Iodination of CART(61-102) peptide: Preserved binding and anorexigenic activity in mice.

CART (cocaine- and amphetamine-regulated transcript) peptides are involved in food intake regulation, stress, and other physiological functions. Although CART peptides have been known for over 25 years, their receptor(s) have not yet been characterized. In this short review, we will summarize our previous studies, where we reported specific binding of 125 I-CART(61-102) to PC12 rat pheochromocytoma cells. Competitive binding experiments performed with mono- and di-iodinated peptides and their isoforms with oxidized Met67 resulted in nanomolar binding affinity. Moreover, in our previous study, CART(61-102), as well as di-iodinated CART(61-102), have shown a strong anorexigenic effect in fasted lean mice after intracerebroventricular administration. In conclusion, from our previous studies, iodination of CART(61-102) resulted in mono- and di-iodinated analogs with or without oxidized Met67 . All analogs revealed a high affinity to binding sites at PC12 cells and preserved biological activity.

The anorectic effect of central PYY1-36 treatment in rainbow trout (Oncorhynchus mykiss) is associated with changes in mRNAs encoding neuropeptides and parameters related to fatty acid sensing and metabolism.

We hypothesized that peptide YY (PYY) is involved in the metabolic regulation of food intake in fish. Therefore, we assessed in rainbow trout (Oncorhynchus mykiss) the effects of intracerebroventricular treatment with 10 ng/g PYY1-36 on food intake, expression of neuropeptides involved in food intake control, and the activity of fatty acid-sensing systems. The administration of PYY1-36 caused a significant reduction in food intake up to 24 h post-treatment. This anorectic action was associated with changes 2 h after treatment in mRNA abundance of neuropeptides involved in metabolic regulation of food intake in hypothalamus (decreased NPY and raised CART values) and hindbrain (increased POMCa1 values). We also observed that PYY1-36 treatment induced changes in mRNA abundance of parameters related to fatty acid sensing and metabolism in hypothalamus (decreased values of ACLY, PPARγ, and SREBP1c) and hindbrain (increased values of LPL, FAT/CD36, PPARα, PPARγ, and SREBP1c and decreased values of UCP2a). PYY1-36 treatment also increased mRNA abundance of mTOR. In general, it seems that mRNAs encoding some components of the machinery required for fatty acid sensing and metabolism are activated by PYY1-36. The response observed was higher in the hindbrain than in the hypothalamus, supporting the greater importance of this brain area in mediating the modulatory effects of gastrointestinal hormones on feeding regulation.

Characteristics and functionality of appetite-reducing thylakoid powders produced by three different drying processes.

BACKGROUND: Thylakoids, a chloroplast membrane extracted from green leaves, are a promising functional ingredient with appetite-reducing properties via their lipase-inhibiting effect. Thylakoids in powder form have been evaluated in animal and human models, but no comprehensive study has been conducted on powder characteristics. The aim was to investigate the effects of different isolation methods and drying techniques (drum-drying, spray-drying, freeze-drying) on thylakoids' physicochemical and functional properties. RESULTS: Freeze-drying yielded thylakoid powders with the highest lipase-inhibiting capacity. We hypothesize that the specific macromolecular structures involved in lipase inhibition were degraded to different degrees by exposure to heat during spray-drying and drum-drying. We identified lightness (Hunter's L-value), greenness (Hunter's a-value), chlorophyll content and emulsifying capacity to be correlated to lipase-inhibiting capacity. Thus, to optimize the thylakoids functional properties, the internal membrane structure indicated by retained green colour should be preserved. This opens possibilities to use chlorophyll content as a marker for thylakoid functionality in screening processes during process optimization. CONCLUSION: Thylakoids are heat sensitive, and a mild drying technique should be used in industrial production. Strong links between physicochemical parameters and lipase inhibition capacity were found that can be used to predict functionality. The approach from this study can be applied towards production of standardized high-quality functional food ingredients. © 2017 Society of Chemical Industry.

