Genetic Deletion of Rheb1 in the Brain Reduces Food Intake and Causes Hypoglycemia with Altered Peripheral Metabolism

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

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A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation

Science Advances ◽

10.1126/sciadv.abf8719 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabf8719

Author(s):

Yong Han ◽

Guobin Xia ◽

Yanlin He ◽

Yang He ◽

Monica Farias ◽

...

Keyword(s):

Weight Gain ◽

Food Intake ◽

Neural Circuit ◽

Neural Circuitry ◽

Dynamic Regulation ◽

Satiety Response ◽

Food Satiation ◽

Lateral Parabrachial Nucleus ◽

Genetic Deletion ◽

Feeding Bout

The neural circuitry mechanism that underlies dopaminergic (DA) control of innate feeding behavior is largely uncharacterized. Here, we identified a subpopulation of DA neurons situated in the caudal ventral tegmental area (cVTA) directly innervating DRD1-expressing neurons within the lateral parabrachial nucleus (LPBN). This neural circuit potently suppresses food intake via enhanced satiation response. Notably, this cohort of DAcVTA neurons is activated immediately before the cessation of each feeding bout. Acute inhibition of these DA neurons before bout termination substantially suppresses satiety and prolongs the consummatory feeding. Activation of postsynaptic DRD1LPBN neurons inhibits feeding, whereas genetic deletion of Drd1 within the LPBN causes robust increase in food intake and subsequent weight gain. Furthermore, the DRD1LPBN signaling manifests the central mechanism in methylphenidate-induced hypophagia. In conclusion, our study illuminates a hindbrain DAergic circuit that controls feeding through dynamic regulation in satiety response and meal structure.

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Atypical antipsychotics and the neural regulation of food intake and peripheral metabolism

Physiology & Behavior ◽

10.1016/j.physbeh.2011.05.033 ◽

2011 ◽

Vol 104 (4) ◽

pp. 590-598 ◽

Cited By ~ 33

Author(s):

Karen L. Teff ◽

Sangwon F. Kim

Keyword(s):

Food Intake ◽

Atypical Antipsychotics ◽

Neural Regulation ◽

Peripheral Metabolism

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Development of Regulation of Food Intake by the Gut and the Brain: Modeling in Animals

Handbook of Behavior, Food and Nutrition ◽

10.1007/978-0-387-92271-3_26 ◽

2011 ◽

pp. 387-403

Author(s):

Takashi Higuchi ◽

Chuma O. Okere

Keyword(s):

Food Intake ◽

Brain Modeling ◽

The Brain

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Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.3.r481 ◽

1993 ◽

Vol 265 (3) ◽

pp. R481-R486 ◽

Cited By ~ 5

Author(s):

Y. Hirosue ◽

A. Inui ◽

A. Teranishi ◽

M. Miura ◽

M. Nakajima ◽

...

Keyword(s):

Food Intake ◽

Receptor Antagonist ◽

Rank Order ◽

Peripheral Circulation ◽

Inhibitory Effect ◽

Peripheral Tissues ◽

Cholecystokinin Octapeptide ◽

The Central Nervous System ◽

The Difference ◽

The Brain

To examine the mechanism of the satiety-producing effect of cholecystokinin (CCK) in the central nervous system, we compared the potency of intraperitoneally (ip) or intracerebroventricularly (icv) administered CCK-8 and its analogues on food intake in fasted mice. The icv administration of a small dose of CCK-8 (0.03 nmol/brain) or of Suc-(Thr28, Leu29, MePhe33)-CCK-7 (0.001 nmol/brain) suppressed food intake for 20 min, whereas CCK-8 (1 nmol/kg, which is equivalent to 0.03 nmol/brain) or Suc-(Thr28, Leu29, MePhe33)-CCK-7 (1 nmol/kg) had satiety effect after ip administration. Dose-response studies indicated the following rank order of potency: Suc-CCK-7 > or = Suc-(Thr28, Leu29, MePhe33)-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of ip administration and Suc-(Thr28, Leu29, MePhe33)-CCK-7 >> Suc-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of icv administration. The selective CCK-A receptor antagonist MK-329 reversed the inhibitory effect of the centrally as well as peripherally administered CCK-8, or of Suc-(Thr28, Leu29, MePhe33)-CCK-7, whereas the selective CCK-B receptor antagonist L-365260 did not. The icv administered CCK-8 did not appear in the peripheral circulation. These findings suggest the participation of CCK-A receptors in the brain in mediating the satiety effect of CCK and the difference in CCK-A receptors in the brain and peripheral tissues.

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Centrally and Peripherally Administered Ghrelin Potently Inhibits Water Intake in Rats

Endocrinology ◽

10.1210/en.2006-0993 ◽

2007 ◽

Vol 148 (4) ◽

pp. 1638-1647 ◽

Cited By ~ 59

Author(s):

Hirofumi Hashimoto ◽

Hiroaki Fujihara ◽

Makoto Kawasaki ◽

Takeshi Saito ◽

Minori Shibata ◽

...

