scholarly journals ICI 182,780 Penetrates Brain and Hypothalamic Tissue and Has Functional Effects in the Brain after Systemic Dosing

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5219-5226 ◽  
Author(s):  
Peter D. Alfinito ◽  
Xiaohong Chen ◽  
James Atherton ◽  
Scott Cosmi ◽  
Darlene C. Deecher
Keyword(s):  
Body Weight ◽  
Skin Temperature ◽  
Ethinyl Estradiol ◽  
Ovariectomized Rats ◽  
Ici 182,780 ◽  
Hot Flush ◽  
Hypothalamic Tissue ◽  
Dependent Model ◽  
The Brain ◽  
Neuroendocrine Functions

Previous reports suggest the antiestrogen ICI 182,780 (ICI) does not cross the blood-brain barrier (BBB). However, this hypothesis has never been directly tested. In the present study, we tested whether ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and affects known neuroendocrine functions in ovariectomized rats. Using HPLC with mass spectrometry, ICI (1.0 mg/kg·d, 3 d) was detected in plasma and brain and hypothalamic tissues for up to 24 h with maximum concentrations of 43.1 ng/ml, and 31.6 and 38.8 ng/g, respectively. To evaluate antiestrogenic effects of ICI in the brain after systemic dosing, we tested its ability to block the effect of 17 α-ethinyl estradiol (EE) (0.3 mg/kg, 8 d) on tail-skin temperature abatement in the morphine-dependent model of hot flush and on body weight change. In the morphine-dependent model, EE abated 64% of the naloxone-induced tail-skin temperature increase. ICI pretreatment (1.0, 3.0 mg/kg·d) dose dependently inhibited this effect. ICI (3.0 mg/kg·d) alone showed estrogenic-like actions, abating 30% the naloxone-induced flush. In body weight studies, EE-treated rats weighed 58.5 g less than vehicle-treated rats after 8 d dosing. This effect was partially blocked by ICI (3.0 mg/kg·d) pretreatment. Similar to EE treatment, rats receiving 1.0 or 3.0 mg/kg·d ICI alone showed little weight gain compared with vehicle-treated controls. Thus, ICI crosses the BBB, penetrates into brain and hypothalamic tissues, and has both antiestrogenic and estrogenic-like actions on neuroendocrine-related functions.

Estrogens and antiestrogens: actions and interactions with fluphenazine on food intake and body weight in rats

1993 ◽  
Vol 264 (6) ◽  
pp. R1214-R1218 ◽  
Author(s):  
J. M. Gray ◽  
S. Schrock ◽  
M. Bishop
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Food Intake ◽  
Ethinyl Estradiol ◽  
Body Weight Gain ◽  
Fatty Acid Synthetase ◽  
Ovariectomized Rats ◽  
Synthetase Activity ◽  
Concurrent Administration

Treatment of ovariectomized rats for 3 days with 2 micrograms estradiol benzoate (E2B), 6 micrograms ethinyl estradiol, or 1-2 mg of either of the antiestrogens nafoxidine or tamoxifen led to similar decreases in food intake, body weight gain, adipose tissue lipoprotein lipase activity, and hepatic fatty acid synthetase activity, despite their different effects on uterine growth and induction of progestin receptors in pituitary and adipose tissue. Longer-term (2 wk) treatment with tamoxifen resulted in similar transient changes in food intake and body weight gain, as did treatment with E2B. Daily administration of 50 micrograms fluphenazine (FLU) led to significant decreases in body weight, although there was no change in food intake. Concurrent administration of FLU with either E2B or tamoxifen led to additive effects on body weight and food intake change. None of the treatments had any effect on in vitro binding of [3H]tamoxifen to antiestrogen binding sites in pooled hypothalamic-preoptic area samples.

ICI 182,780: a pure antiestrogen that affects behaviors and energy balance in rats without acting in the brain

1993 ◽  
Vol 265 (6) ◽  
pp. R1392-R1398 ◽  
Author(s):  
G. N. Wade ◽  
J. D. Blaustein ◽  
J. M. Gray ◽  
J. M. Meredith
Keyword(s):  
Energy Balance ◽  
Estrogen Receptors ◽  
Binding Sites ◽  
Linear Growth ◽  
Ovariectomized Rats ◽  
Ici 182,780 ◽  
Pure Antiestrogen ◽  
The Brain

ICI 182,780 is one of a new class of steroidal antiestrogens that differs from nonsteroidal antiestrogens, such as tamoxifen, in a number of respects. 1) It is bound by estrogen receptors with a high affinity, similar to that for estradiol. 2) It is a "pure" antiestrogen in that it does not mimic any of the effects of estradiol. 3) This class of antiestrogens does not seem to be bound by antiestrogen binding sites. 4) ICI 182,780 may not be active in the brain after peripheral administration. Indeed, ICI 182,780 blocked in vivo cell nuclear binding of [3H]estradiol in uterus, pituitary, and adipose tissue but not in hypothalamus-preoptic area. In vitro, ICI 182,780 competed for binding by neural estrogen receptors with an affinity comparable with that for estradiol. When given to ovariectomized rats, ICI 182,780 did not mimic any of the actions of estradiol. Instead, ICI 182,780 treatment completely blocked the uterotrophic effects of estradiol and attenuated the actions of estradiol on linear growth, carcass fat content, fat pad weight, and sexual receptivity. Treatment with ICI 182,780 also attenuated the estrogenic effects of tamoxifen on food intake, body weight and composition, linear growth, and uterine weight. These findings support the concept that, in addition to its actions in the brain, estradiol can act peripherally to modulate regulatory behaviors, energy balance, and estrous behavior. They are also consistent with the hypothesis that nonsteroidal antiestrogens, such as tamoxifen, affect energy balance via estrogen receptors, rather than antiestrogen binding sites.

