Metabolic inhibitors synergistically decrease hepatic energy status and increase food intake

2000 ◽  
Vol 278 (6) ◽  
pp. R1579-R1582 ◽  
Author(s):  
Hong Ji ◽  
Grazyna Graczyk-Milbrandt ◽  
Mark I. Friedman
Keyword(s):  
Food Intake ◽  
Synergistic Effect ◽  
Feeding Behavior ◽  
Combined Treatment ◽  
Metabolic Inhibitors ◽  
Metabolic Inhibitor ◽  
Atp Content ◽  
Energy Status ◽  
Increase Food Intake ◽  
The Common

Previous studies indicate that administration of the metabolic inhibitor, 2,5-anhydro-d-mannitol (2,5-AM) or methyl palmoxirate (MP), induces feeding behavior in rats by lowering hepatic energy status. Combined treatment with these agents synergistically increases food intake. The present study was designed to investigate whether combined treatment also has a synergistic effect on hepatic energy status. Rats treated with both inhibitors increased feeding behavior compared with the controls, whereas those treated with 2,5-AM or MP alone did not. Although 2,5-AM alone lowered hepatic ATP content regardless of MP treatment, only the combination resulted in decreases in hepatic ATP/ADP ratio and phosphorylation potential. MP treatment did not affect the uptake of 2,5-AM into liver. These results suggest that a reduction in hepatic energy status is the common triggering signal for eating behavior induced by 2,5-AM and MP and provide additional evidence for an integrated metabolic control of food intake.

Neural substrate for an integrated metabolic control of feeding behavior

1999 ◽  
Vol 276 (1) ◽  
pp. R113-R119 ◽  
Author(s):  
Charles C. Horn ◽  
Aleymayehu Addis ◽  
Mark I. Friedman
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Metabolic Control ◽  
Area Postrema ◽  
Integrated Control ◽  
Combined Treatment ◽  
Brain Regions ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Neural Substrate

Evidence indicates that feeding behavior in rats is controlled by a mechanism that integrates information about different aspects of fuel metabolism. We investigated the neural substrate for this integrated control by measuring the effect of metabolic inhibitors given alone and in combination on food intake and neuronal activity as reflected by the expression of c-Fos protein. Combined administration of methyl palmoxirate (5 mg/kg po), an inhibitor of fatty acid oxidation, and 2,5-anhydro-d-mannitol (150 mg/kg ip), which decreases liver ATP content, increased feeding in rats more than expected on the basis of eating responses after treatment with either inhibitor given alone. Combined treatment also produced a synergistic increase in Fos-like immunoreactivity in several brain areas, including the nucleus of the solitary tract, area postrema, and parvocellular portion of the hypothalamic paraventricular nucleus. These findings provide strong evidence for the involvement of selected brain regions in the metabolic control of food intake and suggest that metabolic information used to control feeding behavior is integrated in the periphery or at the level of the brain stem.

High-fat diet prevents eating response and attenuates liver ATP decline in rats given 2,5-anhydro-d-mannitol

2002 ◽  
Vol 282 (3) ◽  
pp. R710-R714 ◽  
Author(s):  
Mark I. Friedman ◽  
James E. Koch ◽  
Grazyna Graczyk-Milbrandt ◽  
Patricia M. Ulrich ◽  
Mary D. Osbakken
Keyword(s):  
Food Intake ◽  
High Fat Diet ◽  
Acid Oxidation ◽  
Atp Content ◽  
Energy Status ◽  
High Fat ◽  
Low Fat ◽  
Low Fat Diet ◽  
Increase Food Intake

Administration of the fructose analog 2,5-anhydro-d-mannitol (2,5-AM) stimulates eating in rats fed a low-fat diet but not in those fed a high-fat diet that enhances fatty acid oxidation. The eating response to 2,5-AM treatment is apparently triggered by a decrease in liver ATP content. To assess whether feeding a high-fat diet prevents the eating response to 2,5-AM by attenuating the decrease in liver ATP, we examined the effects of the analog on food intake, liver ATP content, and hepatic phosphate metabolism [using in vivo 31P-NMR spectroscopy (NMRS)]. Injection (intraperitoneal) of 300 mg/kg 2,5-AM increased food intake in rats fed a high-carbohydrate/low-fat diet, but not in those fed high-fat/low-carbohydrate (HF/LC) food. Liver ATP content decreased in all rats given 2,5-AM compared with saline, but it decreased about half as much in rats fed the HF/LC diet. NMRS on livers of anesthetized rats indicated that feeding the HF/LC diet attenuates the effects of 2,5-AM on liver ATP by reducing phosphate trapping. These results suggest that rats consuming a high-fat diet do not increase food intake after injection of 2,5-AM, because the analog is not sufficiently phosphorylated and therefore fails to decrease liver energy status below a level that generates a signal to eat.

scholarly journals Inhibition of Hypothalamic MCT4 and MCT1–MCT4 Expressions Affects Food Intake and Alters Orexigenic and Anorexigenic Neuropeptide Expressions

2019 ◽  
Vol 57 (2) ◽  
pp. 896-909 ◽  
Author(s):  
Roberto Elizondo-Vega ◽  
Karina Oyarce ◽  
Magdiel Salgado ◽  
María José Barahona ◽  
Antonia Recabal ◽  
...  
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Arcuate Nucleus ◽  
Third Ventricle ◽  
Monocarboxylate Transporters ◽  
Energy Status ◽  
Eating Rate ◽  
Behavior Regulation ◽  
Cellular Processes ◽  
Complex Process

Abstract Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1–MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.

