A night of Transcendent Man

Tonight’s showing at Singularity University, presented by “guest” speakers Ray Kurzweil, Barry Ptolemy and Peter Diamandis.

Barry Ptolemy’s Transcendent Man is a biopic of famed inventor, writer, and futurist Ray Kurzweil. Kurzweil is author of The Singularity is Near, a best-selling book describing humanity’s journey to becoming non-biological life.

Transcendent Man

My takeaway:

“[Your] Ideas have the power to change the world. Choose your challenges carefully.”

- Ray Kurzweil

Ray Kurzweil. He seems like a good guy.

Filed under: transhumanism , singularity, video clips

Herbal supplements, body fat, weight, mass; review of humans and animals

A systematic review of the efficacy and safety of herbal
medicines used in the treatment of obesity

Hasani-Ranjbar S, Nayebi N, Larijani B, Abdollahi M. World J Gastroenterol. 2009 Jul 7;15(25):3073-3085. PMID: 19575486 http://www.wjgnet.com/1007-9327/15/3073.asp http://www.wjgnet.com/1007-9327/15/3073.pdf

Change in human body weight
All studies showed loss of body weight except one[21]
which seemed to have problems with the study design,
and one other study[10] which showed a significant
decrease only in body fat. Studies with Cissus quadrangularis
(CQ)[26] or combined with Irvingia gabonensis (IG)[15], a
combination of Sambucus nigra and Asparagus officinalis[16],
calcium hydroxycitrate in Garcinia atroviridis[18], supplements
containing ephedra and caffeine[9,13,20], and Slimax as an
extract of several plants including Zingiber officinale[8] and
Bofutsushosan[14] showed significant decreases in body
weight.
Body fat
A significant decrease in body fat was shown with CQ[26],
supplements containing ephedra and caffeine[9,13], a natural
compound containing capsicum and some lipotropic
nutrients[10], Bofutsushosan[14], and calcium hydroxycitrate
in Garcinia atroviridis[18]. These phytopharmaceuticals
showed a significant decrease in triceps skin fold thickness
indicating significant loss of fat.
Waist and hip circumference
Efficient decreases in both waist and hip circumferences
in trials with a supplement containing ephedra and
caffeine[9] and Slimax (extract of several plants including
Zingiber officinale[8] were shown whereas Caralluma
fimbriata[19] and CQ with or without IG[15] significantly
decreased waist size.
Food intake
Decreases in appetite or amount of food or energy
intake with a supplement containing ephedra and
caffeine[20] and Caralluma fimbriata[19] were shown (not
significant) but hydroxycitric acid (HCA-SX) with or
without Gymnema sylvestre[23] decreased the amount of
food intake efficiently. A natural compound containing
capsicum and other lipotropic nutrients[10] did not
significantly change energy intake.

Published online: July 7, 2009

Abstract

This review focuses on the efficacy and safety of effective herbal medicines in the management of obesity in humans and animals. PubMed, Scopus, Google Scholar, Web of Science, and IranMedex databases were searched up to December 30, 2008. The search terms were “obesity” and (“herbal medicine” or “plant”, “plant medicinal” or “medicine traditional”) without narrowing or limiting search elements. All of the human and animal studies on the effects of herbs with the key outcome of change in anthropometric measures such as body weight and waist-hip circumference, body fat, amount of food intake, and appetite were included. In vitro studies, reviews, and letters to editors were excluded. Of the publications identified in the initial database, 915 results were identified and reviewed, and a total of 77 studies were included (19 human and 58 animal studies). Studies with Cissus quadrangularis (CQ), Sambucus nigra, Asparagus officinalis, Garcinia atroviridis, ephedra and caffeine, Slimax (extract of several plants including Zingiber officinale and Bofutsushosan) showed a significant decrease in body weight. In 41 animal studies, significant weight loss or inhibition of weight gain was found. No significant adverse effects or mortality were observed except in studies with supplements containing ephedra, caffeine and Bofutsushosan. In conclusion, compounds containing ephedra, CQ, ginseng, bitter melon, and zingiber were found to be effective in the management of obesity. Attention to these natural compounds would open a new approach for novel therapeutic and more effective agents.

