Food Intake In Rodents Research Articles

Starving for AGRP

Activation of hypothalamic agouti-related protein (AGRP)-expressing neurons is known to increase food intake in rodents. Here, Atasoy et al., using channel rhodopsin-assisted circuit mapping and pharmacogenetic techniques, showed that activation of inhibitory projections of AGRP neurons to a small population of oxytocin-expressing neurons in the paraventricular hypothalamus was sufficient to induce this effect. As this population of neurons is lost in Prader–Willi syndrome, these findings provide a mechanism for the insatiable hunger associated with this syndrome and perhaps for other eating disorders.

Novel CCK‐dependent vasorelaxing dipeptide, Arg‐Phe, decreases blood pressure and food intake in rodents

We found that a dipeptide, Arg-Phe (RF), had vasorelaxing activity in mesenteric artery isolated from spontaneously hypertensive rats (SHRs) (EC(50) = 580 nM). We then investigated its mechanism of action, and elucidated its physiological functions. Vasorelaxing activities of RF-related peptides were tested. The retro-sequence dipeptide FR was inactive, suggesting that the RF sequence is important for a potent vasorelaxing effect. RA and AF were also inactive. RF-nh(2) had vasorelaxing activity, implying that the C-terminal amidation of RF is tolerated. Nitric oxide (NO) and prostaglandins (PGs) are known to be vasorelaxing factors; however, the vasorelaxing activity of RF was inhibited by neither N(G) -nitro-l-arginine methyl ester (l-NAME), an NO synthase inhibitor, nor indomethacin, a COX inhibitor. Interestingly, the activity was blocked by lorglumide, an antagonist of the cholecystokinin (CCK)(1) receptor; however, RF had no affinity for CCK receptors, suggesting that RF stimulates CCK release. Orally administered RF decreased blood pressure in SHRs, and this antihypertensive activity was also blocked by a CCK(1) antagonist. RF had CCK-like suppressive effects on food intake and gastrointestinal transit. RF increased intracellular Ca(2+) flux and CCK release in enteroendocrine STC-1 cells. A novel CCK-dependent vasorelaxing RF decreases both blood pressure and food intake.

Rapamycin impacts positively on longevity, despite glucose intolerance induction

Rapamycin impacts positively on longevity, despite glucose intolerance induction

The Glucagon Receptor Is Involved in Mediating the Body Weight‐Lowering Effects of Oxyntomodulin

Oxyntomodulin (OXM) is a peptide secreted postprandially from the L-cells of the gut that has a weak affinity for both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR). Peripheral administration of OXM in humans and rodents causes weight loss reducing food intake and increasing energy expenditure. It has been suggested that OXM modulates energy intake solely through GLP1R agonism. Because glucagon decreases food intake in rodents and humans, we examined whether activation of the GCGR is involved in the body weight-lowering effects of OXM. We identified an equipotent GLP1R-selective peptide agonist that differs from OXM by only one residue (Q3→E, OXMQ3E), but has no significant GCGR agonist activity in vitro and ~100-fold reduced ability to stimulate liver glycogenolysis. Chronic treatment of obese mice with OXM and OXMQ3E demonstrated that OXM exhibits superior weight loss and lipid-lowering efficacy, and antihyperglycemic activity that is comparable to the corresponding GLP1R-selective agonist. Studies in Glp1r−/− mice and coadministration of OXM and a GCGR antagonist revealed that the antiobesity effect of OXM requires activation of both GLP1R and GCGR. Our data provide new insight into the mechanism of action of OXM and suggest that activation of GCGR is involved in the body weight-lowering action of OXM.

