Enhanced Food Intake Research Articles

GABA-A receptor subtypes, benzodiazepines and feeding

Benzodiazepines (BZs) enhance food intake by acting at GABAA receptors which have a pentameric structure consisting of two a, two s and one γ2 subunit. a1, a2, a3, and a5 containing GABAA receptors are sensitive to BZs such as diazepam and midazolam. Cooper (2005) suggested that the effects of BZs on feeding were mediated by a2 or a3 containing GABAA receptors. We tested this hypothesis in two ways. In the first experiment we compared the effects of midazolam on feeding in WT mice and mice lacking the a2 subunit (a2 KO mice). There was a clear stimulation of feeding in the a2 KO mice, suggesting that a2 containing GABAA receptors are not essential to the hyperphagic response to BZs. In a second experiment we used the novel BZ L-838417, which acts as a partial agonist at a2, a3, and a5 containing GABAA receptors but is an antagonist at a1 containing GABAA containing receptors. The effects of L-838417 were compared in wild type and a2(H101R) mice, in which the a2 containing GABAA receptor is BZ-insensitive. L-838417 increased feeding in both groups of animals, thus excluding an involvement of either a1 or a2 containing GABAA receptors and suggesting that either a3 or a5 containing GABAA receptors mediate the hyperphagic effect of BZs. Older evidence suggests that the involvement of a5 containing GABAA receptors is unlikely. Thus our data confirm and extend Cooper's (2005) hypothesis by suggesting that the hyperphagic effect of BZs is mediated by a3 containing GABAA receptors.

The effect of branched-chain amino acids (BCAA) on meal pattern of rats

BCAA (isoleucine, leucine and valine) have been reported to enhance food intake and have been used as anti-anorectic agents, especially in critically-ill patients. However, it is not clear whether their stimulatory effect on food intake is the result of an increase in meal size and/or meal number. Furthermore, the impact of individual BCAA on food intake is not well documented. The present experiment was designed to investigate the effect of individual BCAA on meal patterns of rats. Twenty-four adult male Sprague-Dawley rats were randomly divided into four equal groups and fed control diet or diets supplemented with isoleucine, leucine or valine (50 g/kg). Feeding patterns were monitored for 2 weeks using feed recording equipment (model 80350 series; Campden Instruments Limited, Lafayette, IN, USA).

Cross-talk between estrogen and leptin signaling in the hypothalamus

Obesity, characterized by enhanced food intake (hyperphagia) and reduced energy expenditure that results in the accumulation of body fat, is a major risk factor for various diseases, including diabetes, cardiovascular disease, and cancer. In the United States, more than half of adults are overweight, and this number continues to increase. The adipocyte-secreted hormone leptin and its downstream signaling mediators play crucial roles in the regulation of energy balance. Leptin decreases feeding while increasing energy expenditure and permitting energy-intensive neuroendocrine processes, such as reproduction. Thus, leptin also modulates the neuroendocrine reproductive axis. The gonadal steroid hormone estrogen plays a central role in the regulation of reproduction and also contributes to the regulation of energy balance. Estrogen deficiency promotes feeding and weight gain, and estrogen facilitates, and to some extent mimics, some actions of leptin. In this review, we examine the functions of estrogen and leptin in the brain, with a focus on mechanisms by which leptin and estrogen cooperate in the regulation of energy homeostasis.

Sheep foraging behavior in response to interactions among alkaloids, tannins and saponins

AbstractBACKGROUND: A mixture of plant species adds biochemical diversity to pastures that may enhance productivity while decreasing reliance on herbicides and insecticides. All plants contain secondary metabolites (PSMs) that interact in plant communities in a variety of ways. Our objective was to determine if PSM diversity enhanced food intake when sheep were allowed to select from foods that varied in concentrations of tannins, saponins, and alkaloids. We hypothesized that intake of foods containing alkaloids would increase when sheep were offered supplemental foods with tannins and saponins. The alkaloid gramine is proteinaceous in nature, tannins bind to proteins in the gut, which enhances excretion of proteins, so we hypothesized tannins would bind to gramine and enhance its excretion from the body. The alkaloid ergotamine is steroidal, saponins have a high affinity for binding to lipid and steroidal compounds in the gut and then being excreted, so we hypothesized saponins would bind to ergotamine and enhance its excretion from the body.RESULTS: We found that sheep fed either gramine or ergotamine in combination with tannin‐ or saponin‐containing foods had higher intakes of food than sheep offered only foods with gramine or ergotamine.CONCLUSION: These findings are consistent with the hypothesis that animals can neutralize the negative effects of alkaloids by ingesting tannins and saponins. Our results show that PSMs can complement one another to increase a herbivore's intake of unpalatable plant species, with the potential to maintain healthy animals and bio‐diverse landscapes. Copyright © 2008 Society of Chemical Industry