© 2009 The WJG Press and Baishideng. All rights reserved.

Key words: Animal; Herbal medicine; Human; Obesity

INTRODUCTION

The prevalence of obesity is increasing worldwide^[1] resulting in an association with major health problems such as type 2 diabetes, ischemic heart disease, stroke, and cancer. It is necessary to treat obese individuals by both lifestyle interventions and/or pharmacological therapy. Pharmacologic treatment and surgical interventions used in some circumstances are not always appropriate^[2]. Unfortunately, drug treatment of obesity despite short-term benefits, is often associated with rebound weight gain after the cessation of drug use, side effects from the medication, and the potential for drug abuse^[3]. Pharmacologic options include sibutramine, orlistat, phentermine, diethylpropion, and fluoxetine or bupropion. Phentermine and diethylpropion have potential for abuse and are only approved for short-term use. Approved medications for long term use in the treatment of obesity are sibutramine and orlistat, however, these agents should be used with caution in patients with a history of cardiovascular disorders^[4]. The general public uses many other methods for weight loss including herbs, vitamins, nutritional supplements, and meal replacement preparations. Rigorous scientific studies have not been carried out on these products, and in many cases safety and efficacy take a back seat to marketing.

Complementary and alternative therapies have long been used in the Eastern world but recently these therapies are being used increasingly worldwide^[5]. When conventional medicine fails to treat chronic diseases and conditions such as obesity efficaciously and without adverse events, many people seek unconventional therapies including herbal medicine^[6]. Although the number of randomized trials on complementary therapies has doubled every 5 years and the Cochrane library included 100 systematic reviews of unconventional interventions^[7], none of these studies specifically mentioned herbal therapy in obesity.

This review aimed to evaluate the current science on the efficacy and safety of herbal medicines in the management of obesity.

DATA SOURCES AND STUDY SELECTIONS

PubMed, Scopus, Google Scholar, Web of Science, and IranMedex databases were searched up to December 30, 2008 for all human and animal studies investigating the effects (both harmful and beneficial) of treating obesity with herbal medicines. The search terms were “obesity” and (“herbal medicine” or “plant”, “plant medicinal” or “medicine traditional”) without narrowing or limiting search elements. Only publications with available abstracts were reviewed. The main outcome measures sought at the end of treatments as anti-obesity effects, were body weight, body fat including fat mass/fat weight or fat percentage/visceral adipose tissue weight, triceps skin fold thickness, waist or hip circumference, and appetite or amount of food intake.

Herbal medicines are defined in this review as raw or refined products derived from plants or parts of plants (e.g. leaves, stems, buds, flowers, roots, or tubers) used for the treatment of diseases. The synonyms of herbal medicines are herbal remedies, herbal medications, herbal products, herbal preparations, medicinal herbs, and phytopharmaceuticals, etc.

All of the abstracts from human and animal studies with the main outcome of change in anthropometric measures such as body weight and waist-hip circumference, body fat (weight or mass of visceral adipose tissue, fat mass or percent), amount of food intake, and appetite in participants were included. Even studies on other relevant diseases such as diabetes were also reviewed and included if the appropriate outcomes were shown. In vitro studies, review articles, and letters to the editor were excluded. Unpublished data such as theses were also excluded. Two reviewers independently examined the title, abstract and references of each article meeting the inclusion criteria and eliminated duplications and those showing exclusion criteria.

FINDINGS

Of the publications identified from the initial database search, 915 results were identified and reviewed for inclusion or exclusion. A total of 77 studies were included (19 human and 58 animal studies). Human studies included 17 randomized clinical trials (RCTs) and two before-after clinical trials^[8-26]. RCTs reported random allocation of humans to herbal medicines vs (placebo/another plant/combination of plants) with or without specific dietary and exercise programs outlined in Tables 1 and 2 as weight loss programs. Human subjects were healthy overweight, obese or with impaired glucose tolerance test volunteers. Animal studies included healthy, genetically or experimentally obese or diabetic mice, rats and other rodents. The route of administration of herbs in almost all studies was oral intake with the exception of some animal studies as indicated in Table 2.