Fatty acid oxidation affects food intake by altering hepatic energy status

1999 ◽  
Vol 276 (4) ◽  
pp. R1046-R1053 ◽  
Author(s):  
Mark I. Friedman ◽  
Ruth B. Harris ◽  
Hong Ji ◽  
Israel Ramirez ◽  
Michael G. Tordoff
Keyword(s):  
Fatty Acid ◽  
Food Intake ◽  
Feeding Behavior ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Energy Status ◽  
Hepatic Fatty Acid ◽  
Hepatic Fatty Acid Oxidation

Inhibition of fatty acid oxidation stimulates feeding behavior in rats. To determine whether a decrease in hepatic fatty acid oxidation triggers this behavioral response, we compared the effects of different doses of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, on food intake with those on in vivo and in vitro liver and muscle metabolism. Administration of 1 mg/kg MP selectively decreased hepatic fatty acid oxidation but did not stimulate food intake. In contrast, feeding behavior increased in rats given 5 or 10 mg/kg MP, which inhibited hepatic fatty acid oxidation to the same extent as did the low dose but in addition suppressed fatty acid oxidation in muscle and produced a marked depletion of liver glycogen. Dose-related increases in food intake tracked dose-related reductions in liver ATP content, ATP-to-ADP ratio, and phosphorylation potential. The findings suggest that a decrease in hepatic fatty acid oxidation can stimulate feeding behavior by reducing hepatic energy production.

2,5-anhydro-D-mannitol acts in liver to initiate feeding

1991 ◽  
Vol 261 (2) ◽  
pp. R283-R288 ◽  
Author(s):  
M. G. Tordoff ◽  
N. Rawson ◽  
M. I. Friedman
Keyword(s):  
Food Intake ◽  
Vagus Nerve ◽  
Feeding Behavior ◽  
Low Doses ◽  
Increase Food Intake ◽  
Hepatic Portal ◽  
The Brain

We determined the site at which the fructose analogue 2,5-anhydro-D-mannitol (2,5-AM) acts to increase food intake in rats. Rats began eating sooner and ate more food during hepatic portal than during jugular infusions of 2,5-AM (50, 100, or 150 mg/h). After rats were intubated with 2,5-[14C]AM (1.15 microCi in 200 mg/kg), significant quantities of radioactivity were found in liver but not in brain. Hepatic vagotomy prevented the eating response to 200 mg/kg 2,5-AM without altering the effect of the analogue on plasma fuels. These results indicate that low doses of 2,5-AM act in the liver to increase food intake and suggest that the signal for feeding generated in the liver is transmitted to the brain through the hepatic vagus nerve. Taken together, this work provides the strongest evidence to date that a signal initiating feeding behavior originates in the liver.

scholarly journals Energy Status Differentially Modifies Feeding Behavior and POMCARC Neuron Activity After Acute Treadmill Exercise in Untrained Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Taylor Landry ◽  
Daniel Shookster ◽  
Alec Chaves ◽  
Katrina Free ◽  
Tony Nguyen ◽  
...  
Keyword(s):  
Tyrosine Hydroxylase ◽  
Food Intake ◽  
Feeding Behavior ◽  
Exercise Intensity ◽  
High Intensity ◽  
Treadmill Exercise ◽  
High Intensity Exercise ◽  
Neuron Activity ◽  
Energy Status ◽  
Post Exercise

Emerging evidence identifies a potent role for aerobic exercise to modulate activity of neurons involved in regulating appetite; however, these studies produce conflicting results. These discrepancies may be, in part, due to methodological differences, including differences in exercise intensity and pre-exercise energy status. Consequently, the current study utilized a translational, well-controlled, within-subject, treadmill exercise protocol to investigate the differential effects of energy status and exercise intensity on post-exercise feeding behavior and appetite-controlling neurons in the hypothalamus. Mature, untrained male mice were exposed to acute sedentary, low (10m/min), moderate (14m/min), and high (18m/min) intensity treadmill exercise in a randomized crossover design. Fed and 10-hour-fasted mice were used, and food intake was monitored 48h. post-exercise. Immunohistochemical detection of cFOS was performed 1-hour post-exercise to determine changes in hypothalamic NPY/AgRP, POMC, tyrosine hydroxylase, and SIM1-expressing neuron activity concurrent with changes in food intake. Additionally, stains for pSTAT3tyr705 and pERKthr202/tyr204 were performed to detect exercise-mediated changes in intracellular signaling. Results demonstrated that fasted high intensity exercise suppressed food intake compared to sedentary trials, which was concurrent with increased anorexigenic POMC neuron activity. Conversely, fed mice experienced augmented post-exercise food intake, with no effects on POMC neuron activity. Regardless of pre-exercise energy status, tyrosine hydroxylase and SIM1 neuron activity in the paraventricular nucleus was elevated, as well as NPY/AgRP neuron activity in the arcuate nucleus. Notably, these neuronal changes were independent from changes in pSTAT3tyr705 and pERKthr202/tyr204 signaling. Overall, these results suggest fasted high intensity exercise may be beneficial for suppressing food intake, possibly due to hypothalamic POMC neuron excitation. Furthermore, this study identifies a novel role for pre-exercise energy status to differentially modify post-exercise feeding behavior and hypothalamic neuron activity, which may explain the inconsistent results from studies investigating exercise as a weight loss intervention.