Neuropeptide B and W regulate leptin and resistin secretion, and stimulate lipolysis in isolated rat adipocytes

Neuropeptide B (NPB) and W (NPW) regulate food intake and energy homeostasis in humans via two G-protein-coupled receptor subtypes, termed as GPR7 and GPR8. Rodents express GPR7 only. In animals, NPW decreases insulin and leptin levels, whereas the deletion of either NPB or GPR7 leads to obesity and hyperphagia.Metabolic and endocrine in vitro activities of NPW/NPB in adipocytes are unknown. We therefore characterize the effects of NPB and NPW on the secretion and expression of leptin and resistin, and on lipolysis, using rat adipocytes.Isolated rat adipocytes express GPR7 mRNA. NPB and NPW are expressed in macrophages and preadipocytes but are absent in mature adipocytes. Both, NPB and NPW reduce the secretion and expression of leptin from isolated rat adipocytes. NPB stimulates the secretion and expression of resistin, whereas both, NPB and NPW increase lipolysis.Our study demonstrates for the first time that NPB and NPW regulate the expression and secretion of leptin and resistin, and increase lipolysis in isolated rat adipocytes. These effects are presumably mediated via GPR7. The increase of resistin secretion, stimulation of lipolysis and the decrease of leptin secretion may represent mechanisms, through which NPB and NPW can affect glucose and lipid homeostasis, and food intake in rodents.

Serotonergic Anti-Obesity Agents

The role of serotonin (5-hydroxytryptamine) in appetite control is long established. Serotonergic manipulations reduce food intake in rodents in a manner consistent with satiety. In humans, drugs such as fenfluramine, dexfenfluramine and sibutramine all reduce energy intake, suppress hunger and enhance satiety. Effects on eating behaviour and subjective sensations of appetite are associated with the weight loss-inducing effects of these treatments. Currently, no appetite-suppressing drugs are approved specifically for the treatment of obesity. However, a new generation of serotonergic drugs have progressed through clinical development. The serotonin 5-HT(2C)-receptor selective agonist lorcaserin, a drug specifically developed to target satiety without producing the side effect profiles of its predecessors, has been shown to significantly reduce energy intake and body weight. The weight loss produced by lorcaserin appears modest, and behavioural effects, particularly its supposed satiety-enhancing effects, have yet to be characterized. The monoaminergic re-uptake inhibitor tesofensine has also been shown to produce impressive weight loss in smaller-scale clinical studies. It remains unclear if this drug produces any effects on appetite mediated by serotonin, or whether weight loss is produced largely through enhanced energy expenditure. Evidence indicates that tesofensine strengthens satiety, but behavioural specificity and psychological side effects remain an issue. The serotonergic system remains a viable target for anti-obesity treatment. In this review, we examine the limited behavioural data available on these two new CNS-acting appetite suppressants.

Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients

Chemotherapeutic agents, especially cisplatin, cause severe gastrointestinal disorders, including nausea, vomiting, and anorexia, which markedly impair quality of life and encourage discontinuation of chemotherapy. Since cisplatin was recently reported to decrease plasma ghrelin and food intake in rodents, we monitored the plasma ghrelin level and its association with nutritional status and adverse events during chemotherapy in patients with esophageal cancer. Twenty patients with advanced esophageal cancer who underwent cisplatin-based neoadjuvant chemotherapy were enrolled in a prospective observational study. Changes in gastrointestinal hormones including ghrelin were measured and correlated with feeding activity, including appetite and dietary intake, nutritional status including rapid turnover proteins, and adverse events from chemotherapy. Plasma total ghrelin significantly decreased at days 3 and 8 of chemotherapy but recovered at day 28 (baseline: 140 ± 54; day 3: 107 ± 46; day 8: 82 ± 32; day 28: 126 ± 43 fmol/ml; p = 0.023 for day 3 and p = 0.034 for day 8). No changes were noted in plasma leptin (baseline: 3.2 ± 1.8; day 8: 2.5 ± 1.5 ng/ml; p = 0.18). Among blood nutritional parameters, transferrin was the only parameter that decreased significantly and its decline, as well as loss of oral intake and appetite, correlated significantly with plasma ghrelin levels (p = 0.0013, p = 0.0063, and p = 0.013, respectively). Neutropenia and anorexia were more frequent in patients with low plasma ghrelin than in those with high plasma ghrelin (p = 0.015 and p = 0.011, respectively). Cisplatin-based chemotherapy significantly reduced plasma ghrelin and feeding activity. Ghrelin is a potentially useful novel therapy for minimizing the adverse effects of chemotherapy.