HUMAN STUDIES

Change in human body weight

All studies showed loss of body weight except one^[21] which seemed to have problems with the study design, and one other study^[10] which showed a significant decrease only in body fat. Studies with Cissus quadrangularis (CQ)^[26] or combined with Irvingia gabonensis (IG)^[15], a combination of Sambucus nigra and Asparagus officinalis^[16], calcium hydroxycitrate in Garcinia atroviridis^[18], supplements containing ephedra and caffeine^[9,13,20], and Slimax as an extract of several plants including Zingiber officinale^[8] and Bofutsushosan^[14] showed significant decreases in body weight.

Body fat

A significant decrease in body fat was shown with CQ^[26], supplements containing ephedra and caffeine^[9,13], a natural compound containing capsicum and some lipotropic nutrients^[10], Bofutsushosan^[14], and calcium hydroxycitrate in Garcinia atroviridis^[18]. These phytopharmaceuticals showed a significant decrease in triceps skin fold thickness indicating significant loss of fat.

Waist and hip circumference

Efficient decreases in both waist and hip circumferences in trials with a supplement containing ephedra and caffeine^[9] and Slimax (extract of several plants including Zingiber officinale^[8] were shown whereas Caralluma fimbriata^[19] and CQ with or without IG^[15] significantly decreased waist size.

Food intake

Decreases in appetite or amount of food or energy intake with a supplement containing ephedra and caffeine^[20] and Caralluma fimbriata^[19] were shown (not significant) but hydroxycitric acid (HCA-SX) with or without Gymnema sylvestre^[23] decreased the amount of food intake efficiently. A natural compound containing capsicum and other lipotropic nutrients^[10] did not significantly change energy intake.

Other effects

Anti-hyperlipidemic, antihyperglycemic, and other relevant anti-obesity effects of medicinal plants in human studies are summarized in Table 1.

Adverse effects

No significant adverse effects compared to controls were mentioned and no mortality was reported, except in studies with supplements containing ephedra and caffeine^[9,20] which caused minor adverse effects such as dry mouth, insomnia, nervousness, palpitation and headache. Bofutsushosan^[14] caused loose bowel movements.

ANIMAL STUDIES

Change in body weight and body fat

The majority of animal studies (41 out of 58) showed significant weight loss or inhibition of weight gain when supplemented with high fat diets containing extracts of plants, with or without an efficient decrease in fat mass^[27-85] (Table 2).

Food intake

Clinical trials with Agave tequilana (TEQ) and Dasylirion spp (DAS)^[30], Pomegranate leaf^[43], Korean red ginseng^[58], Tree peony^[69], Gyeongshang angjeehwan containing a variety of plants including platycodongrandiflorum, Magnoliaceae and Ephedra^[81], Parasitic loranthus^[70], and Panax ginseng berry^[85] showed significant reductions in food intake or appetite. In studies with Cucurbita moschata^[40], Cyperus rotundus^[42], Nomame Herba^[66], Acanthopanax senticosus^[57] PM-F2-OB (a traditional herbal medicine used for the treatment of obesity in Korea composed of Lycii Fructus), and several other plants^[73], bofu-tsusho-san^[79], Galega officinalis^[77], and Oolong tea^[67], no change in the amount of food intake or appetite was observed.

DISCUSSION

In many studies^{[8-10,12-16,20-23,27,39,73,74,79-81,83]}, a combination of plants or compounds containing minerals and or chemical extracts of plants were investigated and the scientific names are summarized in Tables 1 and 2. Most of these studies showed anti-obesity effects such as decreasing body weight in humans or body weight gain in animals with or without changes in body fat.

Currently available anti-obesity medications attack the body fat dilemma in three different ways. They can stimulate metabolism, suppress appetite, affect serotonin, or they can impede digestion of fat. In this review, we can categorize the target effects of herbal medicines in the same way.

Arachis hypogaea^[50] decreased body weight gain, liver triglyceride content and liver size in association with increased fecal lipid excretion, suggesting an inhibitory mechanism on lipid absorption. Phillyrin^[52], Allium victorialis^[32], Pomegranate leaf^[43], Kochia scoparia^[46], Panax japonicus^[55], Oolong tea^[67], and Aesculus turbinata Blume^[71] also had the same effect.

