Effect of injection of antisense oligodeoxynucleotides of GAD isozymes into rat ventromedial hypothalamus on food intake and locomotor activity

Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration.

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CCK-8 and CCK-58 differ in their effects on nocturnal solid meal pattern in undisturbed rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00365.2011 ◽

2012 ◽

Vol 303 (8) ◽

pp. R850-R860 ◽

Cited By ~ 13

Author(s):

Miriam Goebel-Stengel ◽

Andreas Stengel ◽

Lixin Wang ◽

Gordon Ohning ◽

Yvette Taché ◽

...

Keyword(s):

Locomotor Activity ◽

Food Intake ◽

Molecular Forms ◽

Reduce Food Intake ◽

Dark Phase ◽

Sprague Dawley ◽

Solid Meal ◽

Sprague Dawley Rats ◽

And Behavior

Various molecular forms of CCK reduce food intake in rats. Although CCK-8 is the most studied form, we reported that CCK-58 is the only detectable endocrine peptide form in rats. We investigated the dark-phase rat chow intake pattern following injection of CCK-8 and CCK-58. Ad libitum-fed male Sprague-Dawley rats were intraperitoneally injected with CCK-8, CCK-58 (0.6, 1.8, and 5.2 nmol/kg), or vehicle. Food intake pattern was assessed during the dark phase using an automated weighing system that allowed continuous undisturbed monitoring of physiological eating behavior. Both CCK-8 and CCK-58 dose dependently reduced 1-h, dark-phase food intake, with an equimolar dose of 1.8 nmol being similarly effective (−49% and −44%). CCK-58 increased the latency to the first meal, whereas CCK-8 did not. The intermeal interval was reduced after CCK-8 (1.8 nmol/kg, −41%) but not after CCK-58. At this dose, CCK-8 increased the satiety ratio by 80% and CCK-58 by 160%, respectively, compared with vehicle. When behavior was assessed manually, CCK-8 reduced locomotor activity (−31%), whereas grooming behavior was increased (+59%). CCK-58 affected neither grooming nor locomotor activity. In conclusion, reduction of food intake by CCK-8 and CCK-58 is achieved by differential modulation of food intake microstructure and behavior. These data highlight the importance of studying the molecular forms of peptides that exist in vivo in tissue and circulation of the animal being studied.

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Inhibition of Food Intake by Neuropeptide Y Y5 Receptor Antisense Oligodeoxynucleotides

Diabetes ◽

10.2337/diab.46.11.1792 ◽

1997 ◽

Vol 46 (11) ◽

pp. 1792-1798 ◽

Cited By ~ 86

Author(s):

A. O. Schaffhauser ◽

A. Stricker-Krongrad ◽

L. Brunner ◽

F. Cumin ◽

C. Gerald ◽

...

Keyword(s):

Food Intake ◽

Neuropeptide Y ◽

Antisense Oligodeoxynucleotides

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Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy

Endocrinology ◽

10.1210/en.2004-0338 ◽

2004 ◽

Vol 145 (8) ◽

pp. 3704-3711 ◽

Cited By ~ 98

Author(s):

S. R. Ladyman ◽

D. R. Grattan

Keyword(s):

Food Intake ◽

Arcuate Nucleus ◽

Ventromedial Hypothalamus ◽

Leptin Resistance ◽

Signal Transducer ◽

Pregnant Rats ◽

Hypothalamic Nuclei ◽

Stat3 Phosphorylation ◽

Vehicle Treatment ◽

Plasma Leptin

Abstract Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 μg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.

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Abstract MP17: Time Restricted Feeding Improves Cardiovascular Rhythms And Vascular Metabolism In Mice On A Chronic High Fat Diet

Hypertension ◽

10.1161/hyp.76.suppl_1.mp17 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Paramita Pati ◽

Dingguo Zhang ◽

Jackson Colson ◽

Shannon M Bailey ◽

Karen L Gamble ◽

...

Keyword(s):