Presynaptic Facilitation by Neuropeptide Signaling Mediates Odor-Driven Food Search

Internal physiological states influence behavioral decisions. We have investigated the underlying cellular and molecular mechanisms at the first olfactory synapse for starvation modulation of food-search behavior in Drosophila. We found that a local signal by short neuropeptide F (sNPF) and a global metabolic cue by insulin are integrated at specific odorant receptor neurons (ORNs) to modulate olfactory sensitivity. Results from two-photon calcium imaging show that starvation increases presynaptic activity via intraglomerular sNPF signaling. Expression of sNPF and its receptor (sNPFR1) in Or42b neurons is necessary for starvation-induced food-search behavior. Presynaptic facilitation in Or42b neurons is sufficient to mimic starvation-like behavior in fed flies. Furthermore, starvation elevates the transcription level of sNPFR1 but not that of sNPF, and insulin signaling suppresses sNPFR1 expression. Thus, starvation increases expression of sNPFR1 to change the odor map, resulting in more robust food-search behavior.

Nesfatin‐1: a novel inhibitory regulator of food intake and body weight

The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release.

Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists

A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.

Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents

Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

Cannabinoid CB(1) receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. AM6545 binds to CB(1) receptors with a K(i) of 1.7 nM and CB(2) receptors with a K(i) of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB(1) receptor antagonist. AM6545 reversed the effects of WIN55212-2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose-dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB(1) receptor gene-deficient mice, but not in CB(1)/CB(2) receptor double knockout mice. Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.

High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice.

Nicotine treatment has known to produce an inverse relationship between body weight and food intake in rodents. Present study determined the effect of repeated treatment with nicotine and withdrawal in control and obese mice, on: (1) body weight, caloric intake and energy expenditure; (2) hypothalamic neuropeptides mRNA expression; and (3) serum leptin. 21-week-old C57BL/6 mice (n = 65) received nicotine (3.0 mg/kg/day; 2 weeks) and saline (1 ml/kg/day; 2 weeks) subcutaneously. Animals were given either a normal-fat (10% kcal from fat, NF) or a high-fat diet (45% kcal from fat, HF) from the 12th week to 25th week. While, nicotine treatment for 14 days induced an increase in hypothalamic agouti-related protein, cocaine- and amphetamine- regulated transcript, pro-opiomelanocortin mRNA expressions, nicotine also produced a reducing effect in body weight gain and leptin concentration in NF mice. High-fat diet induced obese mice showed a blunted hypothalamic and leptin response to nicotine. Remarkable weight loss in obese mice was mediated not just by decreasing caloric intake, but also by increasing total energy expenditure (EE). During nicotine withdrawal period, weight gain occurred in NF and HF groups, which was ascribed to a decrease in EE rather than changes in caloric intake. Hypothalamic AgRP might play a role for maintaining energy balance under the nicotine-induced negative energy status.

The metabotropic glutamate mGluR5 receptor agonist CHPG stimulates food intake

The metabotropic glutamate receptor 5 (mGluR5) has been suggested to modulate energy balance. For example, mGluR5 antagonists inhibit food intake in rodents and mGluR5 knockout mice resist diet-induced obesity. However, nonspecific effects can reduce food intake. Thus, to further support the role of mGluR5 in feeding behaviour, we evaluated if the mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) would induce the opposite effect, i.e. increased food intake in rats. Intracerebroventricularly injected CHPG (0.5-1.5 micromol) induced a dose-dependent stimulation of food intake (349% increase at 2 h with 1.5 micromol). The mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (10 mg/kg intraperitoneally) reduced 24 h food intake, without altering CHPG-induced feeding. These findings further support a physiologically relevant role of mGluR5 in appetite regulation.