A decrease in food intake as a result of a decrease in appetite and an influence on hormonal status was observed with TEQ and DAS^[30], Pomegranate leaf^[43], Korean red ginseng^[58], Tree peony^[69], Gyeongshang angjeehwan containing a variety of plants including platycodon grandiflorum and Magnoliaceae and ephedra^[81], and Parasitic loranthus^[70], refined Rhubarb^[34], Caralluma fimbriata^[19] and Panax ginseng berry^[85]. Possible stimulation of metabolism has been reported as a mechanism of action for compounds such as Slimax^[8], supplements containing ephedra^[9,13,14,20] and Terminalia arjuna Roxb^[11] which showed modification of lipid metabolism and a reduction in serum lipid levels.

Ephedra known as Ma Huang is a well known natural product with amphetamine-like stimulation effects. Although it’s efficacy in weight loss need more investigations, its adverse effects are well established in the literature. In this review, nine studies investigated the effects of ephedra as one of the major components in the combinations with caffeine^[9,13,22] or with several other plants^{[14,20,79,81,83]} 5 of which were human studies^{[9,13,14,20,22]}.

In one study^[13], efficient decreases in body weight and fat were observed with the administration of 210 mg caffeine and 72 mg ephedra per day for 12 wk with an improvement in lipid metabolism and blood pressure without serious adverse effects. In this study, the weight loss at 12-wk was -3.5 ± 0.6 kg with the test compound which was significantly (P < 0.02) higher than that of the placebo. The percentage fat loss shown by DXA was -7.9% ± 2.9% and -1.9% ± 1.1%, respectively (P < 0.05). In another study^[20], ephedra at a dose of 40 mg/d and caffeine at a dose of 100 mg/d for a longer time (9 mo) was found to be more efficient than the previous study in lowering body fat and weight, improving lipid metabolism and blood pressure and had no serious adverse effects. The treatment group lost significantly more body weight (-7.18 kg) and body fat (-5.33 kg) than the control group (-2.25 and -0.99 kg, respectively). The difference in data from these two studies possibly resulted from the different dosages and duration of interventions.

In a human study^[9], a significantly greater weight loss was observed (-4.0 ± 3.4 kg or 3.5% of baseline) in the test group vs (-0.8 ± 2.4 kg or 0.09% of baseline) in the placebo group. Changes were significantly greater for body fat and percentage of body fat in the active group (-3.5 ± 3.3 kg and -2.1% ± 3.0%) in comparison to the placebo group (-0.7 ± 2.9 kg and -0.2% ± 2.3%). The tested product also produced several untoward side effects, leading to some actively treated subjects withdrawing from the study. Additional long-term studies are needed to elucidate the effects of chronic treatment. Thus further examinations in healthy individuals using scientific combinations and dose/duration adjustments are required.

Four studies^{[58,59,65,76]} investigated different doses and types of ginseng which is a very popular Chinese herbal medicine. Ginseng significantly decreased weight gain and efficiently improved glucose tolerance^[59,76].

It has been reported^[58] that hormonal influences can reduce food intake and decrease serum leptin and neuropeptide Y in the brain hypothalamus although not significantly. Thus the anti-obesity effect of this plant requires further investigation.

CQ, a succulent vine native to West Africa and Southeast Asia, has been used in traditional African and Ayurvedic medicine for more than a century. Although some studies have examined other uses for CQ, its role in fighting against obesity and for symptoms of metabolic syndrome has recently attracted interest in other parts of the world, because of its milder adverse effects comparing to ephedra. In this review, two studies focused on this herb^[15,26]. CQ in combination with IG^[15] induced marked reductions in body weight and fat. In addition, a reduction in waist size of 1.0 cm in the placebo group vs 21.9 cm in the CQ-IG group was observed.