A potent neuromedin U receptor 2-selective alkylated peptide.

Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe19, Nle21, and Arg(Me)24] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity. Subcutaneous administration of 17 induced anorectic activity in C57BL/6J mice. Owing to its high metabolic stability, 17 would be useful in clarifying the physiological role and therapeutic application of NMU.

The role of 5-HT2c receptor on corticosterone-mediated food intake.

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.

Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin).

Food contamination by the trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) has the potential to adversely affect animal and human health by suppressing food intake and impairing growth. In mice, the DON-induced anorectic response results from aberrant satiety hormone secretion by enteroendocrine cells (EECs) of the gastrointestinal tract. Recent in vitro studies in the murine STC-1 EEC model have linked DON-induced satiety hormone secretion to activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor, and transient receptor potential ankyrin-1 (TRPA1), a TRP channel. However, it is unknown whether similar mechanisms mediate DON's anorectic effects in vivo. Here, we tested the hypothesis that DON-induced food refusal and satiety hormone release in the mouse are linked to activation of CaSR and TRPA1. Oral treatment with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate (AITC)) suppressed food intake in mice, and the agonist's effects were suppressed by pretreatment with corresponding antagonists NPS-2143 or ruthenium red (RR), respectively. Importantly, NPS-2143 or RR inhibited both DON-induced food refusal and plasma elevations of the satiety hormones cholecystokinin (CCK) and peptide YY3-36 (PYY3-36); cotreatment with both antagonists additively suppressed both anorectic and hormone responses to DON. Taken together, these in vivo data along with prior in vitro findings support the contention that activation of CaSR and TRPA1 contributes to DON-induced food refusal by mediating satiety hormone exocytosis from EEC.

Distinguishing rotamers in N-trifluoroacetyl-3-benzazepine derivatives.

This paper provides the full (13) C NMR assignments for the trifluoroacetamides of five potentially appetite-reducing 5-HT2C benzazepine receptor agonists and two open-ring synthetic precursors. These compounds exist in solution as mixtures of two rotamers for each of which the (13) C NMR signals have now been assigned with the assistance of 2D NMR experiments and the carbonyl-induced shifts of the neighboring (13) CH2 resonances and long-range (13) C/(19) F couplings.

Stabilities and structures of islet amyloid polypeptide (IAPP22-28) oligomers: from dimer to 16-mer.

BACKGROUND: The formation of amyloid fibrils is associated with many age-related degenerative diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. METHODS: Here, we performed MD simulations for the NFGAILS motif of hIAPP associated with the type II diabetes to estimate the stabilities of hIAPP22-28 protofibrils with different sizes: from 2 to 16 chains. In addition, to study the initial self-assembly stage, 4 and 8 IAPP22-28 chains in explicit solvent were also simulated. RESULTS: Our results indicate that the ordered protofibrils with no more than 16 hIAPP22-28 chains will be structurally stable in two layers, while one-layer or three-layer models are not stable as expected. Furthermore, the oligomerization simulations show that the initial coil structures of peptides can quickly aggregate and convert to partially ordered ß-sheet-rich oligomers. CONCLUSIONS: Based on the obtained results, we found that the stability of an IAPP22-28 oligomer was not only related with its size but also with its morphology. The driving forces to form and stabilize an oligomer are the hydrophobic effects and backbone H-bond interaction. Our simulations also indicate that IAPP22-28 peptides tend to form an antiparallel strand orientation within the sheet. GENERAL SIGNIFICANCE: Our finding can not only enhance the understanding about potential mechanisms of hIAPP nuclei formation and the extensive structural polymorphisms of oligomers, but also provide valuable information to develop potential ß-sheet formation inhibitors against type II diabetes.

GC-MS and LC-(high-resolution)-MS(n) studies on the metabolic fate and detectability of camfetamine in rat urine.

