scholarly journals Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

2008 ◽  
Vol 295 (3) ◽  
pp. R799-R805 ◽  
Author(s):  
Abdelhak Mansouri ◽  
Susan Aja ◽  
Timothy H. Moran ◽  
Gabriele Ronnett ◽  
Francis P. Kuhajda ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Fatty Acid Synthase ◽  
Inhibitory Effect ◽  
Meal Size ◽  
Vagal Afferents ◽  
Low Doses ◽  
Carnitine Palmitoyl Transferase ◽  
Specific Manner ◽  
Vagal Afferent

Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyl-transferase-1, inhibits eating in mice and rats. Mechanisms involved in feeding inhibition after central C75 have been identified, but little is yet known about how systemic C75 might inhibit eating. One issue is whether intraperitoneal C75 reduces food intake in rats by influencing normal physiological controls of food intake or acts nonselectively, for example by eliciting illness or aversion. Another issue relates to whether intraperitoneal C75 acts centrally or, similar to some other peripheral metabolic controls of eating, activates abdominal vagal afferents to inhibit eating. To further address these questions, we investigated the effects of intraperitoneal C75 on spontaneous meal patterns and the formation of conditioned taste aversion (CTA). We also tested whether the eating inhibitory effect of intraperitoneal C75 is vagally mediated by testing rats after either total subdiaphragmatic vagotomy (TVX) or selective subdiaphragmatic vagal deafferentations (SDA). Intraperitoneal injection of 3.2 and 7.5 mg/kg of C75 significantly reduced food intake 3, 12, and 24 h after injection by reducing the number of meals without affecting meal size, whereas 15 mg/kg of C75 reduced both meal number and meal size. The two smaller doses of C75 failed to induce a CTA, but 15 mg/kg C75 did. The eating inhibitory effect of C75 was not diminished in either TVX or SDA rats. We conclude that intraperitoneal injections of low doses of C75 inhibit eating in a behaviorally specific manner and that this effect does not require abdominal vagal afferents.

NMDA channels control meal size via central vagal afferent terminals

2005 ◽  
Vol 289 (5) ◽  
pp. R1504-R1511 ◽  
Author(s):  
B. R. Gillespie ◽  
G. A. Burns ◽  
R. C. Ritter
Keyword(s):  
Food Intake ◽  
Ion Channel ◽  
Nmda Receptors ◽  
Higher Order ◽  
Meal Size ◽  
Vagal Afferents ◽  
Sucrose Intake ◽  
Mk 801 ◽  
Vagal Afferent ◽  
Afferent Terminals

The N-methyl-d-aspartate (NMDA) ion channel blocker MK-801 administered systemically or as a nanoliter injection into the nucleus of the solitary tract (NTS), increases meal size. Furthermore, we have observed that ablation of the NTS abolishes increased meal size following systemic injection of dizocilpine (MK-801) and that MK-801-induced increases in intake are attenuated in rats pretreated with capsaicin to destroy small, unmyelinated, primary afferent neurons. These findings led us to hypothesize that NMDA receptors on central vagal afferent terminals or on higher-order NTS neurons innervated by these vagal afferents might mediate increased food intake. To evaluate this hypothesis, we examined 15% sucrose intake after 50-nl MK-801 injections ipsilateral or contralateral to unilateral nodose ganglion removal (ganglionectomy). On the side contralateral to ganglionectomy, vagal afferent terminals would be intact and functional, whereas ipsilateral to ganglionectomy vagal afferent terminals would be absent. Three additional control preparations also were included: 1) sham ganglionectomy and 2) subnodose vagotomy either contralateral or ipsilateral to NTS cannula placement. We found that rats with subnodose vagotomies increased their sucrose intake after injections of MK-801 compared with saline, regardless of whether injections were made contralateral (12.6 ± 0.2 vs. 9.6 ± 0.3 ml) or ipsilateral (14.2 ± 0.6 vs. 9.7 ± 0.4 ml) to vagotomy. Rats with NTS cannula placements contralateral to nodose ganglionectomy also increased their intake after MK-801 (12.2 ± 0.9 and 9.2 ± 1.1 ml for MK-801 and saline, respectively). However, rats with placements ipsilateral to ganglionectomy did not respond to MK-801 (8.0 ± 0.5 ml) compared with saline (8.3 ± 0.4 ml). We conclude that central vagal afferent terminals are necessary for increased food intake in response to NMDA ion channel blockade. The function of central vagal afferent processes or the activity of higher-order NTS neurons driven by vagal afferents may be modulated by NMDA receptors to control meal size.

