Olfactory bulbectomy increases food intake and hypothalamic neuropeptide Y in obesity-prone but not obesity-resistant rats

Obese individuals often suffer from depression. The olfactory bulbectomy (OBX) model is an animal model of depression that produces behavioral, physiological, and neurochemical alterations resembling clinical depression. The OBX model was employed to assess depression-related changes in food intake in obesity-prone, Osborne–Mendel (OM) rats and obesity-resistant, S5B/Pl rats. OBX increased food intake in OM rats beginning 7 days following surgery, however, OBX did not alter food intake in S5B/Pl rats at any time point. Fourteen days following surgery, OBX significantly increased locomotor activity (total lines crossed and rears) in the openfield test in OM and S5B/Pl rats. Fifteen days following surgery, prepro-neuropeptide Y (NPY) mRNA levels were significantly increased in the hypothalamus of bulbectomized OM rats and in the medial nucleus of the amygdala of bulbectomized OM and S5B/Pl rats. OBX decreased NPY Y2 receptor mRNA levels in the hypothalamus and medial nucleus of the amygdala in OM rats, while increasing NPY Y2 receptor mRNA levels in the medial nucleus of the amygdala of S5B/Pl rats. These data indicate that though both obesity-prone and obesity-resistant strains were susceptible to the locomotor effects of OBX, food intake and hypothalamic prepro-NPY mRNA were only increased in OM rats. Therefore, strain specific alterations in hypothalamic NPY may account for increased food intake in the obesity-prone rats following OBX, and suggests a potential mechanism to explain the comorbidity of obesity and depression.     

Bromocriptine increased operant responding for high fat food but decreased chow intake in both obesity-prone and resistant rats

Dopamine (DA) and DA D? receptors (D2R) have been implicated in obesity and are thought to be involved in the rewarding properties of food. Osborne-Mendel (OM) rats are susceptible to diet induced obesity (DIO) while S5B/P (S5B) rats are resistant when given a high-fat diet. Here we hypothesized that the two strains would differ in high-fat food self-administration (FSA) and that the D2R agonist bromocriptine (BC) would differently affect their behavior. Ad-libitum fed OM and S5B/P rats were tested in a FSA operant chamber and were trained to lever press for high-fat food pellets under a fixed-ratio (FR1) and a progressive ratio (PR) schedule. After sixteen days of PR sessions, rats were treated with three different doses of BC (1, 10 and 20 mg/kg). No significant differences were found between the two strains in the number of active lever presses. BC treatment (10 mg/kg and 20 mg/kg) increased the number of active lever presses (10 mg/kg having the strongest effect) whereas it decreased rat chow intake in the home cage with equivalent effects in both strains. These effects were not observed on the day of BC administration but on the day following its administration. Our results suggest that these two strains have similar motivation for procuring high fat food using this paradigm. BC increased operant responding for high-fat pellets but decreased chow intake in both strains, suggesting that D2R stimulation may have enhanced the motivational drive to procure the fatty food while correspondingly decreasing the intake of regular food. These findings suggest that susceptibility to dietary obesity (prior to the onset of obesity) may not affect operant motivation for a palatable high fat food and that differential susceptibility to obesity may be related to differential sensitivity to D2R stimulation.     

Reduced hindbrain and enteric neuronal response to intestinal oleate in rats maintained on high-fat diet

Rats maintained on a high-fat diet (HF) reduce their food intake less in response to intestinal infusion of oleic acid than rats maintained on a low-fat diet (LF). Inhibition of gastric emptying by intestinal infusion of oleate also is attenuated in rats fed a high-fat diet. It is well documented that intestinal oleate reduces food intake and inhibits gastric emptying via vagal sensory neurons. In addition, activation of intrinsic myenteric neurons participates in oleate-induced changes in gastrointestinal motility. To determine whether diminished behavioral and gastric reflex responses to intestinal oleate infusion is accompanied by reduced vagal sensory and myenteric neuronal activation, we examined expression of Fos-like immunoreactivity (Fos-li) in the dorsal hindbrains and the small intestinal enteric plexuses of rats maintained on HF or LF, following, intraintestinal infusion of oleate (0.06 kcal/ml) or the oligosaccharide, maltotriose (0.26 kcal/ml). Following oleate infusion there was a dramatic increase in the number of Fos-li nuclei in the NTS and AP of LF rats but not in HF rats. There also were significantly more Fos-li neuronal nuclei in the upper small intestinal submucosal and myenteric plexuses of the LF rats than the HF rats. In contrast to the effects of oleate infusion, maltotriose infusion significantly and similarly increased Fos-li nuclei in the hindbrains of both LF and HF rats. The results indicate that adaptation to high-fat diet selectively reduces vagal and enteric neuronal sensitivity to intestinal oleate and suggests that reduced sensitivity to the satiation and gastric inhibitory effects of oleate in high-fat fed rats may be mediated by a selective reduction in the neuronal response to intestinal stimulation by fatty acid.     