Camfetamine (N-methyl-3-phenyl-norbornan-2-amine; CFA) belongs as amphetamine-type stimulant to the so-called new psychoactive substances. CFA is an analogue of fencamfamine, an appetite suppressant developed in the 1960s. The described effects of CFA are slight stimulation and increased vigilance and the side effects are tachycardia, paranoia, and sleeplessness. The aims of the presented work were to study the metabolic fate and the detectability of CFA in urine and to elucidate which cytochrome-P450 (CYP) isoenzymes are involved in the main metabolic steps. For metabolism studies, rat urine samples were isolated by solid-phase extraction without and after enzymatic cleavage of conjugates. The phase I metabolites were separated and identified after/without acetylation by gas chromatography-mass spectrometry (GC-MS) and/or liquid chromatography-high resolution-linear ion trap mass spectrometry (LC-HR-MS(n)), respectively, and the phase II metabolites by LC-HR-MS(n). From the identified metabolites, the following main metabolic pathways were deduced: N-demethylation, aromatic mono or bis-hydroxylation followed by methylation of one hydroxy group, hydroxylation of the norbornane ring, combination of these steps, and glucuronidation and/or sulfation of the hydroxy metabolites. The N-demethylation was catalyzed by CYP2B6, CYP2C19, CYP2D6, and CYP3A4, the aromatic hydroxylation by CYP2C19 and CYP2D6, and the aliphatic hydroxylation was catalyzed by CYP1A2, CYP2B6, CYP2C19, and CYP3A4. Finally, the intake of a common user's dose of CFA could be confirmed in rat urine using the authors' GC-MS and the LC-MS(n) standard urine screening approaches via CFA and several metabolites, with the hydroxy-aryl CFA and the corresponding glucuronide being the most abundant.

Enzyme-linked immunoassay for simultaneous detection of methyl parathion and sibutramine in apple cider vinegar.

Methyl parathion, a highly toxic, efficient, and persistent organophosphorus pesticide, is widely used in China. Sibutramine, a non-amphetamine central nervous system depressant, helps lose weight by disrupting hormone regulation, stimulating sympathetic nerves, and suppressing appetite. However, some unethical businesses fail to properly handle raw materials in foods like apple cider vinegar, leading to residual methyl parathion in apples or illegal excessive addition of sibutramine. Therefore, it is imperative to develop an immunoassay for the rapid detection of methyl parathion and sibutramine. The corresponding two haptens were prepared and coupled with the carrier proteins according to methyl parathion-sulfur-bovine serum protein (BSA)/chicken ovalbumin (OVA)-sibutramine (20 : 1 : excess, 15 : 1 : excess, 10 : 1 : excess, and 5 : 1 : excess), and sibutramine-BSA/OVA-methyl parathion (20 : 1 : excess, 10 : 1 : excess: 5 : 1 : excess, and 0 : 1 : excess). The result shows that the inhibition rate of the antibody obtained by methyl parathion-BSA/OVA-sibutramine (20 : 1 : excess) was higher than that of sibutramine-BSA/OVA-methyl parathion, which was 67.93%, and the concentration of methyl parathion was 8.65 ng mL-1 at this inhibition rate. Thus, methyl parathion-BSA/OVA-sibutramine (8.65 : 1 : excess) and the corresponding antibodies were selected for subsequent method establishment. By changing the concentration of the coating and antibody, the inhibition rate was found when the coating was 0.125 ng mL-1 and the antibody was diluted 4000 times. The antibody was used to develop a standard curve for the detection of sibutramine at the half-maximum inhibitory concentration (IC50) is 4.59 ng mL-1, the limit of detection (IC10) is 2.21 ng mL-1, the detection range is 2.89 to 7.28 ng mL-1, methyl p-phosphorus at the half-maximum inhibitory concentration (IC50) is 15.34 ng mL-1, the limit of detection (IC10) is 0.42 ng mL-1, the detection range is ng mL-1. Under these conditions, the recovery rate was between 88% and 102%, within reasonable limits, indicating the successful establishment of a rapid enzyme-linked ELISA assay.