Glucocorticoid inhibition of growth in rats: partial reversal with the full-length ghrelin analog BIM-28125

Glucocorticoids are important immunosuppressive hormones; these steroids also inhibit somatic growth by decreased growth hormone (GH) secretion and induced protein catabolism. The ability of ghrelin, the endogenous ligand for the GHS-1a receptor, to increase body weight is attributed to a combination of enhanced food intake, increased gastric emptying and increased food assimilation, coupled with potent GH releasing activity. The aim of the present study was to evaluate the ability of a full-length, metabolically stabilized ghrelin agonist, BIM-28125, to reverse the dexamethasone-induced decrease of growth rate of prepubertal Sprague-Dawley male rats. Twenty-one days old rats were randomly assigned to two treatment groups. Beginning on day 23 of age, 16 animals were treated ip either with saline or DEX (40 microg/kg/day). On day 33 after birth, these two groups were further subdivided and treated sc with either vehicle or BIM-28125 (80 nmol/kg, t.i.d.). On day 47 after birth, rats were killed and trunk blood was collected for hormone determinations. DEX significantly reduced final body weight and nose-anal length; BIM-28125 increased linear growth in saline-treated rats and reversed growth inhibition in DEX-treated rats. The inhibitory effects of DEX on somatic growth was paralleled by decreased 24 h food intake (FI), decreased food efficiency (FE) and lower plasma IGF-1 levels versus vehicle-treated rats. BIM-28125 induced an increase of FI, FE and plasma IGF-1 in saline-treated rats, and reversed the inhibitory effects of DEX. These preclinical results leads to the conclusion that BIM-28125 may represent a good tool to reverse the catabolic effects induced by glucocorticoids.

Neuroendocrine mechanisms of change in food intake during pregnancy: A potential role for brain oxytocin

During pregnancy body weight, and particularly adiposity, increase, due to hyperphagia rather than decreased energy metabolism. These physiological adaptations provide the growing fetus(es) with nutrition and prepare the mother for the metabolically-demanding lactation period following birth. Mechanisms underlying the hyperphagia are still poorly understood. Although the peripheral signals that drive appetite and satiety centers of the brain are increased in pregnancy, the brain may become insensitive to their effects. For example, leptin secretion increases but hypothalamic resistance to leptin actions develops. However, several adaptations in hypothalamic neuroendocrine systems may converge to increase ingestive behavior. Oxytocin is one of the anorectic hypothalamic neuropeptides. Oxytocin neurons, both centrally-projecting parvocellular oxytocin neurons and central dendritic release of oxytocin from magnocellular neurons, may play a key role in regulating energy intake. During feeding in non-pregnant rats, magnocellular oxytocin neurons, especially those in the supraoptic nucleus, become strongly activated indicating their imminent role in meal termination. However, in mid-pregnancy the excitability of these neurons is reduced, central dendritic oxytocin release is inhibited and patterns of oxytocin receptor binding in the brain alter. Our recent data suggest that lack of central oxytocin action may partly contribute to maternal hyperphagia. However, although opioid inhibition is a major factor in oxytocin neuron restraint during pregnancy and opioids enhance food intake, an increase in opioid orexigenic actions were not observed. While changes in several central input pathways to oxytocin neurons are likely to be involved, the high level of progesterone secretion during pregnancy is probably the ultimate trigger for the adaptations.