Diminished Metabolic Responses to Centrally-Administered Apelin-13 in Diet-Induced Obese Rats Fed a High-Fat Diet

The central administration of apelin, a recently identified adipokine, has been shown to affect food and water intake. The present study investigated whether body weight could affect an animal's response to apelin. The effects of centrally-administered apelin-13 on food and water intake, activity and metabolic rate were investigated in adult male diet-induced obese (DIO) rats fed either a high fat (32%) or control diet. Rats were administered i.c.v. apelin-13, 15–30 min prior to lights out, and food and water intake, activity and metabolic rate were assessed. Intracerebroventricular administration of apelin-13 decreased food and water intake and respiratory exchange ratio in DIO rats on the control diet, but had no effect in DIO rats on the high-fat diet. In an effort to identify potential central mechanisms explaining the observed physiological responses, the mRNA level of the apelin receptor, APJ, was examined in the hypothalamus. A high-fat diet induced an up-regulation of the expression of the receptor. Apelin induced a down-regulation of the receptor, but only in the DIO animals on the high-fat diet. In conclusion, we have demonstrated a diminished central nervous system response to apelin that is coincident with obesity.     

Differential effects of enterostatin, galanin and opioids on high-fat diet consumption

Enterostatin, the activation peptide of pancreatic procolipase, suppresses high-fat diet consumption both centrally and peripherally. κ-opioid agonists are also known to stimulate fat intake. These experiments were conducted to determine if an opioidergic central pathway might mediate the effects of enterostatin and galanin on fat intake. Male Sprague-Dawley rats were adapted to a high-fat diet (56% energy) and were implanted with cannulae aimed at the lateral cerebral ventricle (LV) or third cerebral ventricle (3V). Injection of enterostatin (1 nmol, LV) suppressed high-fat diet consumption in fasted (20 h) rats. This inhibition of high-fat intake by enterostatin was attenuated by central injection of the specific κ-agonist U50488 (2.15, 21.5 and 215 nmol, LV) in a dose-dependent manner in fasted rats while only the highest dose of U50488 (215 nmol, LV) independently produced stimulation of high-fat diet consumption in sated rats. Galanin (0.1 nmol, 3V) induced consumption of high-fat diet in sated rats similar to that seen with U50488 and this stimulation was attenuated by peripheral injection of naloxone (1.0 mg/kg i.p.). We present a model which integrates the present data, as well as previous findings, in explaining a potential common opioid pathway modulating fat consumption.     

Exaggerated feeding response to central galanin-like peptide administration in diet-induced obese rats

Galanin-like peptide (GALP) is a newly identified neuropeptide implicated in the regulation of metabolism and reproduction. GALP gene expression is decreased in the hypothalamus of genetically obese rodents, such as fa/fa rats and ob/ob mice, and central administration of GALP increases feeding in satiated rats. The effect of dietary obesity on GALP-induced feeding is unknown, so this study characterized the effects of central administration of GALP on feeding in a rat model of diet-induced obesity. Male Sprague-Dawley rats (n = 21) were randomly assigned to receive standard laboratory chow (12% fat as kcal) or high-fat cafeteria diet (35% fat) for 12 weeks before intracerebroventricular (icv) cannulae were implanted. Seven days later, rats received 0,0.2 or 0.3 nmol doses of GALP in randomized order at least 48 h apart. Food intake was measured at 0.5,1,2, 4 and 24 h post administration and body weight was measured at 24 h. Rats were maintained on their respective diets throughout the entire feeding experiment. Implementation of the high-fat diet led to significantly greater caloric intake (230%) and body weight (28%) compared to chow-fed control rats. GALP-induced feeding was rapid and maximal in both dietary groups at 30 min post injection. The 0.3 nmol dose of GALP led to significantly larger increases in caloric intake in high-fat fed rats than in chow-fed controls (35.4 +/- 3.7 and 22.1 +/- 1.3 kcal, respectively, at 30 min). It is not known if diet-induced obesity alters endogenous GALP levels, but our data suggest that adaptive responses in GALP signaling might occur during chronic overfeeding. One possible explanation is an increased sensitivity and/or number of specific GALP receptors, although actions of exogenous GALP may also represent pharmacological actions at galanin receptors.     