scholarly journals Pharmacological stimulation of brain carnitine palmitoyl-transferase-1 decreases food intake and body weight

2008 ◽  
Vol 294 (2) ◽  
pp. R352-R361 ◽  
Author(s):  
Susan Aja ◽  
Leslie E. Landree ◽  
Amy M. Kleman ◽  
Susan M. Medghalchi ◽  
Aravinda Vadlamudi ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Fatty Acid ◽  
Food Intake ◽  
Taste Aversion ◽  
Conditioned Taste Aversion ◽  
Fatty Acid Synthase ◽  
Intraperitoneal Administration ◽  
Carnitine Palmitoyl Transferase ◽  
Dose Dependent

Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1–56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.

scholarly journals 2-Deoxy-d-glucose, but not mercaptoacetate, increases food intake in decerebrate rats

2009 ◽  
Vol 297 (2) ◽  
pp. R382-R386 ◽  
Author(s):  
Rebecca A. Darling ◽  
Sue Ritter
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Food Consumption ◽  
Sensory Neurons ◽  
Glucose Utilization ◽  
Milk Intake ◽  
Acid Oxidation ◽  
Neural Pathways ◽  
Test Diet ◽  
Vagal Afferent

We examined food intake in chronically maintained decerebrate rats in response to two antimetabolic drugs known to stimulate food intake, 2-mercaptoacetate (MA) and 2-deoxy-d-glucose (2DG). MA reduces fatty acid oxidation, and 2DG reduces glucose utilization. Because previous work has shown that insulin-induced hypoglycemia increases food intake in decerebrate rats, we predicted that 2DG would have this same effect. MA-induced feeding requires vagal sensory neurons that terminate in the hindbrain. Cholecystokinin-induced suppression of feeding, which likewise requires vagal sensory neurons, has been shown to suppress food intake in decerebrate rats. Therefore, we predicted that MA's effects on feeding would also persist in decerebrate rats. In our experiments, the test diet (40% milk, diluted with water) was infused intraorally through a chronic cheek fistula. We found that sham controls consumed 258% and 230% of their baseline milk intake in response to 2DG and MA, respectively. Decerebrates consumed 239% of their baseline milk intake in response to 2DG, but did not increase their intake in response to MA. Because decerebration separates the hindbrain from the forebrain, these results indicate that 2DG-induced glucoprivation is capable of acting within the hindbrain to activate fundamental reflex circuitry for consummatory feeding responses, as shown previously for hypoglycemia. In contrast, MA affects food consumption only after forebrain processing of MA-induced vagal afferent signals and in the presence of intact ascending and descending neural pathways.

scholarly journals Deletion of GPR40 fatty acid receptor gene in mice blocks mercaptoacetate-induced feeding

2016 ◽  
Vol 310 (10) ◽  
pp. R968-R974 ◽  
Author(s):  
Ai-Jun Li ◽  
Michael F. Wiater ◽  
Qing Wang ◽  
Stephen Wank ◽  
Sue Ritter
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Receptor Gene ◽  
Treatment Groups ◽  
Metabolic Monitoring ◽  
Afferent Activation ◽  
Inhibit Food Intake ◽  
Vagal Afferent ◽  
Glucagon Like Peptide 1 ◽  
G Protein Coupled

