2 +/- 3.9 pmol/L) as compared to normal control subjects (5.1 +/- 0.9 pmol/L, p = 0.045), a finding that was more significant when excluding male subjects from analysis (p = 0.02). AVP was not significantly different between the groups as a whole. CONCLUSIONS: These data provide further evidence for hypothalamic and oxytocinergic dysfunction in PWS. The associations between oxytocin, appetite regulation, and obsessive compulsive symptomatology in PWS warrant further investigation.

Adolescent↗

PubMed2004

Neuropeptides and the control of food intake in fish.

The brain, particularly the hypothalamus, integrates input from factors that stimulate (orexigenic) and inhibit (anorexigenic) food intake. In fish, the identification of appetite regulators has been achieved by the use of both peptide injections followed by measurements of food intake, and by molecular cloning combined with gene expression studies. Neuropeptide Y (NPY) is the most potent orexigenic factor in fish. Other orexigenic peptides, orexin A and B and galanin, have been found to interact with NPY in the control of food intake in an interdependent and coordinated manner. On the other hand cholecystokinin (CCK), cocaine and amphetamine-regulated transcript (CART), and corticotropin-releasing factor (CRF) are potent anorexigenic factors in fish, the latter being involved in stress-related anorexia. CCK and CART have synergistic effects on food intake and modulate the actions of NPY and orexins. Although leptin has not yet been identified in fish, administration of mammalian leptin inhibits food intake in goldfish. Moreover, leptin induces CCK gene expression in the hypothalamus and its actions are mediated at least in part by CCK. Other orexigenic factors have been identified in teleost fish, including the agouti-related protein (AgRP) and ghrelin. Additional anorexigenic factors include bombesin (or gastrin-releasing peptide), alpha-melanocyte-stimulating hormone (alpha-MSH), tachykinins, and urotensin I. In goldfish, nutritional status can modify the expression of mRNAs encoding a number of these peptides, which provides further evidence for their roles as appetite regulators: (1) brain mRNA expression of CCK, CART, tachykinins, galanin, ghrelin, and NPY undergo peri-prandial variations; and (2) fasting increases the brain mRNA expression of NPY, AgRP, and ghrelin as well as serum ghrelin levels, and decreases the brain mRNA expression of tachykinins, CART, and CCK. This review will provide an overview of recent findings in this field.

Animals↗

PubMed2004

Ghrelin and measures of satiety are altered in polycystic ovary syndrome but not differentially affected by diet composition.

Polycystic ovary syndrome (PCOS) is a common endocrine condition in women of reproductive age associated with obesity. It may involve dysregulation of ghrelin, a hormone implicated in appetite regulation. The effect of diet composition on ghrelin is unclear. Overweight women with and without PCOS were randomized to a high-protein (40% carbohydrate, 30% protein; 10 PCOS, six non-PCOS) or standard protein diet (55% carbohydrate, 15% protein; 10 PCOS, six non-PCOS) for 12 wk of energy restriction and 4 wk of weight maintenance. Diet composition had no effect on fasting or postprandial ghrelin or measures of satiety. Non-PCOS subjects had a 70% higher fasting baseline ghrelin (P = 0.011), greater increase in fasting ghrelin (57.5 vs. 34.0%, P = 0.033), and greater maximal decrease in postprandial ghrelin after weight loss (-144.1 +/- 58.4 vs. -28.9 +/- 14.2 pg/ml, P = 0.02) than subjects with PCOS. Subjects with PCOS were less satiated (P = 0.001) and more hungry (P = 0.007) after a test meal at wk 0 and 16 than subjects without PCOS. Appetite regulation, as measured by subjective short-term hunger and satiety and ghrelin homeostasis, may be impaired in PCOS.

Adult↗

PubMed2006

Serum retinol-binding protein 4 is reduced after weight loss in morbidly obese subjects.