Feeding responses to a melanocortin agonist and antagonist in obesity induced by a palatable high-fat diet

Hypothalamic melanocortins are critical for the control of food intake, and alterations in POMC mRNA have been described in genetic models of obesity. However, the time course of changes in brain transmitters over the development of dietary obesity is less clear. Therefore, we examined the effect of diet-induced obesity on hypothalamic alpha-MSH content and feeding responsiveness to synthetic melanocortins. Male Sprague-Dawley rats fed a high-fat cafeteria diet (30% fat) or chow (5% fat) for 4 or 12 weeks were implanted with intracerebroventricular cannulae and feeding responses to the MC3/4R agonist MTII (0.5 nmol) and the selective MC4R antagonist HS014 (0.8 nmol) were determined. MTII had a long-lasting inhibitory effect on food intake. Chronically overfed animals had a significantly exaggerated inhibitory feeding response 15 and 24 h after MTII injection and lost more body weight (15 +/- 3 g) compared to control rats (4 +/- 4 g; P < 0.05). Daytime administration of HS014 significantly increased food intake in all rats to the same extent (P < 0.05). No change in hypothalamic alpha-MSH content was observed after 2 or 12 weeks of high-fat diet. The observation of increased responsiveness to the melanocortin agonist, in the face of a high-fat diet, suggests melanocortin analogues may have potential for the pharmacological treatment of obesity.     

Central 5-HT2B/2C and 5-HT3 receptor stimulation decreases salt intake in sodium-depleted rats

In the present study, we investigated the participation of central 5-HT(2B/2C) and 5-HT(3) receptors in the salt intake induced by sodium depletion in Wistar male rats. Sodium depletion was produced by the administration of furosemide associated with a low salt diet. Third ventricle injections of mCPP, a 5-HT(2B/2C) agonist, at doses of 80, 160 and 240 nmol, promoted a dose-dependent reduction in salt intake in sodium-depleted rats. The inhibitory effect produced by central administration of mCPP was abolished by the central pretreatment with SDZ SER 082, a 5-HT(2B/2C) antagonist. Similar results were obtained with third ventricle injections of m-CPBG (80, 160 and 240 nmol), a selective 5-HT(3) agonist that also induced a dose-related decrease in salt intake in sodium-depleted rats. The central pretreatment with LY-278,584, a selective 5-HT(3) receptor antagonist, was able to impair the salt intake inhibition elicited by third ventricle injections of m-CPBG. Central administration of each one of the antagonists alone or a combination of both antagonists together did not significantly change salt intake after sodium depletion. On the other hand, the central administration of both mCPP and m-CPBG, in the highest dose used to test their effect on salt intake (240 nmol), was unable to modify blood pressure in sodium-depleted rats. It is concluded that: (1) pharmacological activation of central 5-HT(2B/2C) and 5-HT(3) receptors diminishes salt intake during sodium depletion, (2) an inhibitory endogenous drive exerted by central 5-HT(2B/2C) and 5-HT(3) receptors does not seem to exist and (3) the reduction in salt intake generated by the pharmacological activation of these central receptors is not produced by an acute hypertensive response.     

Influence of Stress on Gastric Emptying Depends on the Nature of Meals, Stressors, and Animal Species

This work evaluated the effects of 20-minute exposures to acoustic stress, cold (10°C), or immobilization on gastric emptying of test meals containing ⁵¹Cr sodium chromate in rats and mice. Four diets were studied: one consisting of reconstituted cow's milk (diet A), a synthetic diet containing arabic gum, glucose, and casein (diet B), diet B with arachis oil (diet C), and a nonnutritive diet containing methylcellulose and saline (diet D). Test-meal volumes were 0.5 ml in mice and 3 ml in rats. Gastric emptying, expressed as percentage of meal emptied, was measured 30 minutes after gavage with the test meal. Acoustic stress and cold, applied after gavage, increased (p > .05) the rate of gastric emptying of diet A by 46.8% and 70.7%, respectively, in mice and by 13.4% and 22.0% in rats. Immobilization did not affect (p > .05) the gastric emptying of diet A in either species. Cold significantly increased (p ≤ .05) the emptying rate of diets C and D in mice but not in rats. Gastric emptying of diet D was unaffected by the three stressors in mice but was increased (45.7%) by cold in rats. This study shows that the effects of stress on gastric emptying of a nutritive meal depend mainly on the type of stressor. Of the three tested, cold was the most powerful. These results also support the conclusion that stressor, diet, and species are all important in gastric emptying.     