Both increased and decreased fatty acid (FA) availability contribute to control of food intake. For example, it is well documented that intestinal FA reduces feeding by triggering enterondocrine secretion of satietogenic peptides, such as cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). In contrast, mechanisms by which decreased FA availability increase feeding are not well understood. Over the past three decades substantial research related to FA availability and increased feeding has involved use of the orexigenic compound mercaptoacetate (MA). Because MA reportedly inhibits FA oxidation, it has been assumed that reduced FA oxidation accounts for the orexigenic action of MA. Recently, however, we demonstrated that MA antagonizes G protein-coupled receptor 40 (GPR40), a membrane receptor for long and medium chain FA. We also demonstrated that, by antagonizing GPR40, MA inhibits GLP-1 secretion and attenuates vagal afferent activation by FA. Because both vagal afferent activation and GLP-1 inhibit food intake, we postulated that inhibition of GPR40 by MA might underlie the orexigenic action of MA. We tested this hypothesis using male and female GPR40 knockout (KO) and wild-type (WT) mice. Using several testing protocols, we found that MA increased feeding in WT, but not GPR40 KO mice, and that GPR40 KO mice gained more weight than WT on a high-fat diet. Metabolic monitoring after MA or saline injection in the absence of food did not reveal significant differences in respiratory quotient or energy expenditure between treatment groups or genotypes. These results support the hypothesis that MA stimulates food intake by blocking FA effects on GPR40.

scholarly journals The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

2011 ◽  
Vol 301 (5) ◽  
pp. R1479-R1485 ◽  
Author(s):  
Matthew R. Hayes ◽  
Scott E. Kanoski ◽  
Bart C. De Jonghe ◽  
Theresa M. Leichner ◽  
Amber L. Alhadeff ◽  
...  
Keyword(s):  
Food Intake ◽  
Vagal Afferents ◽  
Oral Glucose ◽  
Afferent Fibers ◽  
The Common ◽  
Vagal Afferent ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
And Control ◽  
Hepatic Branch

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9–39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7–36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

Regulation of food intake by metabolic fuels in white-crowned sparrows

1995 ◽  
Vol 269 (6) ◽  
pp. R1462-R1468 ◽  
Author(s):  
T. Boswell ◽  
R. D. Richardson ◽  
R. J. Seeley ◽  
M. Ramenofsky ◽  
J. C. Wingfield ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Carbohydrate Metabolism ◽  
Plasma Lipids ◽  
Migratory Birds ◽  
Low Doses ◽  
Fatty Acid Utilization ◽  
Increase Food Intake ◽  
Fat Stores ◽  
Higher Doses

Migratory birds rely on increased fat storage and fatty acid utilization to meet seasonal changes of energy expenditure and as a result increase food intake and fat stores before migration. To determine whether their feeding behavior is sensitive to carbohydrate and/or fatty acid utilization, white-crowned sparrows maintained on short daylength (9L15D) were injected intraperitoneally with 2-deoxy-D-glucose (2-DG) or 2,5-anhydro-D-mannitol (2,5-AM). Low doses of 2-DG (25 or 50 mg/kg) had no effect on food intake, and higher doses (100 or 300 mg/kg) significantly suppressed feeding after 1 and 2 h. No dose of 2-DG increased meal size. Similarly, low doses of 2,5-AM (25, 50, or 100 mg/kg) had no effect on food intake, and higher doses (300 and 600 mg/kg) significantly suppressed intake. These data suggest that decreased carbohydrate metabolism does not elicit feeding in this species. Importantly, these drugs, as well as insulin and glucagon, were demonstrated to increase plasma fatty acids as well as to decrease feeding. Injections of tributyrin (100, 300, 600, or 2,000 mg/kg i.p.) or glycerol (300, 450, and 600 mg/kg) also significantly suppressed 60-min and 120-min food intake dose dependently in these birds, and equimolar glucose (1,200 mg/kg) had no effect. We conclude that feeding by the white-crowned sparrow is unresponsive to manipulations of carbohydrate metabolism and is decreased after manipulations that increase plasma lipids.

scholarly journals Link between lipid metabolism and voluntary food intake in rainbow trout fed coconut oil rich in medium-chain TAG

2011 ◽  
Vol 107 (11) ◽  
pp. 1714-1725 ◽  
Author(s):  
A. Cláudia Figueiredo-Silva ◽  
Sadasivam Kaushik ◽  
Frédéric Terrier ◽  
Johan W. Schrama ◽  
Françoise Médale ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Rainbow Trout ◽  
Food Intake ◽  
Fatty Acid Synthase ◽  
Lipid Level ◽  
Coconut Oil ◽  
Mrna Levels ◽  
Medium Chain ◽  
Nutrient Utilisation ◽  
Voluntary Food Intake