Peripherally injected CCK-8S activates CART positive neurons of the paraventricular nucleus in rats

Cholecystokinin (CCK) plays a role in the short-term inhibition of food intake. Cocaine- and amphetamine-regulated transcript (CART) peptide has been observed in neurons of the paraventricular nucleus (PVN). It has been reported that intracerebroventricular injection of CART peptide inhibits food intake in rodents. The aim of the study was to determine whether intraperitoneally (ip) injected CCK-8S affects neuronal activity of PVN-CART neurons. Ad libitum fed male Sprague–Dawley rats received 6 or 10 μg/kg CCK-8S or 0.15 M NaCl ip ( n = 4/group). The number of c-Fos-immunoreactive neurons was determined in the PVN, arcuate nucleus (ARC), and the nucleus of the solitary tract (NTS). CCK-8S dose-dependently increased the number of c-Fos-immunoreactive neurons in the PVN (mean ± SEM: 102 ± 6 vs. 150 ± 5 neurons/section, p < 0.05) and compared to vehicle treated rats (18 ± 7, p < 0.05 vs. 6 and 10 μg/kg CCK-8S). CCK-8S at both doses induced an increase in the number of c-Fos-immunoreactive neurons in the NTS (65 ± 13, p < 0.05, and 182 ± 16, p < 0.05). No effect on the number of c-Fos neurons was observed in the ARC. Immunostaining for CART and c-Fos revealed a dose-dependent increase of activated CART neurons (19 ± 3 vs. 29 ± 7; p < 0.05), only few activated CART neuron were observed in the vehicle group (1 ± 0). The present observation shows that CCK-8S injected ip induces an increase in neuronal activity in PVN-CART neurons and suggests that CART neurons in the PVN may play a role in the mediation of peripheral CCK-8S's anorexigenic effects.

In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB 1 receptor antagonist for the management of obesity

Cannabinoid CB 1 receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9 H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB 1 receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB 1 receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB 1 receptors in both binding ( K i = 0.7 nM) and functional assays ( K i = 0.2 nM). The compound has low affinity ( K i = 7600 nM) for human CB 2 receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10 mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB 1 receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB 1 receptor competitive antagonist that may further our understanding of the endocannabinoid system.

Role of neurotensin receptor 1 in the regulation of food intake by neuromedins and neuromedin-related peptides

Central administration of neuromedins and neuromedin-related peptides suppresses food intake in rodents. Neurotensin- and neuromedin U (NMU)-induced anorexia is mainly mediated through neurotensin receptor 1 (Ntsr1) and NMU receptor 2, respectively. Xenin belongs to the neurotensin family and suppresses food intake via an unknown receptor. It has been suggested that Ntsr1 also mediates biological actions of xenin and NMU. Therefore, we examined the effect of intracerebroventricular injection of xenin and NMU on food intake and body weight in wild-type and Ntsr1-deficient mice. The feeding-suppressing and weight gain-inhibiting effects of xenin were abolished in Ntsr1-deficient mice, but NMU reduced food intake and body weight gain in both wild-type and Ntsr1-deficient mice. These findings support the role for Ntsr1 in the mediation of the metabolic effect of xenin as well as neurotensin. Therefore, enhancement of signaling through the Ntsr1 receptor is a potential strategy to reduce appetite and ameliorate obesity.