Intracerebroventricular leptin inhibits gastric emptying of a solid nutrient meal in rats

The effects of leptin injected intracerebroventricularly (i.c.v.) or i.p. on food intake and gastric emptying of a solid nutrient meal were studied in fasted Long-Evan rats. Leptin (3 microg, i.c.v.) reduced the 5 h cumulative food intake by 39% and gastric transit by 50% while i.p. leptin (300 microg) resulted in a 35% decrease in food intake and no change in gastric transit after 5 h. Lower i.p. doses of leptin (30 or 3 microg) did not alter food intake. These results show that central, unlike peripheral, injection of leptin inhibits gastric transit of an ingested meal; such a central action of leptin may contribute to the greater potency of i.c.v. than i.p. leptin to suppress food intake.     

The effect of intracerebroventricular administration of baclofen on food intake in rats

In the present study the effects of intracerebroventricular (ICV) administration of baclofen (0.1-5.0 nmol) was investigated on food intake in non-fasted rats. Baclofen (1.0, 2.5 and 5.0 nmol) increased food consumption in a dose-related manner during the first 15-30 min after administration. The effects of baclofen (5.0 nmol) on feeding were prevented by pretreating the rats with the specific GABA-B receptor antagonist phaclofen (40 nmol, ICV). These results suggest that baclofen increases food intake in rats by an action at central GABA-B receptors.     

Capsaicin pretreatment attenuates multiple responses to cholecystokinin in rats

Systemic injection of the peptide hormone cholecystokinin (CCK) is known to inhibit food intake and gastric emptying, and to stimulate neurohypophyseal secretion of oxytocin (OT) in rats. Previous studies also have shown that surgical destruction of afferent fibers in the gastric vagus eliminates the inhibitory effects of CCK on food intake. The present experiments used capsaicin to destroy peripheral sensory fibers in rats, and confirmed the failure of CCK to inhibit food intake. Similarly, capsaicin pretreatment markedly attenuated the stimulatory effect of CCK on OT secretion and the inhibitory effect of CCK on gastric emptying in rats. These and other results suggest that in rats CCK acts on receptors located on afferent fibers in the gastric vagus and stimulates inhibition of gastric emptying predominantly via a vagovagal reflex arc through the brainstem.     

Contribution of fat metabolism to 'glucoprivic' feeding produced by fourth ventricular 5-thio-D-glucose

We examined whether manipulations of fat metabolism influence the feeding response to peripheral or central administration of 5-thio-D-glucose (5-TG), a potent inhibitor of glucose utilization. The increase in food intake produced by peritoneal (50 mg/kg) or fourth ventricular (50, 100, 150 micrograms) 5-TG was potentiated by administration of the fatty acid oxidation inhibitor, methyl palmoxirate (10 mg/kg, p.o.). In addition, rats maintained on a high-fat diet ate less in response to fourth ventricular 5-TG (150 micrograms) than did rats maintained on an equicaloric low-fat diet. These results suggest that the feeding response to 'glucoprivation' is determined by the interaction of glucose and fat oxidation.     

Visceral factors in the control of food intake

Some years ago, we reported that the increased blood intake of hypoglycemic rats was inhibited by the intravenous infusion of fructose, a sugar that cannot cross the blood-brain barrier and nourish cerebral chemoreceptors. More recent experiments therefore have focused on visceral factors in the control of food intake. Three observations have been emphasized in this review. First, we found that gastric emptying was increased during insulin-induced hypoglycemia, and that this effect also was eliminated by administration of fructose. Hepatic vagotomy abolished both this effect of fructose on gastric emptying and its effect on food intake. Second, we found that in rats with severe diabetes, the rate of gastric emptying did decrease in proportion to increasing concentration of an administered glucose load, as it does in intact rats, but calories emptied more rapidly than normal regardless of the concentration of the load. Third, we found that rats with varying degrees of streptozotocin-induced damage to the pancreas ate more food than intact rats did after an overnight fast, and that individual intakes were proportional to the induced glucose intolerance. The increased eating took the form of shorter intermeal intervals, as if the initial postfast meal did not remain satiating for a normal amount of time. These and other findings suggest that food intake is controlled in part by satiety signals apparently related to the delivery of utilizable calories plus insulin to the liver. These signals also seem to affect gastric emptying and thereby might influence other satiety signals related to gastric distention.     

