Myrtha Arnold

Intrameal Hepatic Portal and Intraperitoneal Infusions of Glucagon-Like Peptide-1 Reduce Spontaneous Meal Size in the Rat via Different Mechanisms

Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2-3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain.

Gut Vagal Afferents Are Not Necessary for the Eating-Stimulatory Effect of Intraperitoneally Injected Ghrelin in the Rat

Ghrelin is unique among gut peptides in that its plasma level increases during fasts and its administration stimulates eating. Although ghrelin physiology has been intensively studied, whether its eating-stimulatory effect arises from endocrine-neural signal transduction at peripheral or central sites remains unresolved. To address this issue, we tested the effects of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method available, on ghrelin-induced eating. SDA was verified with a cholecystokinin satiation test, retrograde labeling of vagal motor neurons in the dorsal motor nucleus of the vagus with fluorogold, and anterograde labeling of vagal afferents in the nucleus tractus solitarius with wheat germ agglutinin-horseradish peroxidase. Intraperitoneal injections of 10–40 μg/kg ghrelin stimulated eating as robustly in rats with verified complete SDA as in sham-operated controls. Ghrelin also stimulated eating in rats with total subdiaphragmatic vagotomies. We also recorded the electrophysiological responses of gastric load-sensitive vagal afferent neurons to intravenous ghrelin. Ghrelin (10 nmol) phasically (0–30 s) increased activity in two of seven gastric load-sensitive fibers in the absence of gastric loads and tonically (5–30 min) increased activity in only one fiber. Ghrelin did not affect any of the eight fibers tested in the presence of 1–3 ml gastric loads. We conclude that although phasic increases in plasma ghrelin may affect the activity of a fraction of gastric load-sensitive vagal afferents, the acute eating-stimulatory effect of intraperitoneal ghrelin does not require vagal afferent signaling.

Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

UNLABELLED The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after i.p. delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 μg), attenuated the intake suppression by i.p. liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after i.p. delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4. CONCLUSION Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

Iron from nanocompounds containing iron and zinc is highly bioavailable in rats without tissue accumulation

Effective iron fortification of foods is difficult, because water-soluble compounds that are well absorbed, such as ferrous sulphate (FeSO(4)), often cause unacceptable changes in the colour or taste of foods. Poorly water-soluble compounds, on the other hand, cause fewer sensory changes, but are not well absorbed. Here, we show that poorly water-soluble nanosized Fe and Fe/Zn compounds (specific surface area approximately 190 m(2) g(-1)) made by scalable flame aerosol technology have in vivo iron bioavailability in rats comparable to FeSO(4) and cause less colour change in reactive food matrices than conventional iron fortificants. The addition of Zn to FePO(4) and Mg to Fe/Zn oxide increases Fe absorption from the compounds, and doping with Mg also improves their colour. After feeding rats with nanostructured iron-containing compounds, no stainable Fe was detected in their gut wall, gut-associated lymphatics or other tissues, suggesting no adverse effects. Nanosizing of poorly water-soluble Fe compounds sharply increases their absorption and nutritional value.

Melanocortin signaling in the CNS directly regulates circulating cholesterol

Cholesterol circulates in the blood in association with triglycerides and other lipids, and elevated blood low-density lipoprotein cholesterol carries a risk for metabolic and cardiovascular disorders, whereas high-density lipoprotein (HDL) cholesterol in the blood is thought to be beneficial. Circulating cholesterol is the balance among dietary cholesterol absorption, hepatic synthesis and secretion, and the metabolism of lipoproteins by various tissues. We found that the CNS is also an important regulator of cholesterol in rodents. Inhibiting the brains melanocortin system by pharmacological, genetic or endocrine mechanisms increased circulating HDL cholesterol by reducing its uptake by the liver independent of food intake or body weight. Our data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver.

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

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-1s glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1s 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.

Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia

Nutrient stimulation of enteroendocrine L cells induces the release of the incretin and satiating peptide glucagon-like peptide 1 (GLP-1). The vagus nerve innervates visceral organs and may contribute to the mediation of gut-derived GLP-1’s effects on food intake, energy homeostasis, and glycemic control. To test the hypothesis that vagal afferent neuron (VAN) GLP-1 receptors (GLP-1Rs) are necessary for these effects of endogenous GLP-1, we established a novel bilateral nodose ganglia injection technique to deliver a lentiviral vector and to knock down VAN GLP-1Rs in male Sprague Dawley rats. We found that a full expression of VAN GLP-1Rs is not necessary for the maintenance of long-term energy balance in normal eating conditions. VAN GLP-1R knockdown (kd) did, however, increase meal size and accelerated gastric emptying. Moreover, postmeal glycemia was elevated and insulin release was blunted in GLP-1R kd rats, suggesting that VAN GLP-1Rs are physiological contributors to the neuroincretin effect after a meal. Collectively, our results highlight a crucial role for the VANs in mediating the effects of endogenous GLP-1 on food intake and glycemia and may promote the further development of GLP-1–based therapies.