Peripheral and Central Administration of Xenin and Neurotensin Suppress Food Intake in Rodents

Xenin is a 25-amino acid peptide highly homologous to neurotensin. Xenin and neurotensin are reported to have similar biological effects. Both reduce food intake when administered centrally to fasted rats. We aimed to clarify and compare the effects of these peptides on food intake and behavior. We confirm that intracerebroventricular (ICV) administration of xenin or neurotensin reduces food intake in fasted rats, and demonstrate that both reduce food intake in satiated rats during the dark phase. Xenin reduced food intake more potently than neurotensin following ICV administration. ICV injection of either peptide in the dark phase increased resting behavior. Xenin and neurotensin stimulated the release of corticotrophin-releasing hormone (CRH) from ex vivo hypothalamic explants, and administration of alpha-helical CRH attenuated their effects on food intake. Intraperitoneal (IP) administration of xenin or neurotensin acutely reduced food intake in fasted mice and ad libitum fed mice in the dark phase. However, chronic continuous or twice daily peripheral administration of xenin or neurotensin to mice had no significant effect on daily food intake or body weight. These studies confirm that ICV xenin or neurotensin can acutely reduce food intake and demonstrate that peripheral administration of xenin and neurotensin also reduces food intake. This may be partly mediated by changes in hypothalamic CRH release. The lack of chronic effects on body weight observed in our experiments suggests that xenin and neurotensin are unlikely to be useful as obesity therapies.

Night and day: Diurnal differences in the behavioural satiety sequence in male rats

The behavioural satiety sequence (BSS) is an important method for assessing the selectivity of treatment (physiological, pharmacological and/or genetic) effects on food intake in rodents. The concept describes the natural progression from feeding to resting, with the transition between the two a useful biomarker of behavioural satiety. Although treatments can accelerate (anorexigenics) or delay (orexigenics) this transition without disrupting behavioural structure, the detection of such changes depends upon the timing of the transition under control conditions. Fasting and presatiation are known to affect this timing. However, recent observations in our laboratory have suggested that phase of testing (light or dark) might also be an important consideration. The present study therefore directly compared food intake and the BSS in thoroughly habituated male rats maintained either on a normal light cycle and tested during the light phase or on a reversed light cycle and tested during the dark phase. The results show that phase of testing had relatively little impact on food intake or diverse measures of ingestive and non-ingestive behaviour. Although modest differences were detected in locomotion, grooming and scratching (higher in dark phase), by far the largest difference concerned resting behaviour which had both a later onset and a much lower peak level during dark phase testing. Importantly, these behavioural differences delayed the transition between eating and resting. The potential contribution of diurnal differences in rate of eating is discussed as are the implications of these findings for future studies on the neurobiology of feeding behaviour.

The thyroid hormone derivative 3‐iodothyronamine increases food intake in rodents

The thyroid hormone derivative 3-iodothyronamine (T(1)AM), an endogenous biogenic amine, is a potent agonist of the G protein-coupled trace amine-associated receptor 1 (TAAR1). T(1)AM is present in rat brain, and TAAR1 is expressed in hypothalamic nuclei associated with the regulation of energy homeostasis. The aim of this study was to determine the effects of T(1)AM on food intake in rodents. We determined the effect of (i) intraperitoneal (i.p.) administration of T(1)AM on food intake, oxygen consumption (VO(2)) and locomotor activity in mice; (ii) intracerebroventricular (ICV) injection of T(1)AM on food intake in male rats; (iii) c-fos expression following ventricular administration of T(1)AM in male rats; and (iv) direct injection of T(1)AM into the arcuate nucleus (ARC) of male rats on food intake. (i) T(1)AM (4 nmol/kg) significantly increased food intake following i.p. injection in mice but had no effect on VO(2) or locomotor activity. (ii) ICV administration of T(1)AM (1.2 nmol/kg) significantly increased food intake in male rats. (iii) Intraventricular administration of T(1)AM significantly increased c-fos expression in the ARC of male rats. (iv) Direct administration of T(1)AM (0.12, 0.4 and 1.2 nmol/kg) into the ARC of male rats significantly increased food intake. These data suggest that T(1)AM is an orexigenic factor that may act through the ARC to increase food intake in rodents.