Dietary galacto-oligosaccharides and calcium: effects on energy intake, fat-pad weight and satiety-related, gastrointestinal hormones in rats.

Galacto-oligosaccharides (GOS) are carbohydrates that are fermented by colonic microbiota. The present study examined effects of a 3-week dietary enrichment with 6 % (w/w) GOS on parameters of energy balance in forty-three male Wistar rats. GOS was tested with two doses of calcium phosphate (30 and 100 mmol/kg), known to differently affect colonic fermentation. After 17 d, isoenergetic test meals were presented and plasma responses of ghrelin, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured. On day 21 (study termination) epididymal fat pads and caecum were weighed. Additionally, gastrointestinal mucosal samples and proximal colonic contents were analysed for gene expression (ghrelin, proglucagon and PYY) and fermentation metabolites (SCFA and lactate), respectively. GOS reduced energy intake most prominently during the first week, without provoking compensatory overeating later on (average intake reduction: 14 %). The GOS-fed rats showed increased caecal and reduced fat-pad weight and increased gene expression of the satiety-related peptides, PYY (1.7-fold) and proglucagon (3.5-fold). Pre-meal baseline and post-meal plasma levels of PYY, but not of ghrelin or GLP-1, were higher in GOS-fed rats than in control rats. Ca enrichment resulted in higher energy intake (average 4.5 %). GOS diets increased lactic acid levels and slightly reduced butyric acid in proximal colonic contents. Ca abolished the GOS-related elevation of lactic acid, while increasing propionic acid levels, but did not inhibit GOS-related effects on energy intake, fat-pad weight or gene expression. These results indicate that dietary GOS stimulate a number of physiological mechanisms that can reduce energy intake, regardless of the calcium phosphate content of the diet.

The effects of bulking, viscous and gel-forming dietary fibres on satiation.

The objective was to determine the effects of dietary fibre with bulking, viscous and gel-forming properties on satiation, and to identify the underlying mechanisms. We conducted a randomised crossover study with 121 men and women. Subjects were healthy, non-restrained eaters, aged 18-50 years and with normal BMI (18.5-25 kg/m²). Test products were cookies containing either: no added fibre (control), cellulose (bulking, 5 g/100 g), guar gum (viscous, 1.25 g/100 g and 2.5 g/100 g) or alginate (gel forming, 2.5 g/100 g and 5 g/100 g). Physico-chemical properties of the test products were confirmed in simulated upper gastrointestinal conditions. In a cinema setting, ad libitum intake of the test products was measured concurrently with oral exposure time per cookie by video recording. In a separate study with ten subjects, 4 h gastric emptying rate of a fixed amount of test products was assessed by ¹³C breath tests. Ad libitum energy intake was 22 % lower for the product with 5 g/100 g alginate (3.1 (sd 1.6) MJ) compared to control (4.0 (sd 2.2) MJ, P< 0.001). Intake of the other four products did not differ from control. Oral exposure time for the product with 5 g/100 g alginate (2.3 (sd 1.9) min) was 48 % longer than for control (1.6 (sd 0.9) min, P= 0.01). Gastric emptying of the 5 g/100 g alginate product was faster compared to control (P< 0.05). We concluded that the addition of 5 g/100 g alginate (i.e. gel-forming fibre) to a low-fibre cookie results in earlier satiation. This effect might be due to an increased oral exposure time.

A PEGylated analog of the gut hormone oxyntomodulin with long-lasting antihyperglycemic, insulinotropic and anorexigenic activity.

Peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor (GLP1R) are rapidly gaining favor as antidiabetic agents, since in addition to increasing glucose-dependent insulin secretion, they also cause weight loss. Oxyntomodulin (OXM), a natural peptide with sequence homology to both glucagon and GLP-1, has glucose-lowering activity in rodents and anorectic activity in rodents and humans, but its clinical utility is limited by a short circulatory half-life due to rapid renal clearance and degradation by dipeptidyl peptidase IV (DPP-IV). Here, we describe the development of a novel DPP-IV-resistant, long-acting GLP1R agonist, based on derivatization of a suitably chosen OXM analog with high molecular weight polyethylene glycol (PEG) ('PEGylation'). PEG-OXM exerts an anti-hyperglycemic effect in diet-induced obese (DIO) mice in a glucose-dependent manner, with a maximally efficacious dose of 0.1mg/kg, and reduces food intake and body weight with a minimally efficacious dose of 1mg/kg. If this pharmacology is recapitulated in patients with type 2 diabetes, these results indicate PEG-OXM as a potential novel once-weekly GLP-1 mimetic with both glucose-lowering activity and weight loss efficacy.

Combined effect of sesamin and α-lipoic acid on hepatic fatty acid metabolism in rats.

PURPOSE: Dietary sesamin (1:1 mixture of sesamin and episesamin) decreases fatty acid synthesis but increases fatty acid oxidation in rat liver. Dietary α-lipoic acid lowers hepatic fatty acid synthesis. These changes can account for the serum lipid-lowering effect of sesamin and α-lipoic acid. It is expected that the combination of these compounds in the diet potentially ameliorates lipid metabolism more than the individual compounds. We therefore studied the combined effect of sesamin and α-lipoic acid on lipid metabolism in rats. METHODS: Male Sprague-Dawley rats were fed diets supplemented with 0 or 2 g/kg sesamin and containing 0 or 2.5 g/kg α-lipoic acid for 22 days. RESULTS AND CONCLUSIONS: Sesamin and α-lipoic acid decreased serum lipid concentrations and the combination of these compounds further decreased the parameters in an additive fashion. These compounds reduced the hepatic concentration of triacylglycerol, the lignan being less effective in decreasing this value. The combination failed to cause a stronger decrease in hepatic triacylglycerol concentration. The combination of sesamin and α-lipoic acid decreased the activity and mRNA levels of hepatic lipogenic enzymes in an additive fashion. Sesamin strongly increased the parameters of hepatic fatty acid oxidation enzymes. α-Lipoic acid antagonized the stimulating effect of sesamin of fatty acid oxidation through reductions in the activity of some fatty acid oxidation enzymes and carnitine concentration in the liver. This may account for the failure to observe strong reductions in hepatic triacylglycerol concentration in rats given a diet containing both sesamin and α-lipoic acid.

Differential pharmacologic properties of the two C75 enantiomers: (+)-C75 is a strong anorectic drug; (-)-C75 has antitumor activity.

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identifying it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential different biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that (-)-C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Adrenergic metabolic and hemodynamic effects of octopamine in the liver.

The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate), as revealed by the increase in ¹4CO2 production derived from ¹4C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the ß-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.

Studies on the anorectic effect of N-acylphosphatidylethanolamine and phosphatidylethanolamine in mice.

N-acyl-phosphatidylethanolamine is a precursor phospholipid for anandamide, oleoylethanolamide, and other N-acylethanolamines, and it may in itself have biological functions in cell membranes. Recently, N-palmitoyl-phosphatidylethanolamine (NAPE) has been reported to function as an anorectic hormone secreted from the gut and acting on the brain (Gillum et al., [5]). In the current study, two of our laboratories independently investigated whether NAPE metabolites may be involved in mediating the anorectic action of NAPE i.p. injected in mice. Thus, the anorectic activity of a non-hydrolysable NAPE analogue, having ether bonds instead of ester bonds at sn1 and sn2 was compared with that of NAPE in molar equivalent doses. Furthermore, the anorectic effect of NAPE in NAPE-hydrolysing phospholipase D knockout animals was investigated. As negative controls, the NAPE precursor phosphatidylethanolamine and the related phospholipids phosphatidylcholine and phosphatidic acid were also tested. All compounds except one were found to inhibit food intake, raising the possibility that the effect of NAPE is non-specific.

The return of rainbow diet pills.