Enhanced food intake regulatory responses after a glucose drink in hyperinsulinemic men

To determine the effect of hyperinsulinemia on food intake and plasma concentrations of glucose and food intake regulatory hormones in men after a glucose drink. Cross-sectional clinical intervention study of the effect of a glucose drink on food intake regulation. Thirty-three normoinsulinemic (NI) (body mass index (BMI)=25.3+/-0.6; age=41.4+/-2.4) and 32 hyperinsulinemic (HI) men (BMI=29.5+/-0.6; age=43.4+/-2.6). Food intake was measured from a pizza meal 1 h after subjects consumed either a noncaloric sweetened drink or a glucose-containing drink (75 g/300 ml) in random order on two occasions. On another occasion, blood samples were taken every 30 min for 2 h after the glucose drink. Fasting insulin in the HI and NI men was 65+/-3 (mean+/-s.e.m.) and 26+/-1.5 pmol/l, respectively. Food intake at the pizza meal was reduced by the glucose drink (P<0.01), but more so in HI (-9.7+/-4.1 %) than NI men (-5.4+/-3.4 %) (P=0.06). The increase in plasma insulin and cholecystokinin (CCK) after the glucose drink was greater and the plasma concentrations of leptin were higher, and ghrelin and adiponectin were lower in HI men than in NI men (P<0.05). These results support epidemiological data suggesting that hyperinsulinemia, at least in the early stages, may provide resistance to weight gain, possibly through physiological mechanisms of food intake control.

Eating behaviour and obesity

Eating behaviour and obesity

Thermogenesis, food intake and serum leptin in cold-exposed lactating Brandt's volesLasiopodomys brandtii

Lactation is the most energetically expensive period for mammals and is associated with increased metabolism and energy intake, but decreased thermogenic capacity. It is well known that small mammals increase both food intake and thermogenesis in the cold. The present study aimed to examine whether Brandt's voles Lasiopodomys brandtii could adjust energy intake and thermogenesis to accommodate simultaneous lactation and cold exposure. The voles were placed into two temperature treatments: warm (23+/-1 degrees C) and cold (5+/-1 degrees C). Animals at each temperature treatment were further divided into two groups: non-reproductive (NR) and lactating females. We found that lactating voles at peak lactation in the cold enhanced food intake by 2.6 g day(-1) compared with those in the warm, and increased uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT), to the same level as the cold-exposed NR females. Serum leptin levels decreased significantly during lactation and were positively correlated with body mass and fat mass. After correcting for the effects of body mass, residual serum leptin was negatively correlated with residual gross energy intake and residual RMR. In addition, residual serum leptin levels were positively correlated with UCP1 contents in the warm, but not in the cold. Together, these data suggest that lactating voles can increase thermogenic capacity and energy intake to meet the high energetic costs of simultaneous lactation and cold exposure. Further, serum leptin appears to be involved in the energy intake regulation and thermoregulation, but the thermoregulation in the cold may be mainly mediated by other factors.

Functional changes of the small intestine in over- and undernourished suckling rats support the development of obesity risk on a high-energy diet in later life

To investigate the relationship between early nutritional experience, ontogeny of the small intestinal functions and predisposition to obesity development, the following experimental models of male Sprague-Dawley rats were used: 1) rats in which the quantity of nutrition was manipulated from birth to weaning (day 30) by adjusting the number of pups in the nest to 4 (SL), 10 (NL) and 16 pups (LL) and 2) littermates of SL, NL and LL rats fed either a standard or a hypercaloric diet from days 80 to 135 of age. The overfed SL pups were overweight after day 15 and became permanently obese, whereas the underfed smaller LL pups, due to accelerated growth and enhanced food intake from day 30 to day 35, attained a body fat level that did not differ from normally fed NL rats. Moreover, a significantly increased duodenal and jejunal alkaline phosphatase (AP) activity was found in SL and LL rats and these acquired somatic and intestinal characteristics persisted from weaning throughout life. Eight weeks of high-energy diet feeding elicited a similar pattern of intestinal response in SL and LL rats that was clearly different from NL rats. Despite energy over-consumption in these three groups, both SL and LL rats still displayed enhanced AP activity and showed a significant increase in protein/DNA ratio accompanied with a significant body fat accretion. These results indicate that the postnatally acquired small intestinal changes induced by over- and undernutrition could be involved in the similar predisposition to obesity risk in later life when caloric density of the diet is raised.