We examined the long-term effect of feeding coconut oil (CO; rich in lauric acid, C12) on voluntary food intake and nutrient utilisation in rainbow trout (Oncorhynchus mykiss), with particular attention to the metabolic use (storage or oxidation) of ingested medium-chain TAG. Trout were fed for 15 weeks one of the four isoproteic diets containing fish oil (FO) or CO as fat source (FS), incorporated at 5 % (low fat, LF) or 15 % (high fat, HF). Fat level or FS did not modify food intake (g/kg0·8per d), despite higher intestinal cholecystokinin-T mRNA in trout fed the HF-FO diet. The HF diets relative to the LF ones induced higher growth and adiposity, whereas the replacements of FO by CO resulted in similar growth and adiposity. This, together with the substantial retention of C12 (57 % of intake), suggests the relatively low oxidation of ingested C12. The down-regulation of carnitine palmitoyl-transferase-1 (CPT-1) confirms the minor dependency of medium-chain fatty acids (MCFA) on CPT-1 to enter the mitochondria. However, MCFA did not up-regulate mitochondrial oxidation evaluated using hepatic hydroxyacyl-CoA dehydrogenase as a marker, in line with their high retention in body lipids. At a low lipid level, MCFA increased mRNA levels of fatty acid synthase, elongase and stearoyl-CoA desaturase in liver, showing the hepatic activation of fatty acid synthesis pathways by MCFA, reflected by increased 16 : 0, 18 : 0, 16 : 1, 18 : 1 body levels. The high capacity of trout to incorporate and transform C12, rather than to readily oxidise C12, contrasts with data in mammals and may explain the absence of a satiating effect of CO in rainbow trout.

scholarly journals Circadian Feeding Drive of Metabolic Activity in Adipose Tissue and not Hyperphagia Triggers Overweight in Mice: Is There a Role of the Pentose-Phosphate Pathway?

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 690-699 ◽  
Author(s):  
Paula Stucchi ◽  
Marta Gil-Ortega ◽  
Beatriz Merino ◽  
Rocío Guzmán-Ruiz ◽  
Victoria Cano ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Food Intake ◽  
Pentose Phosphate Pathway ◽  
Fatty Acid Synthase ◽  
Pentose Phosphate ◽  
Plasma Parameters ◽  
Dependent Protein Kinase ◽  
Dependent Protein

High-fat (HF) diets trigger an increase in adipose tissue and body weight (BW) and disordered eating behavior. Our study deals with the hypothesis that circadian distribution of energy intake is more relevant for BW dynamics than diet composition. Four-week-old mice were exposed for 8 wk to a HF diet and compared with animals receiving control chow. HF mice progressively increased BW, decreased the amount of nocturnal (1800–0900 h) calories (energy or food intake) (30%) and increased diurnal (0900–1800 h) caloric intake (energy or food intake), although total daily intake was identical between groups. Animals were killed at 3-h intervals and plasma insulin, leptin, corticosterone, glucose, and fatty acid levels quantified. Adipose tissue was weighed, and enzymatic activities integral to the pentose phosphate pathway (PPP) assayed in lumbar adipose tissue. Phosphorylated AMP-dependent protein kinase and fatty acid synthase were quantified by Western blotting. In HF mice, there was a shift in the circadian oscillations of plasma parameters together with an inhibition of PPP activity and a decrease in phosphorylated AMP-dependent protein kinase and fatty acid synthase. In a second experiment, HF mice were forced to adhere to a circadian pattern of food intake similar to that in control animals. In this case, BW, adipose tissue, morning plasma parameters and PPP activity appeared to be normal. These data indicate that disordered feeding behavior can trigger BW gain independently of food composition and daily energy intake. Because PPP is the main source of reduced nicotinamide adenine dinucleotide phosphate, we suggest that PPP inhibition might be an early marker of adipose dysfunction in diet-induced obesity.

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