Locomotor Activity ◽

Food Intake ◽

High Fat Diet ◽

Disease Risk ◽

Plasma Metabolites ◽

Diurnal Changes ◽

Restricted Feeding ◽

High Fat ◽

Inactive Period ◽

Cardiovascular Rhythms

Irregular timing of food intake increases hypertension and cardiometabolic disease risk. A chronic high fat diet (HFD) also disrupts circadian rhythms. We hypothesized that active period time restricted feeding (TRF) during the last 2 weeks in mice on a chronic HFD will improve blood pressure rhythm, diurnal variation of circulating plasma factors, and vascular metabolism. Mice (male 8-week old, C57BL/6J) were fed a normal diet (ND; 10% fat) or HFD (45% fat) for 20 weeks ad libitum. For the final 2 weeks, half of the HFD mice were subjected to TRF. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were assessed by telemetry. TRF significantly increased the active-inactive period difference in MAP and HR in in mice fed a HFD (ΔMAP: ND: 16±0.7 mmHg, HFD: 15±0.8 mmHg, HFD+TRF: 18±0.9 mmHg, n=6-8, p=0.01; ΔHR: ND: 68±5.1 bpm, HFD: 69±6.5 bpm, HFD+TRF: 113±7.9 bpm, n=6-8, p<0.01). Diurnal changes in locomotor activity are not different between groups. At the end of the study, plasma was collected at 4 hour intervals over a 24 hour period (ZT0 at 7AM; ZT12 at 7PM). Circulating levels of liver-derived mediators β-hydroxybutyrate (βHB) and insulin-like growth factor-1 (IGF-1) showed significant differences due to diet but not TRF (βHB, ZT21: ND: 0.16±0.01 mM, HFD: 0.20±0.02 mM, HFD+TRF: 0.19±0.01 mM, n=5-6, p=0.02; IGF-1, ZT5: ND: 232±18 ng/mL, HFD: 292±34 ng/mL , HFD+TRF: 371±14 ng/mL, n=5-6, p<0.01). Plasma leptin was significantly higher in mice on HFD and reduced by TRF at ZT12 (ND: 5.3±1.3 ng/mL, HFD: 22.5±2.9 ng/mL, HFD+TRF: 10.3±3.5ng/mL, n=5-6, p<0.01) and ZT17 (ND: 6.7±1.1 ng/mL, HFD: 32.5±3.0 ng/mL, HFD+TRF: 25.0±1.3 ng/mL, n=5-6, p<0.01). Plasma adiponectin was unchanged between all groups. TRF in HFD mice increased NAD + , important for metabolism, in renal vessels at ZT17 (HFD: 0.10±0.02 pmol/μg; HFD+TRF: 0.19±0.03 pmol/μg; n=5, p=0.03). Aortic NAD + at ZT1 was not affected by TRF in HFD mice (HFD: 1.83±0.35 pmol/μg, HFD+TRF: 1.35±0.35 pmol/μg, n=4, p=0.37). Our results indicate that TRF in mice on HFD increases the active-inactive period difference in MAP and HR and alters plasma metabolites, suggesting the timing of food intake on a chronic HFD improves cardiovascular rhythms with increased renal vascular metabolism and reduced leptin levels.

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Intraventricular but not intraparaventricular nucleus metergoline elicits feeding in satiated rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.5.r1562 ◽

1994 ◽

Vol 266 (5) ◽

pp. R1562-R1567 ◽

Cited By ~ 2

Author(s):

D. V. Coscina ◽

D. Feifel ◽

J. N. Nobrega ◽

P. J. Currie

Keyword(s):

Locomotor Activity ◽

Food Intake ◽

Total Dose ◽

Paraventricular Nucleus ◽

Dose Response ◽

Feeding Experiment ◽

High Potency ◽

Drug Doses ◽

Dose Response Study ◽

The Brain

Previous research has shown that systemic injections of the nonselective serotonin (5-HT) antagonist metergoline (MET) can stimulate feeding in both rats and humans. Five experiments were conducted to determine if this drug would elicit feeding in otherwise satiated rats after direct injections into the brain. In experiment 1, intraventricular infusions of 100 nmol MET produced reliable enhancements of feeding for 1 h compared with control infusions of a 5% tartaric acid (vehicle) solution. In experiment 2, a dose-response study of 0, 50, 100, and 150 nmol MET intraventricularly revealed that both 100 and 150 nmol doses reliably enhanced 1-h feeding, whereas 50 nmol did not. In experiment 3, tests of 90-min locomotor activity and water intake in the absence of food revealed that 100 nmol MET intraventricularly did not modify either behavior compared with vehicle infusions, suggesting a degree of feeding specificity to this effect. In an attempt to determine the site of intraventricular MET effects on feeding, experiment 4 tested 1-h feeding responses after 0, 5, 10, 20, 40, or 60 nmol MET were infused unilaterally into the paraventricular nucleus (PVN) of the hypothalamus. No reliable feeding was induced at any of these drug doses, although injections of 30 nmol norepinephrine (NE) were effective in doubling food intake. Experiment 5 further showed that bilateral infusions of 50 nmol MET in each PVN (total dose, 100 nmol) were ineffective in altering 1-h feeding. This contrasted markedly to the high potency of 15 nmol NE per site (total dose, 30 nmol), which elicited fivefold greater feeding than control infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

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Role of central melanocortins in endotoxin-induced anorexia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.3.r864 ◽

1999 ◽

Vol 276 (3) ◽

pp. R864-R871 ◽

Cited By ~ 17

Author(s):

Qin-Heng Huang ◽

Victor J. Hruby ◽

Jeffrey B. Tatro

Keyword(s):