Stimulation of hypothalamic P2Y1 receptors in rats causes enhanced food intake depending on P2Y1 receptor mediated nitric oxide production

Stimulation of hypothalamic P2Y1 receptors in rats causes enhanced food intake depending on P2Y1 receptor mediated nitric oxide production

Enhanced food intake after stimulation of hypothalamic P2Y1 receptors in rats: modulation of feeding behaviour by extracellular nucleotides

The present study was aimed to clarify the role of purinergic signalling in the regulation of ingestion behaviour. The ATP/ADP analogues 2-methylthioATP (2-MeSATP) and adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS) increased the food intake after intracerebroventricular infusion in 18-h food-deprived rats. This effect was abolished by pretreatment with the non-selective P2X/P2Y receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) or the selective P2Y1 receptor antagonist MRS 2179, respectively. The stimulation of food intake mediated by ADPbetaS was also blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor Nw-nitro-L-arginine methylester (L-NAME), as well as with the inhibitor of the soluble guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), suggesting that the orexigenic effect seems to be closely related with the ensuing formation of nitric oxide. The immunohistochemical staining indicating a co-localization of P2Y1 receptor- and nNOS-immunoreactivities in a population of neurons in the ventromedial hypothalamic nucleus (VMH) agrees with this assumption. Further experiments with the direct local application of these compounds into the VMH and lateral hypothalamic nucleus (LH) show that the stimulation of P2Y1 receptors in these functionally antagonistic brain regions exerts an increased food intake. Hence, different signal transduction mechanisms may operate in the VMH and LH. Our assumption is supported by distinct effects of the NOS inhibitor L-NAME in these two hypothalamic nuclei. The present data suggest that ATP/ADP, acting as extracellular signal molecules in the rat brain, are involved in the regulation of food intake, possibly depending on P2Y1-receptor-mediated nitric oxide production.

Ghrelin: a hormone regulating food intake and energy homeostasis

Regulation of energy homeostasis requires precise coordination between peripheral nutrient-sensing molecules and central regulatory networks. Ghrelin is a twenty-eight-amino acid orexigenic peptide acylated at the serine 3 position mainly with an n-octanoic acid, which is produced mainly in the stomach. It is the endogenous ligand of the growth hormone secretagogue (GHS) receptors. Since plasma ghrelin levels are strictly dependent on recent food intake, this hormone plays an essential role in appetite and meal initiation. In addition, ghrelin is involved in the regulation of energy homeostasis. The ghrelin gene is composed of four exons and three introns and renders a diversity of orexigenic peptides as well as des-acyl ghrelin and obestatin, which exhibit anorexigenic properties. Ghrelin stimulates the synthesis of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus neurons of the hypothalamus and hindbrain, which in turn enhance food intake. Ghrelin-expressing neurons modulate the action of both orexigenic NPY/AgRP and anorexigenic pro-opiomelanocortin neurons. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acids, and this appears to be the molecular signal for the expression of NPY and AgRP. Recent data suggest that ghrelin has an important role in the regulation of leptin and insulin secretion and vice versa. The present paper updates the effects of ghrelin on the control of energy homeostasis and reviews the molecular mechanisms of ghrelin synthesis, as well as interaction with GHS receptors and signalling. Relationships with leptin and insulin in the regulation of energy homeostasis are addressed.

An operant determination of the behavioral mechanism of benzodiazepine enhancement of food intake

A recent review paper by Cooper (Appetite 44:133-150, 2005) has pointed out that a role for benzodiazepines as appetite stimulants has been largely overlooked. Cooper's review cited several studies that suggested the putative mechanism of enhancement of food intake after benzodiazepine administration might involve increasing the perceived pleasantness of food (palatability). The present study examined the behavioral mechanism of increased food intake after benzodiazepine administration. The cyclic-ratio operant schedule has been proposed as a useful behavioral assay for differentiating palatability from regulatory effects on food intake (Ettinger and Staddon, Physiol Behav 29:455-458, 1982 and Behav Neurosci 97:639-653, 1983). The current study employed the cyclic-ratio schedule to determine whether the effects on food intake of chlordiazepoxide (CDP) (5.0 mg/kg), sodium pentobarbital (5.0 mg/kg), and picrotoxin (1.0 mg/kg) were mediated through palatability or regulatory processes. The results of this study show that both the benzodiazepine CDP and the barbiturate sodium pentobarbital increased food intake in a manner similar to increasing the palatability of the ingestant, and picrotoxin decreased food intake in a manner similar to decreasing the palatability of the ingestant. These results suggest that the food intake enhancement properties of benzodiazepines are mediated through a mechanism affecting perceived palatability.