CONTEXT: Administration of retinol-binding protein 4 (RBP-4) impairs insulin sensitivity in animals, and elevated serum concentrations have been associated with insulin resistance in humans. OBJECTIVE: We have studied whether weight loss influences RBP-4. PATIENTS AND METHODS: Fasting serum concentrations of RBP-4 were measured before and 6 months after gastric banding surgery in 33 morbidly obese patients aged 40 +/- 11 yr with a body mass index (BMI) of 46 +/- 5 kg/m(2). Fourteen healthy subjects aged 29 +/- 5 yr with a BMI less than 25 kg/m(2) served as controls. To characterize the association of weight loss with central and peripheral appetite regulation, the signaling protein agouti-related protein (AGRP), the orexigenic hormone ghrelin, and its recently identified antagonist obestatin were determined. RESULTS: At baseline, RBP-4 levels were markedly higher in obese than in lean subjects (2.7 +/- 0.5 vs. 0.9 +/- 0.5 microg/ml; P < 0.001). In contrast, AGRP and obestatin were lower in obese subjects compared with lean controls (all P < 0.001). Six months after gastric banding, BMI was reduced to 40 +/- 5 kg/m(2), RBP-4 was reduced to 2.0 +/- 0.7 microg/ml, AGRP increased from 1.8 +/- 1.1 to 3.4 +/- 1.1 ng/ml, ghrelin increased from 93 +/- 58 to 131 +/- 70 pg/ml, and obestatin increased from 131 +/- 52 to 173 +/- 35 pg/ml (all P < 0.05). Individual changes of RBP-4 were associated with changes of BMI (r = 0.72), the homeostasis model assessment insulin resistance-index (r = 0.53), and total cholesterol (r = 0.42, for all P < 0.05). CONCLUSION: Reductions in circulating RBP-4 may contribute to improved insulin resistance in morbidly obese subjects after weight loss. This is accompanied by favorable changes in appetite-regulating hormones, which might support the sustained weight loss after obesity surgery.

Adult↗

PubMed1999

Evidence that nitric oxide stimulates feeding in the marsupial Sminthopsis crassicaudata.

Nitric oxide (NO) synthase inhibitors reduce food intake in rodents and chickens, suggesting that NO may stimulate feeding. We used two competitive, non-selective inhibitors of NO synthase (NOS), (NG-monomethyl-L-arginine ester [L-NMMA] and NG-nitro-L-arginine methyl ester [L-NAME]), to evaluate the role of NO mechanisms in the control of food intake in a marsupial model previously used in studies of appetite regulation. Adult male Sminthopsis crassicaudata (n = 11-16, 15 +/- 0.3 g, mean +/- S.E.M.) received L-NMMA (50, 100, 200 and 1000 mg/kg), L-NAME (50, 100 and 200 mg/kg), L-arginine (L-arg) the precursor of NO (1000 and 2000 mg/kg), L-NAME (200 mg/kg) in combination with L-arg (2000 mg/kg), or saline (0.9%). All drugs were administered intraperitoneally after 24 h of food deprivation, after which food was immediately made available ad libitum. Food intake was measured 0, 0.5, 1, 2, 4 and 24 h after treatments. In addition, we studied the effect of acute L-NAME administration on hypothalamic, cortical, hepatic and cardiac NOS activity by quantifying citrulline production. L-NMMA (1000 mg/kg) and L-NAME (100 and 200 mg/kg) suppressed food intake by 25%, 21%, and 30%, respectively, over 24 h after treatments (P < 0.05). L-arg (1000 and 2000 mg/kg) by itself had no significant effect on food intake when compared with saline (P > 0.05). When administered in combination with L-NAME (200 mg/kg), L-arg (2000 mg/kg) reversed L-NAME induced suppression of appetite (P> 0.05). Furthermore, L-NAME (200 mg/kg) significantly decreased hypothalamic (P < 0.01), cortical (P < 0.01) and hepatic (P < 0.03) NOS activity. L-NAME had no effect on cardiac NOS activity (P> 0.05). These data show that peripheral administration of L-NAME has a significant central effect, particularly in brain areas involved in appetite regulation, and suggest in marsupials, as in other mammals and birds, that NO plays a role in the regulation of food intake.