Locomotor Activity ◽

Food Intake ◽

Acute Phase ◽

Acute Phase Response ◽

Phase Response ◽

Melanocortin Receptor ◽

Receptor Subtype ◽

Microbial Infection ◽

Melanocyte Stimulating Hormone ◽

The Central Nervous System

Inflammation and microbial infection produce symptoms, including fever, anorexia, and hypoactivity, that are thought to be mediated by endogenous proinflammatory cytokines. Melanocortins are known to act centrally to suppress effects on fever and other sequelae of proinflammatory cytokine actions in the central nervous system, but the roles of melanocortins in anorexia and hypoactivity occurring during the acute phase response are unknown. The present study was designed to determine the effects of exogenous and endogenous α-melanocyte stimulating hormone (α-MSH) on lipopolysaccharide (LPS)-induced anorexia in relation to their effects on fever. Rats were fasted overnight to promote feeding behavior, then injected intraperitoneally with LPS (100 μg/kg ip), followed 30 min later by intracerebroventricular injection of either α-MSH or the melanocortin receptor subtype 3/subtype 4 (MC3-R/MC4-R) antagonist SHU-9119. Food intake, locomotor activity, and body temperature (Tb) were monitored during the ensuing 24-h period. Each of two intracerebroventricular doses of α-MSH (30 and 300 ng) potentiated the suppressive effects of LPS on food intake and locomotion, despite the fact that the higher dose alleviated LPS-induced fever. In control rats that were not treated with LPS, only the higher dose of α-MSH significantly inhibited food intake, and Tband locomotor activity were unaffected. To assess the roles of endogenous central melanocortins, LPS-treated rats received intracerebroventricular SHU-9119 (200 ng). Central MC3-R/MC4-R blockade did not affect Tbor food intake in the absence of LPS treatment, but it reversed the LPS-induced reduction in 24-h food intake and increased LPS-induced fever without altering the LPS-induced suppression of locomotion. Taken together, the results suggest that exogenous and endogenous melanocortins acting centrally exert divergent influences on different aspects of the acute phase response, suppressing LPS-induced fever but contributing to LPS-induced anorexia and hypoactivity.

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Prior vagotomy blocks VMH obesity in pair-fed rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1981.240.5.e573 ◽

1981 ◽

Vol 240 (5) ◽

pp. E573-E583 ◽

Cited By ~ 4

Author(s):

J. E. Cox ◽

T. L. Powley

Keyword(s):

Food Intake ◽

Cell Loss ◽

Ventromedial Hypothalamus ◽

Motor Nucleus ◽

Previous Suggestion ◽

Hypothalamic Obesity ◽

Dorsal Motor Nucleus ◽

Gastric Contents ◽

Feeding Regimen ◽

Protein Output

Previously vagotomized, ventromedial hypothalamus (VMH)-lesioned rats and sham-lesioned controls were maintained on an intragastric pair-feeding regimen in which nonvagotomized VMH rats deposit excessive fat. Hypothalamic lesions were produced after 6 days of adaptation to pair feeding, and the experiment continued for 30 days postlesion. Extent of vagotomy was determined with a multiple-regression procedure with cell loss in the dorsal motor nucleus of the vagus, fasting gastric contents, and basal pancreatic protein output as predictor variables. The correlation was 0.95 between this set of indexes and the adequacy of a vagotomy for preventing hypothalamic obesity. Thus, radical vagotomies precluded the typical accumulation of significantly increased levels of carcass fat in lesioned animals (16.3 vs. 14.0% for controls). VMH rats with less extensive transections accumulated substantially more fat (25.9%). This outcome suggests that vagotomy produces a specific blockade of lesion-produced disturbances in metabolism leading to obesity. It fails to support a previous suggestion that vagal section blocks VMH obesity merely as a nonspecific surgical restriction of food intake because vagotomy was effective even though its effects on food intake could not operate.

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Obesity-inducing hypothalamic knife cuts: effects on lipolysis and blood insulin levels

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1982.243.3.r445 ◽

1982 ◽

Vol 243 (3) ◽

pp. R445-R449

Author(s):

G. A. Bray ◽

A. Sclafani ◽

D. Novin

Keyword(s):

Adipose Tissue ◽

Food Intake ◽

Plasma Insulin ◽

Ventromedial Hypothalamus ◽

Insulin Levels ◽

Blood Insulin ◽

Body Weights ◽

Glucose Plasma

The effect of two experimental manipulations designed to mobilize lipids from adipose tissue have been investigated in rats with parasagittal knife cuts in the ventromedial hypothalamus (VMH). Those animals which displayed hyperphagia during the initial 5 days VMH knife cuts were then restricted in food intake to reduce body weights to levels comparable to that of the sham-operated controls. Two weeks following the knife-cut lesions, or sham operations, animals in the first experiment were exposed to the cold for 60 min, and those in the second experiment were injected with 2-deoxy-D-glucose (2-DG). The injections of 2-DG increased the level of glycerol in the control animals but not in the animals with VMH knife cuts. Both groups showed a rise in glucose. Plasma insulin and triglycerides were the same in both groups. Exposure to the cold increased the level of glycerol in both groups. The insulin levels were lower in the corresponding groups with knife cuts. These studies show that VMH knife cuts do not produce hyperinsulinemia in pair-gained rats.

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