Regulation of Adipocyte Formation by GLP-1/GLP-1R Signaling

Background: Nutrient intake directly affects adipose tissue function and growth. Results: The gut peptide GLP-1 controls adipogenesis via its receptor through regulation of cell proliferation and apoptosis. Conclusion: GLP-1 is a signaling molecule from the intestine relating nutritional status to the adipose tissue. Significance: GLP-1 is used in treatment of type 2 diabetes, and regulation of adipose tissue mass might be one influencing factor. Increased nutrient intake leads to excessive adipose tissue accumulation, obesity, and the development of associated metabolic disorders. How the intestine signals to adipose tissue to adapt to increased nutrient intake, however, is still not completely understood. We show here, that the gut peptide GLP-1 or its long-lasting analog liraglutide, function as intestinally derived signals to induce adipocyte formation, both in vitro and in vivo. GLP-1 and liraglutide activate the GLP-1R, thereby promoting pre-adipocyte proliferation and inhibition of apoptosis. This is achieved at least partly through activation of ERK, PKC, and AKT signaling pathways. In contrast, loss of GLP-1R expression causes reduction in adipogenesis, through induction of apoptosis in pre-adipocytes, by inhibition of the above mentioned pathways. Because GLP-1 and liraglutide are used for the treatment of type 2 diabetes, these findings implicate GLP-1 as a regulator of adipogenesis, which could be an alternate pathway leading to improved lipid homeostasis and controlled downstream insulin signaling.

Effects of L-carnitine supplementation on physical performance and energy metabolism of endurance-trained athletes: a double-blind crossover field study.

A double-blind crossover field study was performed to investigate the effects of acute L-carnitine supplementation on metabolism and performance of endurance-trained athletes during and after a marathon run. Seven male subjects were given supplements of 2 g L-carnitine 2 h before the start of a marathon run and again after 20 km of the run. The plasma concentration of metabolites and hormones was analysed 1 h before, immediately after and 1 h after the run, as well as the next morning after the run. In addition, the respiratory exchange ratio (R) was determined before and at the end of the run, and a submaximal performance test was completed on a treadmill the morning after the run. The administration of L-carnitine was associated with a significant increase in the plasma concentration of all analysed carnitine fractions (i.e. free carnitine, short-chain acylcarnitine, long-chain acylcarnitine, total acid soluble carnitine, total carnitine) but caused no significant change in marathon running time, in R, in the plasma concentrations of carbohydrate metabolites (glucose, lactate, pyruvate), of fat metabolites (free fatty acids, glycerol, β-hydroxybutyrate), of hormones (insulin, glucagon, cortisol), and of enzyme activities (creatine kinase, lactate dehydrogenase). Moreover, there was no difference in the result of the submaximal performance test the morning after the run. In conclusion, acute administration of L-carnitine did not affect the metabolism or improve the physical performance of the endurance-trained athletes during the run and did not alter their recovery.

Dietary Fat Sensing via Fatty Acid Oxidation in Enterocytes - Possible Role in the Control of Eating

Various mechanisms detect the presence of dietary triacylglycerols (TAG) in the digestive tract and link TAG ingestion to the regulation of energy homeostasis. We here propose a novel sensing mechanism with the potential to encode dietary TAG-derived energy by translating enterocyte fatty acid oxidation (FAO) into vagal afferent signals controlling eating. Peripheral FAO has long been implicated in the control of eating (141). The prevailing view was that mercaptoacetate (MA) and other FAO inhibitors stimulate eating by modulating vagal afferent signaling from the liver. This concept has been challenged because hepatic parenchymal vagal afferent innervation is scarce and because experimentally induced changes in hepatic FAO often fail to affect eating. Nevertheless, intraperitoneally administered MA acts in the abdomen to stimulate eating because this effect was blocked by subdiaphragmatic vagal deafferentation (21), a surgical technique that eliminates all vagal afferents from the upper gut. These and other data support a role of the small intestine rather than the liver as a FAO sensor that can influence eating. After intrajejunal infusions, MA also stimulated eating in rats through vagal afferent signaling, and after infusion into the superior mesenteric artery, MA increased the activity of celiac vagal afferent fibers originating in the proximal small intestine. Also, pharmacological interference with TAG synthesis targeting the small intestine induced a metabolic profile indicative of increased FAO and inhibited eating in rats on a high-fat diet but not on chow. Finally, cell culture studies indicate that enterocytes oxidize fatty acids, which can be modified pharmacologically. Thus enterocytes may sense dietary TAG-derived fatty acids via FAO and influence eating through changes in intestinal vagal afferent activity. Further studies are necessary to identify the link between enterocyte FAO and vagal afferents and to examine the specificity and potential physiological relevance of such a mechanism.