Animals↗

PubMed2002

Contrasting effects of different levels of food intake and adiposity on LH secretion and hypothalamic gene expression in sheep.

Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.

Adipose Tissue↗

PubMed2004

Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency.

To examine leptin's role in human appetite regulation, we studied recombinant methionyl human leptin's effects on satiation and satiety in a model of leptin insufficiency, lipodystrophy. Eight females with hypoleptinemia and lipodystrophy were given sc injections of A-100 (maximal dose, 200% of that predicted to normalize serum leptin) for 4 months. Satiation and satiety were determined before and again during leptin treatment. Satiation was measured as the time to voluntary cessation of eating from a standardized food array after a 12-h fast. Satiety was determined as the time to hunger sufficient to consume a full meal after consumption of a standardized preload. During leptin treatment, satiation time decreased (41.2 +/- 18.2 to 19.5 +/- 10.6 min; P = 0.01), satiety time increased (62.9 +/- 64.8 to 137.8 +/- 91.6 min; P = 0.04), energy consumed to produce satiation decreased (2034 +/- 405 to 1135 +/- 432 kcal or 8.5 +/- 1.7 to 4.7 +/- 1.8 MJ; P < 0.01), and the amount of food desired in the postabsorptive state decreased (P < 0.02). Ghrelin concentrations also decreased during leptin administration (284.3 +/- 127.9 to 140.6 +/- 104.5 pmol/liter; P < 0.002). We conclude that increased leptin in patients with lipodystrophy results in less caloric, shorter, more satiating meals and longer-lived satiety. These data support the hypothesis that leptin plays an important, permissive role in human appetite regulation.

Adolescent↗

PubMed2005

Neuropeptides, including neuropeptide Y and melanocortins, mediate lipolysis in murine adipocytes.

OBJECTIVE: To determine whether key appetite-regulating neuropeptides such as melanin-concentrating hormone (MCH), neuropeptide Y (NPY), and alpha-melanocyte-stimulating hormone (alpha-MSH), which are known to mediate energy balance through centrally mediated pathways, also have direct acute effects on the lipolytic activity of murine adipocytes. RESEARCH METHODS AND PROCEDURES: Fully differentiated 3T3-L1 adipocytes serum starved overnight in Dulbecco's modified Eagle medium containing 2% bovine serum albumin or freshly isolated mouse adipocytes were incubated for up to 2 hours in the absence and presence of 100 nM each of NPY, MCH, alpha-MSH, the melanocortin receptor agonist MTII, or isoproterenol as a control. Free fatty acids secreted into the incubation medium were measured using a commercially available nonesterified fatty acid C test kit. RESULTS: Treatment of 3T3-L1 cells with 100 nM NPY decreased basal free fatty acid secretion (basal, 0.006 +/- 0.001 vs. NPY, 0.001 +/- 0.0003 nM at 90 minutes; p < 0.05), whereas both alpha-MSH and MTII stimulated up to a 7-fold increase in free fatty acid release (MTII, 0.238 +/- 0.004 vs. basal, 0.024 +/- 0.002 nM at 2 hours; p < 0.05; and alpha-MSH, 0.22 +/- 0.005 vs. basal, 0.04 +/- 0.003 nM at 2 hours; p < 0.05). Treatment with 100 nM MCH had no effect on basal free fatty acid release or on alpha-MSH-induced lipolysis during concurrent treatment. Conversely, concurrent treatment with 100 nM NPY dramatically inhibited (by approximately 90%) alpha-MSH-induced lipolysis. Similar treatment of freshly isolated mouse adipocytes showed virtually identical results. DISCUSSION: In addition to their centrally mediated actions, appetite-regulating neuropeptides modulate adipose tissue mass through direct peripheral effects. Systemic administration of pharmacological agents altering the effects of these neuropeptides may form the basis of future obesity therapies. Thus, some of these agents will likely have direct effects on adipocytes that may serve to alter their therapeutic effectiveness.

3T3-L1 Cells↗