The US Food and Drug Administration (FDA) has recently warned consumers about the risks of weight loss supplements adulterated with multiple pharmaceutical agents. Some of these supplements combine potent anorectics, such as amphetamines derivatives, with benzodiazepines, beta-blockers, and other medications to suppress the anorectics' adverse effects. These weight loss supplements represent the most recent generation of rainbow diet pills, named for their bright and varied colors, which date back more than 70 years. Beginning in the 1940s, several US pharmaceutical firms aggressively promoted rainbow pills to physicians and patients. By the 1960s the pills had caused dozens of deaths before the FDA began removing them from the US market. We used a variety of original resources to trace these deadly pills from their origins in the United States to their popularity in Spain and Brazil to their reintroduction to the United States as weight loss dietary supplements.

Contrasting effects of different cannabinoid receptor ligands on mouse ingestive behaviour.

This study characterized the effects of seven diverse cannabinoid receptor agonists (and one antagonist) on ingestive behaviour in nondeprived adult, male CD1 mice. Microstructural analysis of licking for a range of concentrations of condensed milk (10, 15 and 20%) was carried out following administration of vehicle or: Δ9-tetrahydrocannabinol (Δ9-THC) at 1, 3 or 6 mg/kg; CP55,940 at 10, 30 or 50 µg/kg; Win 55,212-2 at 0.5, 1 or 3 mg/kg; HU-210 at 0.01, 0.03 or 0.1 mg/kg; methanandamide at 1, 3 or 6 mg/kg; arachidonyl-2'-chloroethylamide at 1, 3 or 6 mg/kg and JWH133 at 1, 3 or 6 mg/kg. The cannabinoid receptor antagonist/inverse agonist rimonabant was also tested at 0.3, 1 or 3 mg/kg. Test sessions comprised three 30 s presentations of the milk concentrations separated by 10 s interpresentation intervals. The nonselective CB1 receptor agonists Δ9-THC, CP55,940 and Win 55,212-2 increased the number of licks for condensed milk, primarily by a significant increase in bout number. The potent and nonselective CB1 receptor agonist HU-210 and the selective CB1 receptor agonists methanandamide and arachidonyl-2'-chloroethylamide did not significantly affect licking behaviour but did significantly increase the latency to start licking. The CB1 receptor antagonist rimonabant produced effects that were opposite in direction to those produced by Δ9-THC, CP55,940 and Win 55,212-2. Finally, the selective CB2 receptor agonist JWH133 had no significant effects on behaviour. These data add to reports that cannabinoid agonists can enhance the appetitive aspects of feeding, but they also demonstrate that not all CB1 receptor agonists do this, and therefore the relationship between action at CB1 receptors and appetitive feeding effects is not straightforward.

Effect of different long-chain fatty acids on cholecystokinin release in vitro and energy intake in free-living healthy males.

Long-chain fatty acids have been shown to suppress appetite and reduce energy intake (EI) by stimulating the release of gastrointestinal hormones such as cholecystokinin (CCK). The effect of NEFA acyl chain length on these parameters is not comprehensively understood. An in vitro screen tested the capacity of individual NEFA (C12 to C22) to trigger CCK release. There was a gradient in CCK release with increasing chain length. DHA (C22) stimulated significantly (P < 0.01) more CCK release than all other NEFA tested. Subsequently, we conducted a randomised, controlled, crossover intervention study using healthy males (n 18). The effects of no treatment (NT) and oral doses of emulsified DHA-rich (DHA) and oleic acid (OA)-rich oils were compared using 24 h EI as the primary endpoint. Participants reported significantly (P = 0.039) lower total daily EI (29 % reduction) with DHA compared to NT. There were no differences between DHA compared to OA and OA compared to NT. There was no between-treatment difference in the time to, or EI of, the first post-intervention eating occasion. It is concluded that NEFA stimulate CCK release in a chain length-dependent manner up to C22. These effects may be extended to the in vivo setting, as a DHA-based emulsion significantly reduced short-term EI.