Sensory responses, dietary-induced obesity and biochemical values in Sprague-Dawley rats

Food intake and body weight gain variability in Sprague-Dawley (SD) rats exposed to a palatable high-fat diet were examined in relation to sensory responses and biochemical parameters in two experiments. In the first experiment, varying sucrose concentrations (4-32% wt./vol.) were randomly presented for 20 minutes to ad lib chow-fed rats. Each rat's sensory response was expressed as Beta (B), or the slope of the regression between solute intake and concentration, and used to assign rats to diet groups. In the second experiment, responsiveness to fat emulsions (1-37%) were similarly measured and categorized. In both experiments sensory responses to sucrose were significantly related to weight gain/fatness on the high-fat diet (lab chow-corn oil). Sensory responsiveness to the fat emulsions was unrelated to sucrose responsiveness or to high-fat feeding. Biochemical parameters (insulin, cholesterol, triglycerides, lipoproteins) reflected increased caloric (fat) intake, as well as sucrose responsiveness. Predictors (sensory responses, biochemical values) of response to chronic (4 months) or short-term (less than 2 months) high-fat diets are discussed.     

The satiety effect of growth hormone-releasing factor in rats

The effect of growth hormone-releasing factor (GRF) on feeding behavior in rats was examined. Starvation-induced feeding was suppressed by intraventricular administration of 1 nmol and 4 nmol of synthetic human GRF (hGRF). Food intake was not affected when the peptide was administered by intraperitoneal injection. Furthermore, centrally administered hGRF also suppressed feeding in hypophysectomized rats. These results suggest that GRF suppression of food intake is mediated through the central nervous system independent of its effect on pituitary growth hormone secretion.     

Corticotropin-releasing factor (CRF) or CRF binding-protein ligand inhibitor administration suppresses food intake in mice and elevates body temperature in rats

Corticotropin-releasing factor (CRF) receptor agonist and CRF binding-protein (CRF-BP) ligand inhibitor peptides both activate CRF systems but exert very distinct functional profiles in animal models of arousal, energy balance and emotionality. The present studies were designed to extend the dissimilar efficacy profiles of central administration of a CRF agonist, r/h CRF(1–41), versus a CRF-BP ligand inhibitor, r/h CRF(6–33), into mouse and rat models of energy balance in order to further explore in vivo efficacy of these ligands in two separate animal species. In CD-1 mice, food intake was significantly attenuated 3 h after acute administration of CRF(1–41) (0.007–0.2 nmol), but not CRF(6–33). In obese Ob/Ob mice, both CRF(1–41) (0.007–0.2 nmol) and CRF(6–33) (0.02–2.3 nmol) significantly attenuated basal feeding over 3 h following acute peptide administration. In rats, CRF(1–41) (1 nmol) and CRF(6–33) (1.5–7.7 nmol) infusion significantly increased rectal temperature. In studies employing a telemetry apparatus, core temperature was also increased by CRF(1–41) (1 nmol) and CRF(6–33) (1.5 nmol), whereas only CRF(1–41) increased locomotor activity and heart rate. These results suggest that CRF receptor agonist administration is capable of producing a global profile of negative energy balance by reducing food intake in mice and increasing energy expenditure in rats. In contrast, CRF-BP ligand inhibitor administration appears to suppress food intake in a mouse strain selective manner and to elevate rectal and core temperature in rats without accompanying cardiovascular activation.     