Central but not peripheral glucoprivation is impaired in monosodium glutamate-treated rats

In the present study, newborn male Wistar rats were injected, subcutaneously, five times, every other day, with monosodium glutamate (MSG, 4 g/kg bw) or saline (as control, C), during the neonatal period. MSG animals developed destruction of the arcuate nuclei (ARC) with absence of NPY-immunoreactive cell bodies, which impaired both the food intake (baseline) and the 2-deoxy- d-glucose (2DG) glucoprivic feeding response. Increases in the immunoreactivity of corticotropin-releasing hormone-cell bodies in the paraventricular nuclei might have developed to compensate for the atrophy of the pituitary in MSG-treated rats. After systemic 2DG injection, neither the C nor the MSG rats increased their food intake, but they showed similar hyperglycemic responses, whereas plasma free fatty acids (FFA) increased only in the C group. In other groups, 2DG, norepinephrine (NE), neostigmine (NEO) and saline were intracerebroventricularly (i.c.v.) administered. In this condition, impairment of the hyperglycemic and food intake responses, associated to a lower increase in plasma FFA levels, were observed. As opposed to this, the MSG treatment gives support to NE effects, enhancing food intake, as well as plasma glucose and FFA levels. After NEO, plasma glucose increased only in the MSG group, while plasma FFA levels were elevated in the C rats. Taken together, the results obtained after MSG treatment point to a separate neural control of the hyperglycemic response and of the lipid mobilization when stimulated by central 2DG, NE or NEO administration. It seems likely that the excitatory neural pathway that controls lipid metabolism and is present in C rats was destroyed by the MSG treatment.

Stimulatory effect of n-octanoylated ghrelin on locomotor activity in the goldfish, Carassius auratus

Ghrelin is implicated in growth and feeding regulation in fish. The influence of ghrelin on behavior has not been well studied and the physiological role of des-fatty acid modification of this peptide is unclear. Therefore, the effects of intracerebroventricular (ICV) and intraperitoneal (IP) administration of synthetic n-octanoylated (acyl) goldfish ghrelin and des- n-octanoylated (des-acyl) ghrelin on locomotor and orexigenic activity in the goldfish were examined. ICV administration of acyl ghrelin at doses of 1 and 2 pmol/g body weight (BW) and IP administration at 16 pmol/g BW both induced significant increases in locomotor activity during for 45–60 min after treatment. Cumulative food intake was significantly increased by ICV injection of acyl ghrelin at doses of 1 and 2 pmol/g BW and IP injection at 8 and 16 pmol/g BW during the 60-min post-treatment observation period. In contrast, ICV and IP administration of des-acyl ghrelin produced no changes in locomotor and orexigenic activity. We also analyzed fasting-induced changes in the expression of ghrelin mRNA in the brain and intestine using a real-time PCR method. The level of ghrelin mRNA in the intestine, but not in the brain, obtained from fish fasted for 7 days was significantly higher than that in fish that had been fed normally. These results suggest that, in the goldfish, acyl ghrelin, but not des-acyl ghrelin, stimulates locomotor activity and enhances food intake via central and peripheral pathways.

Decreased intestinal glucose transport in the sgk3-knockout mouse

Xenopus oocyte coexpression experiments revealed the capacity of the serum- and glucocorticoid-inducible kinase isoform 3 (SGK3) to up-regulate a variety of transport systems including the sodium-dependent glucose transporter SGLT1. The present study explored the functional significance of SGK3-dependent regulation of intestinal transport. To this end, experiments were performed in gene targeted mice lacking functional sgk3 (sgk3(-/-)) and their wild type littermates (sgk3(+/+)). Oral food intake and fecal dry weight were significantly larger in sgk3(-/-) than in sgk3(+/+) mice. Glucose-induced current (I(g)) in Ussing chamber as a measure of Na(+) coupled glucose transport was significantly smaller in sgk3(-/-) than in sgk3(+/+) mouse jejunal segments. Fasting plasma glucose concentrations were significantly lower in sgk3(-/-) than in sgk3(+/+) mice. Intestinal electrogenic transport of phenylalanine, cysteine, glutamine and proline were not significantly different between sgk3(-/-) and sgk3(+/+) mice. In conclusion, SGK3 is required for adequate intestinal Na(+) coupled glucose transport and impaired glucose absorption may contribute to delayed growth and decreased plasma glucose concentrations of SGK3 deficient mice. The hypoglycemia might lead to enhanced food intake to compensate for impaired intestinal absorption.