ICI 182,780 antagonizes the effects of estradiol on estrous behavior and energy balance in Syrian hamsters

1993 ◽  
Vol 265 (6) ◽  
pp. R1399-R1403 ◽  
Author(s):  
G. N. Wade ◽  
J. B. Powers ◽  
J. D. Blaustein ◽  
D. E. Green
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Fat Content ◽  
Estradiol Treatment ◽  
Syrian Hamsters ◽  
Ici 182,780 ◽  
The Brain ◽  
Estrous Behavior

Three experiments examined the effects of ICI 182,780, a steroidal "pure" antiestrogen that is thought to be active peripherally but not in the brain when given systemically, on energy balance, estrous behavior, and in vivo cell nuclear binding of [3H]estradiol in Syrian hamsters. Pretreatment with ICI 182,780 reduced in vivo uptake of [3H]estradiol in uterus but not in pooled hypothalamus-preoptic area. Ovariectomized Syrian hamsters were treated with estradiol benzoate (EB, 5 micrograms/day), ICI 182,780 (250 micrograms/day), or both EB and ICI 182,780 for 4 wk. Estradiol treatment caused significant decreases in food intake, body weight and fat content, and linear growth. Given alone, ICI 182,780 had no effect on these measures. When they were given concurrently, ICI 182,780 attenuated the effects of estradiol on body weight, growth, and fat content but not on food intake. Treatment with ICI 182,780 significantly diminished estrous behavior induced with either EB plus progesterone or with EB alone. These findings support the hypothesis that, in addition to its actions in the brain, estradiol acts peripherally to modulate estrous behavior and energy balance.

Leptin Functioning in Eating Disorders

CNS Spectrums ◽  
2004 ◽  
Vol 9 (7) ◽  
pp. 523-529 ◽  
Author(s):  
Palmiero Monteleone ◽  
Antonio DiLieto ◽  
Eloisa Castaldo ◽  
Mario Maj
Keyword(s):  
Physical Activity ◽  
Eating Disorders ◽  
Body Weight ◽  
Eating Behaviors ◽  
Clinical Manifestations ◽  
Immune Functions ◽  
Abnormal Eating ◽  
The Brain

AbstractLeptin is an adipocyte-derived hormone, which is involved predominantly in the long-term regulation of body weight and energy balance by acting as a hunger suppressant signal to the brain. Leptin is also involved in the modulation of reproduction, immune function, physical activity, and some endogenous endocrine axes. Since anorexia nervosa (AN) and bulimia nervosa (BN) are characterized by abnormal eating behaviors, dysregulation of endogenous endocrine axes, alterations of reproductive and immune functions, and increased physical activity, extensive research has been carried out in the last decade in order to ascertain a role of this hormone in the pathophysiology of these syndromes. In this article, we review the available data on leptin physiology in patients with eating disorders. These data support the idea that leptin is not directly involved in the etiology of AN or BN. However, malnutrition-induced alterations in its physiology may contribute to the genesis and/or the maintenance of some clinical manifestations of AN and BN and may have an impact on the prognosis of AN.

scholarly journals Effect of selective expression of dominant-negative PPARγ in pro-opiomelanocortin neurons on the control of energy balance

2016 ◽  
Vol 48 (7) ◽  
pp. 491-501 ◽  
Author(s):  
Madeliene Stump ◽  
Deng-Fu Guo ◽  
Ko-Ting Lu ◽  
Masashi Mukohda ◽  
Xuebo Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Energy Balance ◽  
High Fat Diet ◽  
Control Diet ◽  
Cre Recombinase ◽  
Dominant Negative ◽  
High Fat ◽  
Pparγ Agonist ◽  
The Brain

Peroxisome proliferator-activated receptor-γ (PPARγ), a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the pro-opiomelanocortin (POMC) neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we constructed a Cre-recombinase-dependent conditionally activatable transgene expressing either wild-type (WT) or dominant-negative (P467L) PPARγ and the tdTomato reporter. Inducible expression of both forms of PPARγ was validated in cells in culture, in liver of mice infected with an adenovirus expressing Cre-recombinase (AdCre), and in the brain of mice expressing Cre-recombinase either in all neurons (NESCre/PPARγ-P467L) or selectively in POMC neurons (POMCCre/PPARγ-P467L). Whereas POMCCre/PPARγ-P467L mice exhibited a normal pattern of weight gain when fed 60% high-fat diet, they exhibited increased weight gain and fat mass accumulation in response to a 10% fat isocaloric-matched control diet. POMCCre/PPARγ-P467L mice were leptin sensitive on control diet but became leptin resistant when fed 60% high-fat diet. There was no difference in body weight between POMCCre/PPARγ-WT mice and controls in response to 60% high-fat diet. However, POMCCre/PPARγ-WT, but not POMCCre/PPARγ-P467L, mice increased body weight in response to rosiglitazone, a PPARγ agonist. These observations support the concept that alterations in PPARγ-driven mechanisms in POMC neurons can play a role in the regulation of metabolic homeostasis under certain dietary conditions.

scholarly journals Resveratrol regulates body weight in healthy and ovariectomized rats

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Rupali Sharma ◽  
Neel Kamal Sharma ◽  
M. Thungapathra
Keyword(s):  
Body Weight ◽  
Ovariectomized Rats

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

Endocrinology ◽  
2019 ◽  
Vol 160 (10) ◽  
pp. 2441-2452 ◽  
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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