As we focused on herbal medicines, all dietary interventions such as the consumption of fruits and vegetables, whole grains, different types of fibers, functional food components including omega three fatty acids or phytochemicals such as flavonoids were omitted. Lifestyle modification is still the safest and efficacious method of inducing a persistent weight loss. In this review, some of the studies were carried out on subjects who simultaneously received diet and exercise programs (mentioned as weight loss programs in Tables). These results demonstrated that specific phytochemical supplements increase the effectiveness of weight loss programs and additional significant anti-obesity effects are observed.

Although few studies mentioned adverse effects, it should be noted that many serious adverse events which would have stopped a trial of a pharmaceutical agent would likely not have been identified by the authors’ search methods. Moreover, important safety issues including significant adverse events or supplement-drug interactions relevant to many clinical populations may not be fully addressed by the trials available for review.

CONCLUSION

Compliance with conventional weight-management programs, which often include increasing energy expenditure via physical activity, is low. It is not surprising to see the marketing of many new dietary slimming aids aimed at satisfying the need for palatable (as well as safe, effective, and therapeutic) options. In accord with this approach there are numerous investigations on the effectiveness of medicinal plants as natural supplements to reduce body weight. In this paper a variety of herbal supplements had beneficial effects on obesity especially compounds containing ephedra, CQ, ginseng, bitter melon (Momordica charantia), and zingiber. Most of the introduced herbals (Tables 1 and 2) have also been shown to have antioxidant effects, and with regard to the role of oxidative stress in the pathophysiology of some diseases and conditions, their further positive effects may be very promising^[86-95]. Attention to these natural compounds and further work on the isolation and characterization of their constituents is highly recommended.

Filed under: scientific study , weight gain, bodyweight, obesity, food intake, herbs, supplements

True Protein 4th of July Sale, Coupon Code & Free Shipping

this one’s a good deal if you’re in the market for 8+ lbs protein powder. if you’re not, you should be, unless you were 2 months ago.

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Filed under: Frugality , deals

Exploring a cultural obsession with toasters

they could not possibly be the greatest thing since sliced bread. they were invented to apply heat to sliced bread. cuz some like it hot.

flying toaster screen saver. give wings to my sliced bread heater

email me a toaster. (or “better yet. i could email you toast” – from Transcendent Man) a sign of the future?

why toasters? why bread at all? there are answers. I will be thinking about this today. some thoughts for now. bread is Man’s diet, a sign of our domesticity. More than that, a symbol of our cross from stone age, animal slaughtering beasts to overall-wearing, hoe carrying farmers. we break bread (or mechanically slice it). we feed prisoners bread and water (ie, we SURVIVE on bread). toasters: a symbol of technology applied to the essence of human survival. we are masters of sustenance. we have control over bread.

as we toast, we approach god-dom.

toast me. give me wings.

Filed under: a thought

4th OF July Weekend Savings – Bulk Nutrition

BulkNutrition.com Would Like To Offer Special Savings On Your Order This Weekend! Coupon Code: 4JULY09 Use the above coupon on your order to receive savings throughout this holiday weekend. Have a Safe and Happy July 4th *coupon valid until midnight 07/05/2009

Filed under: Frugality

Stress, Lifespan & the Smell of Death

“The reversal by food odors of the effects of dietary restriction can be explained as a response to information that population size is less likely to decrease”.

The below paper is free full-text.

When stress predicts a shrinking gene pool, trading early reproduction for longevity can increase fitness, even with lower fecundity.

Ratcliff WC, Hawthorne P, Travisano M, Denison RF.
PLoS One. 2009 Jun 25;4(6):e6055. PMID: 19557134 http://tinyurl.com/m8flaa

BACKGROUND: Stresses like dietary restriction or various toxins increase
lifespan in taxa as diverse as yeast, Caenorhabditis elegans, Drosophila and
rats, by triggering physiological responses that also tend to delay
reproduction. Food odors can reverse the effects of dietary restriction,
showing that key mechanisms respond to information, not just resources. Such
environmental cues can predict population trends, not just individual
prospects for survival and reproduction. When population size is increasing,
each offspring produced earlier makes a larger proportional contribution to
the gene pool, but the reverse is true when population size is declining.