Keyword(s):

Food Intake ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Intravenous Injection ◽

Water Intake ◽

Water Deprivation ◽

Area Postrema ◽

Urine Volume ◽

The Brain ◽

Atrial Natriuretic

Ghrelin is known as a potent orexigenic hormone through its action on the brain. In this study, we examined the effects of intracerebroventricular (icv) and iv injection of ghrelin on water intake, food intake, and urine volume in rats deprived of water for 24 h. Water intake that occurred after water deprivation was significantly inhibited by icv injection of ghrelin (0.1, 1, and 10 nmol/rat) in a dose-related manner, although food intake was stimulated by the hormone. The antidipsogenic effect was as potent as the orexigenic effect. Similarly, water intake was inhibited, whereas food intake was stimulated dose dependently after iv injection of ghrelin (0.1, 1, and 10 nmol/kg). The inhibition of drinking was comparable with, or even more potent than, atrial natriuretic peptide (ANP), an established antidipsogenic hormone, when administered icv, although the antidipsogenic effect lasted longer. ANP had no effect on food intake. Urine volume decreased dose relatedly after icv injection of ghrelin but not by ANP. Intravenous injection of ghrelin had no effect on urine volume. Because drinking usually occurs with feeding, food was withdrawn to remove the prandial drinking. Then the antidipsogenic effect of ghrelin became more potent than that of ANP and continued longer than when food was available. Expression of Fos was increased in the area postrema and the nucleus of the tractus solitarius by using immunohistochemistry after icv and iv injection of ghrelin. The present study convincingly showed that ghrelin is a potent antidisogenic peptide in rats.

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Cholecystokinin Inhibits Food Intake Independent of Interleukin-1β Expression in the Brain

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.26.1181 ◽

2003 ◽

Vol 26 (8) ◽

pp. 1181-1183 ◽

Cited By ~ 3

Author(s):

Libin Zhan ◽

Toru Hosoi ◽

Yasunobu Okuma ◽

Yasuyuki Nomura

Keyword(s):

Food Intake ◽

Interleukin 1Β ◽

The Brain

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The Gut Microbiome Derived From Anorexia Nervosa Patients Impairs Weight Gain and Behavioral Performance in Female Mice

Endocrinology ◽

10.1210/en.2019-00408 ◽

2019 ◽

Vol 160 (10) ◽

pp. 2441-2452 ◽

Cited By ~ 15

Author(s):

Tomokazu Hata ◽

Noriyuki Miyata ◽

Shu Takakura ◽

Kazufumi Yoshihara ◽

Yasunari Asano ◽

...

Keyword(s):

Body Weight ◽

Anorexia Nervosa ◽

Weight Gain ◽

Food Intake ◽

Brain Stem ◽

Body Weight Gain ◽

Field Tests ◽

Compulsive Behavior ◽

The Brain ◽

Poor Weight Gain

Abstract Anorexia nervosa (AN) results in gut dysbiosis, but whether the dysbiosis contributes to AN-specific pathologies such as poor weight gain and neuropsychiatric abnormalities remains unclear. To address this, germ-free mice were reconstituted with the microbiota of four patients with restricting-type AN (gAN mice) and four healthy control individuals (gHC mice). The effects of gut microbes on weight gain and behavioral characteristics were examined. Fecal microbial profiles in recipient gnotobiotic mice were clustered with those of the human donors. Compared with gHC mice, gAN mice showed a decrease in body weight gain, concomitant with reduced food intake. Food efficiency ratio (body weight gain/food intake) was also significantly lower in gAN mice than in gHC mice, suggesting that decreased appetite as well as the capacity to convert ingested food to unit of body substance may contribute to poor weight gain. Both anxiety-related behavior measured by open-field tests and compulsive behavior measured by a marble-burying test were increased only in gAN mice but not in gHC mice. Serotonin levels in the brain stem of gAN mice were lower than those in the brain stem of gHC mice. Moreover, the genus Bacteroides showed the highest correlation with the number of buried marbles among all genera identified. Administration of Bacteroides vulgatus reversed compulsive behavior but failed to exert any substantial effect on body weight. Collectively, these results indicate that AN-specific dysbiosis may contribute to both poor weight gain and mental disorders in patients with AN.

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Lateral ventricular ghrelin and fourth ventricular ghrelin induce similar increases in food intake and patterns of hypothalamic gene expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00785.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1565-R1569 ◽

Cited By ~ 17

Author(s):

Kimberly P. Kinzig ◽

Karen A. Scott ◽

Jayson Hyun ◽

Sheng Bi ◽

Timothy H. Moran

Keyword(s):

Gene Expression ◽

Food Intake ◽

Fourth Ventricle ◽

Time Course ◽

Arcuate Nucleus ◽

Central Administration ◽

Stimulatory Action ◽

Hypothalamic Arcuate Nucleus ◽

Ghrelin Receptors ◽

The Brain

The gut peptide ghrelin has been shown to stimulate food intake after both peripheral and central administration, and the hypothalamic arcuate nucleus has been proposed to be the major site for mediating this feeding stimulatory action. Ghrelin receptors are widely distributed in the brain, and hindbrain ghrelin administration has been shown to potently stimulate feeding, suggesting that there may be other sites for ghrelin action. In the present study, we have further assessed potential sites for ghrelin action by comparing the ability of lateral and fourth ventricular ghrelin administration to stimulate food intake and alter patterns of hypothalamic gene expression. Ghrelin (0.32, 1, or 3.2 nmol) in the lateral or fourth ventricle significantly increased food intake in the first 4 h after injection, with no ventricle-dependent differences in degree or time course of hyperphagia. One nanomole of ghrelin into either the lateral or fourth ventricle resulted in similar increases in arcuate nucleus neuropeptide Y mRNA expression. Expression levels of agouti-related peptide or proopiomelanocortin mRNA were not affected by ghrelin administration. These data demonstrate that ghrelin can affect food intake and hypothalamic gene expression through interactions at multiple brain sites.

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