Selective lack of tolerance to delayed gastric emptying after daily administration of WIN 55,212-2 in the rat

Abstract  The use of cannabinoids to treat gastrointestinal (GI) motor disorders has considerable potential. However, it is not clear if tolerance to their actions develops peripherally, as it does centrally. The aim of this study was to examine the chronic effects of the cannabinoid agonist WIN 55,212-2 (WIN) on GI motility, as well as those in the central nervous and cardiovascular systems. WIN was administered for 14 days, at either non-psychoactive or psychoactive doses. Cardiovascular parameters were measured in anaesthetized rats, whereas central effects and alterations in GI motor function were assessed in conscious animals using the cannabinoid tetrad and non-invasive radiographic methods, respectively. Tests were performed after first (acute effects) and last (chronic effects) administration of WIN, and 1 week after discontinuing treatment (residual effects). Food intake and body weight were also recorded throughout treatment. Blood pressure and heart rate remained unchanged after acute or chronic administration of WIN. Central activity and GI motility were acutely depressed at psychoactive doses, whereas non-psychoactive doses only slightly reduced intestinal transit. Most effects were reduced after the last administration. However, delayed gastric emptying was not and could, at least partially, account for a concomitant reduction in food intake and body weight gain. The remaining effects of WIN administration in GI motility were blocked by the CB1 antagonist AM 251, which slightly accelerated motility when administered alone. No residual effects were found 1 week after discontinuing cannabinoid treatment. The different systems show differential sensitivity to cannabinoids and tolerance developed at different rates, with delayed gastric emptying being particularly resistant to attenuation upon chronic treatment.     

Microinjection of galanin-like peptide into the medial preoptic area stimulates food intake in adult male rats

Galanin-like peptide (GALP) is a neuropeptide implicated in the regulation of feeding behaviour, metabolism and reproduction. GALP is an endogenous ligand of the galanin receptors, which are widely expressed in the hypothalamus. GALP is predominantly expressed in arcuate nucleus (ARC) neurones, which project to the paraventricular nucleus (PVN) and medial preoptic area (mPOA). Intracerebroventricular or intraparaventricular (iPVN) injection of GALP acutely increases food intake in rats. The effect of GALP injection into the mPOA on feeding behaviour has not previously been studied. In the present study, intra-mPOA (imPOA) injection of GALP potently increased 0-1-h food intake in rats. The dose-response effect of imPOA GALP administration on food intake was similar to that previously observed following iPVN administration. The effects of GALP (1 nmol) or galanin (1 nmol) on food intake were then compared following injection into the PVN, mPOA, ARC, dorsal medial nucleus (DMN), lateral hypothalamus and rostral preoptic area (rPOA). GALP (1 nmol) increased food intake to a similar degree when injected into the imPOA or iPVN, but produced no significant effect when injected into the ARC, DMN, lateral hypothalamus or rPOA. Similarly, galanin (1 nmol) significantly increased food intake following injection imPOA and iPVN. However, the effect was significantly smaller than that following administration of GALP (1 nmol). Galanin also had no significant effect on food intake when administered into the ARC, DMN, lateral hypothalamus and rPOA. These data suggest that the mPOA and the PVN may have specific roles in mediating the orexigenic effect of GALP and galanin.     

Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice

ObjectiveThe proinflammatory cytokine interleukin-18 (IL-18) putatively modulates food intake and energy metabolism, but the effects of IL-18 in high-fat diet fed animals are unknown. Whether IL-18 alters basal metabolic rate or metabolic processes of living is unknown. Here, we tested the hypothesis that IL-18 modulates weight gain, energy intake, whole-body energy expenditure, and utilization of lipid as a fuel substrate in high-fat diet fed mice.MethodsFood intake, whole-body metabolism, and motor activity of IL-18 knockout mice were compared to those of wildtype littermates; anorectic effects of intracerebroventricular IL-18 administration were compared between IL-18 receptor knockout, IL-18/IL-18R knockout and wildtype mice.ResultsChow-reared IL-18 knockout mice were overweight at 6 months of age and then gained excess weight on both low-fat and high-fat diets, ate more high-fat diet, and showed reduced whole-body energy expenditure and increased respiratory exchange ratios. Reductions in energy expenditure of IL-18 knockout mice were seen across fasting vs. feeding conditions, low- vs. high-fat diets, high vs. low levels of physical activity and times of day, suggesting actions on basal metabolic rate. The circadian amplitude of energy expenditure, but not respiratory exchange ratio, food intake, or motor activity, also was blunted in IL-18 knockout mice. Central IL-18 administration reduced high-fat diet intake in wildtype mice, but not in mice lacking the IL-18 receptor.ConclusionThe loss-of-function results support the hypothesis that endogenous IL-18 suppresses appetite and promote energy expenditure and lipid fuel substrate utilization not only during sickness, but also in healthy adults consuming high-fat diets.