PRINCIPAL FINDINGS: We show mathematically that natural selection can favor
facultative delay in reproduction when environmental cues predict a decrease
in total population size, even if lifetime fecundity decreases with delay.
We also show that increased reproduction from waiting for better conditions
does not increase fitness (proportional representation) when the whole
population benefits similarly.

CONCLUSIONS: We conclude that the beneficial effects of stress on longevity
(hormesis) in diverse taxa are a side-effect of delaying reproduction in
response to environmental cues that population size is likely to decrease.
The reversal by food odors of the effects of dietary restriction can be
explained as a response to information that population size is less likely
to decrease, reducing the chance that delaying reproduction will increase
fitness.

- – - – -
Does the sense of smell deter effective CR? The below Editorial and Express
Report papers are pdf-availed.

Science 23 February 2007: 1049.

Smelling Their Way to an Early Grave

When animals are reared on a near-starvation diet, they live much longer
than those that eat freely. Even the fruit fly Drosophila has this reaction
to a low glucose diet, and lives considerably longer on a 5% than on a 15%
sugar-yeast diet. This effect of dietary restriction is easily reversed when
flies consume more food. Libert et al. (p. 1133, published online 1
February, see the 2 February news story by Leslie) report a less expected
effect: Just the smell of the flies’ food (yeast) can inhibit some of the
effects of dietary restriction and shorten the flies’ life span by 6 to 18%.
Flies lacking an essential part of their odor receptors, which results in
their having greatly impaired senses of smell, live longer than flies with
intact odor sensation.

Regulation of Drosophila Life Span by Olfaction and Food-Derived Odors
Sergiy Libert, Jessica Zwiener, Xiaowen Chu, Wayne VanVoorhies, Gregg Roman,
and Scott D. Pletcher
Science 23 February 2007: 1133-1137. Published online 1 February 2007 (in
Science Express Reports)

[Journal introduction:] In flies, the ability of a severely
calorie-restricted diet to extend life span can be partially reversed by
exposing the flies to the odor of their main food, yeast.

Smell is an ancient sensory system present in organisms from bacteria to
humans. In the nematode Caeonorhabditis elegans, gustatory and olfactory
neurons regulate aging and longevity. Using the fruit fly, Drosophila
melanogaster, we showed that exposure to nutrient-derived odorants can
modulate life span and partially reverse the longevity-extending effects of
dietary restriction. Furthermore, mutation of odorant receptor Or83b
resulted in severe olfactory defects, altered adult metabolism, enhanced
stress resistance, and extended life span. Our findings indicate that
olfaction affects adult physiology and aging in Drosophila, possibly through
the perceived availability of nutritional resources, and that olfactory
regulation of life span is evolutionarily conserved.

As in many species, reduced nutrient availability (dietary restriction)
increases life span in the fruit fly, Drosophila melanogaster, and leads to
alterations in age-dependent patterns of gene expression, physiology, and
behavior (1-4). Acute nutrient manipulation causes sudden and rapid changes
in age-specific mortality (5, 6). Whole-genome expression data, containing
age-dependent patterns of gene expression in diet-restricted long-lived
flies and fully fed control flies (1), revealed that expression of genes
encoding odorant-binding proteins was strongly affected by both age and
nutrient availability (fig. S1).

To determine whether detection of food-related odors is sufficient to affect
fly life span, we measured the life spans of flies in the presence and
absence of odorants from live yeast. Yeast odorants were used because
demographic and gene-expression data suggested that yeast availability is a
major component of the longevity response to diet in Drosophila (7-9).
Exposure to yeast odorants reduced life span in long-lived flies from two
laboratory fly strains (Canton-S and yw) that had been subjected to dietary
restriction (Fig. 1, A and C). Life span was further reduced when flies were
allowed to consume yeast paste. The magnitude of the odorant effect was
variable and usually small, relative to that caused by the consumption of
yeast paste; odorant-mediated life-span reductions ranged from 6 to 18% in
Canton-S flies and from 7 to 8% in yw flies (Fig. 1C). Such variability is
reminiscent of the dietary-restriction response in flies, which depends on
genetic background (8). Odorants are therefore sufficient to modulate life
span, and currently unidentified odors may alter longevity with greater
potency.