Influence de la nutrition sur le sommeil et la vigilance

Numerous data suggest that food intake is able to influence sleep and wakefulness. The knowledge on the sleep physiology allows to formulate several hypothesis on the mechanisms involved in the relationship between diet and sleep. It has been observed that enhanced food intake increases sleep duration whereas a reduced food supply decreases sleep duration. Moreover, the nature of nutriment is able to influence wakefulness. A rich carbohydrate meal can decrease vigilance in a subject submitted to sleep deprivation whereas a protein diet can improve psychocognitive performances in such a situation. The physiological mechanisms suggested to explain the role of volume and nature of a meal are related with the role of nutriment on neuromediators metabolism or the hormonal changes induced by the feeding pattern. From a practical point of view the knowledge of the diet impact on sleep and wakefulness may be useful in the management of healthy subject and also of consequencies of metabolic diseases.

Subcutaneous Ghrelin Enhances Acute Food Intake in Malnourished Patients Who Receive Maintenance Peritoneal Dialysis

Anorexia and malnutrition confer significant morbidity and mortality to patients with end-stage kidney disease but are resistant to therapy. The aim of this study was to determine whether subcutaneous administration of ghrelin, an appetite-stimulating gut hormone, could enhance food intake in patients who are receiving maintenance peritoneal dialysis and have evidence of malnutrition. The principal outcome measure was energy intake during a measured study meal. Secondary outcome measures were BP and heart rate and 3-d food intake after intervention. Nine peritoneal dialysis patients with mild to moderate malnutrition (mean serum albumin 28.6 +/- 5.0 g/L, total cholesterol 4.4 +/- 0.6 mmol/L, subjective global assessment score of 5.7 +/- 1.7) were given subcutaneous ghrelin (3.6 nmol/kg) and saline placebo in a randomized, double-blind, crossover protocol. Administration of subcutaneous ghrelin significantly increased the group mean absolute energy intake, compared with placebo, during the study meal (690 +/- 190 versus 440 +/- 250 kcal; P = 0.0062). When expressed as proportional energy increase for each individual, ghrelin administration resulted in immediate doubling of energy intake (204 +/- 120 versus 100%; P = 0.0319). Administration of ghrelin maintained a nonsignificant increase in energy intake over 24 h after intervention (2009 +/- 669 versus 1579 +/- 330 kcal) and was not followed by subsequent underswing (1790 +/- 370 versus 1670 +/- 530 and 1880 +/- 390 versus 1830 +/- 530 kcal on days 2 and 3, respectively). Ghrelin administration resulted in a significant fall in mean arterial BP (P = 0.0030 by ANOVA). There were no significant adverse events during the study. Subcutaneous ghrelin administration enhances short-term food intake in dialysis patients with mild to moderate malnutrition.

Periplakin Interferes with G Protein Activation by the Melanin-concentrating Hormone Receptor-1 by Binding to the Proximal Segment of the Receptor C-terminal Tail

In mice genetic ablation of expression of either melanin-concentrating hormone or the melanin-concentrating hormone-1 receptor results in alterations in energy metabolism and a lean phenotype. There is thus great interest in the function and regulation of this receptor. Using the yeast two-hybrid system we identified an interaction of the actin- and intermediate filament-binding protein periplakin with the intracellular C-terminal tail of the melanin-concentrating hormone-1 receptor. Direct association of these proteins was verified in pull-down and coimmunoprecipitation experiments. Truncations and internal deletions delineated the site of interaction to a group of 11 amino acids proximal to transmembrane helix VII, which was distinct from the binding site for the melanin-concentrating hormone-1 receptor-interacting zinc finger protein. Immunohistochemistry demonstrated coexpression of periplakin with melanin-concentrating hormone-1 receptor in specific cells of the piriform cortex, amygdala, and other structures of the adult mouse brain. Coexpression of the melanin-concentrating hormone-1 receptor with periplakin in human embryonic kidney 293 cells did not prevent agonist-mediated internalization of the receptor but did interfere with binding of (35)S-labeled guanosine 5'-3-O-(thio)triphosphate ([(35)S]GTPgammaS) to the G protein Galpha(o1) and the elevation of [Ca(2+)](i). Coexpression of the receptor with the interacting zinc finger protein did not modulate receptor internalization or G protein activation. The interaction of periplakin with receptors was selective. Coexpression of periplakin with the IP prostanoid receptor did not result in coimmunoprecipitation nor interfere with agonist-mediated binding of [(35)S]GTPgammaS to the G protein Galpha(s). Periplakin is the first protein described to modify the capacity of the melanin-concentrating hormone-1 receptor to initiate signal transduction.