scholarly journals Role of Neuronal Energy Status in the Regulation of Adenosine 5′-Monophosphate-Activated Protein Kinase, Orexigenic Neuropeptides Expression, and Feeding Behavior

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 3-10 ◽  
Author(s):  
Kichoon Lee ◽  
Bing Li ◽  
Xiaochun Xi ◽  
Yeunsu Suh ◽  
Roy J. Martin
Keyword(s):  
Protein Kinase ◽  
Food Intake ◽  
Feeding Behavior ◽  
High Glucose ◽  
Ex Vivo ◽  
Nutrient Sensing ◽  
Central Administration ◽  
Energy Status ◽  
Low Glucose

Nutrient sensing in the hypothalamus is tightly related to food intake regulation. However, the mechanisms by which the nutrient-sensing cells of the brain translate this signal of energy need into feeding behavior via regulation of neuropeptide expression are not known. To address this issue, we investigated two neuronal cell lines expressing agouti-related protein (AgRP), ex vivo hypothalamic tissues, and in vivo whole animals. Maintaining cells in a low cellular ATP concentration generated by low glucose, 2-deoxyglucose (2-DG), ATP synthesis inhibitor, and 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside increased phosphorylation of AMP-activated protein kinase (AMPK) and increased AgRP expression, whereas maintaining cells in high ATP status by high glucose and pyruvate supplementation in 2-DG-treated cells decreased phosphorylation of AMPK and decreased AgRP expression. Overexpression of a dominant-inhibitory mutant of AMPK significantly decreased low-glucose- or 2-DG-induced AgRP expression. Furthermore, ex vivo hypothalamus culture in high glucose concentrations decreased both expression and phosphorylation of AMPK and expression of both AgRP and neuropeptide Y, whereas pyruvate supplementation suppressed a 2-DG-induced AgRP expression. Finally, our in vivo studies clearly show that central administration of pyruvate dramatically delayed 2-DG-induced food intake. These data indicate that modulation of ATP levels in neuronal cells triggers a cascade of events via AMPK that modulate feeding behavior to restore energy status of cells.

Effects of neurosecretory protein GL on food intake and fat accumulation under different dietary nutrient compositions in rats

2021 ◽  
Author(s):  
Keisuke Fukumura ◽  
Kenshiro Shikano ◽  
Yuaki Narimatsu ◽  
Eiko Iwakoshi-Ukena ◽  
Megumi Furumitsu ◽  
...  
Keyword(s):  
Food Intake ◽  
Feeding Behavior ◽  
Body Mass ◽  
Mass Gain ◽  
Chow Diet ◽  
Tissue Mass ◽  
Fat Accumulation ◽  
Intracerebroventricular Infusion ◽  
Body Mass Gain ◽  
Sucrose Diet

Abstract We recently identified a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), which is involved in energy homeostasis in birds and mammals. However, whether the action of NPGL is influenced by nutritional composition remains unknown. Thus, we investigated the effect of chronic intracerebroventricular infusion of NPGL for 13 days on feeding behavior and body mass gain under a normal chow diet (NC), high-fat diet, high-sucrose diet (HSD), and medium-fat/medium-sucrose diet (MFSD) in rats. NPGL stimulated food intake of NC and MFSD, especially during the light period. By contrast, NPGL decreased body mass gain under NC and increased total white adipose tissue mass in HSD- and MFSD-fed rats. These data suggest that the effects of NPGL on feeding behavior, body mass gain, and fat accumulation depend on nutrient type. Among them, sucrose in diets seems to contribute to fat accumulation elicited by NPGL.

scholarly journals Central administration of sodium-glucose cotransporter-2 inhibitors increases food intake involving adenosine monophosphate-activated protein kinase phosphorylation in the lateral hypothalamus in healthy rats

2021 ◽  
Vol 9 (1) ◽  
pp. e002104
Author(s):  
Kenji Takeda ◽  
Hiraku Ono ◽  
Ko Ishikawa ◽  
Tomohiro Ohno ◽  
Jin Kumagai ◽  
...  
Keyword(s):  
Food Intake ◽  
Lateral Hypothalamus ◽  
Molecular Mechanisms ◽  
Intraperitoneal Administration ◽  
Adenosine Monophosphate ◽  
Sglt2 Inhibitors ◽  
Central Administration ◽  
Hypothalamic Area ◽  
Sodium Glucose Cotransporter ◽  
Increase Food Intake

IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

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