Fig. 1. Exposure to yeast odorants alters life span in Drosophila. (A)
Canton-S female flies were maintained under dietary restriction (5% SY
medium) … with the addition of odorants from live yeast … or yeast for
consumption … ( Canton-S female flies were unaffected by yeast odorants
when fully fed (15% SY medium). … (C) The effect of yeast odorants on
longevity is repeatable and depends on diet. … Multivariate profile
analysis reveals no significant treatment effects (P > 0.05). The decline in
dye uptake at later time points is a consistent finding that may reflect
diurnal patterns of feeding and the dynamics of dye uptake and excretion.
For survival data, block effects were adjusted for by analysis of variance
(based on yeast paste treatments) to allow for comparisons across multiple
experiments. …

We tested whether diet-restricted flies might exhibit altered feeding
behavior or altered investment in reproduction when exposed to
nutrient-related odors, thereby accounting for the longevity effect.
Increases in the intensity of either of these behaviors would reduce life
span by compensating for our diet-restriction procedure or by augmenting the
costs of reproduction, respectively. In our experiments, neither food
consumption (as measured by the rate of dye ingestion, proboscis extension,
and fecal output) nor fecundity was affected by yeast odorants (Fig. 1D and
figs. S2 and S3). Behavioral alterations leading to increased nutrient
intake or reproductive effort are therefore not responsible for reduced
longevity upon exposure to yeast odorants.

The effects of yeast odorants on fly life span depend on nutrient
availability. Longevity was not affected by yeast odorants when flies were
fully fed (Fig. 1, B and C). Thus, the odor effect is a regulated biological
response, and yeast odorants are not a generalized toxin that shortens life
span. Our data support the hypotheses that diet- and odorant-mediated
regulation of aging act at least partly through the same molecular pathway
and that nutrient-related odors can rescue, albeit incompletely, the
extension of longevity through dietary restriction. Consequently, the
beneficial effects of dietary restriction may be due in part to the
decreased perception of nutrient availability.

We next asked whether the loss of olfactory function is sufficient to
increase life span. In vertebrates and insects, each olfactory neuron
expresses a small number of odorant receptors that impart response
characteristics of the neuron to specific odors (10-13). Of the 62 putative
odorant receptors in Drosophila, Or83b is atypical in that it is broadly
expressed throughout olfactory tissues (14, 15). Or83b interacts with
conventional odorant receptors and is required for their localization to the
neuronal dendrite (14-16). Loss-of-function mutations in Or83b limit
spontaneous activity in many odorant-receptor neurons and severely reduce
physiological and behavioral responses to a wide range of odorants (14, 16),
including nutrient-related odors (fig. S4).

We measured the life span of flies carrying the Or83b2 allele, in which the
first five of seven transmembrane domains were replaced with the w+ marker
(14) (fig. S6). Or83b2 homozygous flies lack detectable levels of Or83b mRNA
and protein, which suggests that it is a null allele (14). Fully fed female
Or83b2 mutant flies exhibited a 56% increase in median life span when
compared to appropriate wild-type animals (Fig. 2A). Males were also
significantly long-lived, but the magnitude of the extension was generally
smaller (Fig. 2. Heterozygous flies exhibited intermediate longevity in
both sexes, and heterozygous adult females showed a similar deficiency in
attraction to live yeast paste (fig. S4, B and C). We found no evidence of
such impairment in heterozygous mutant males (fig. S4D). It may be that
odor-evoked behaviors are less affected or that different classes of
odorants are critical for male longevity. Longevity was also extended when
olfactory signaling was suppressed in Or83b-expressing neurons through the
disruption of guanine nucleotide-binding protein (G protein) signaling (fig.
S5). Because the Or83b mutant also disrupts G protein activity, it is
possible that G protein function in olfactory neurons, rather than
perception per se, influences life span.

Fig. 2. Mutation of Or83b increases life span. (A and Both female and
male flies carrying the Or83b2 mutation are long-lived. … P <1 x 10-6 for
all paired comparisons except ( (males) where P = 0.001 for +/+ versus
+/-. (C) Or83b2 homozygous mutant flies expressing UAS-GFP:Or83b under
control of the Or83b-Gal4 driver … have comparable life spans to those of
background control animals … Controls for the transgenic constructs had no
effect on life span … Data are presented for females and are qualitatively
similar for males … Experiments were carried out with the use of 15% SY
media and were repeated by means of independent transgenic insertions with
identical results. …

To verify that the extended life span of Or83b2 flies was not due to
heterosis or to comparison against a relatively weak control stock, we
backcrossed the Or83b2 allele into two additional laboratory stocks
(Canton-S and yw). In all cases, the longevity of mutant flies was
considerably greater than that of their wild-type controls (Tables 1 and 2).
The degree of life-span extension was independent of the longevity of the
corresponding wild-type stock, establishing that loss of Or83b function
extends life span in healthy animals (17).

Table 1. Life-span data for female Or83b mutant Drosophila.
==========================================================
Genetic background Nutrient level (% SY)—Control longevity—Or83b
longevity—Absolute change % Increase
—n Mean (SE)—n Mean (SE)—
==========================================================
Canton-S
3% 319 50.1 (0.77) 311 61.6 (0.86) 11.5 23.0%
5% 319 50.1 (0.81) 304 62.5 (0.78) 12.3 24.6%
7.5% 324 43.9 (0.80) 315 58.9 (0.83) 15.0 34.1%
10% 313 44.8 (0.82) 318 58.6 (0.92) 13.8 30.7%
15% 314 41.6 (0.69) 329 55.6 (0.76) 14.0 33.7%
yw
3% 249 58.0 (0.85) 234 76.1 (0.63) 18.1 31.2%
5% 244 60.0 (0.83) 239 76.5 (0.60) 16.5 27.6%
7.5% 254 62.0 (0.74) 236 76.0 (0.76) 14.0 22.6%
10% 241 61.9 (0.74) 238 75.6 (0.81) 13.7 22.1%
15% 242 50.5 (0.57) 246 69.4 (0.60) 18.9 37.4%
YP* 237 42.9 (0.84) 243 65.7 (0.73) 22.8 53.1%
w1118
3% 315 51.9 (0.89) 318 75.6 (0.86) 23.7 45.6%
5% 326 53.2 (0.90) 320 76.0 (0.81) 22.8 43.0%
7.5% 333 49.6 (0.83) 319 78.0 (0.77) 28.4 57.3%
10% 316 51.1 (0.79) 317 77.6 (0.84) 26.5 51.9%
15% 314 49.3 (0.79) 319 72.7 (0.78) 23.4 47.3%
Mean life spans of Or83b2 homozygous mutant and wild-type control
females. The Or83b2 allele was backcrossed into each of three genetic
backgrounds. For all comparisons, longevity extension in the mutant was
calculated with respect to the wild-type background to which it had been
backcrossed.
All increases are statistically significant (P < 1 ? 10-6), determined by
means of a log-rank test and Cox regression.
*YP represents live yeast paste added to the vials.

Table 2. Life-span data for male Or83b mutant Drosophila.
==========================================================
Genetic background Nutrient level (% SY)—Control longevity—Or83b
longevity—Absolute change % Increase
—n Mean (SE)—n Mean (SE)—
==========================================================
Canton-S
3% 322 52.1 (0.83) 317 66.8 (0.75) 14.7 28.2%
5% 315 53.2 (0.67) 282 66.3 (0.80) 13.1 24.6%
7.5% 331 52.3 (0.71) 313 68.7 (0.77) 16.4 31.3%
10% 330 52.0 (0.76) 296 67.5 (0.82) 15.6 30.0%
15% 325 47.2 (0.74) 301 67.1 (0.85) 19.9 42.1%
yw
3% 257 63.6 (0.81) 238 73.8 (0.57) 10.3 16.2%
5% 242 63.9 (0.89) 243 75.2 (0.57) 11.4 17.8%
7.5% 251 64.4 (0.75) 240 74.3 (0.72) 9.9 15.4%
10% 246 65.3 (0.92) 246 75.8 (0.67) 10.5 16.0%
15% 244 60.1 (0.73) 222 70.3 (0.69) 10.1 16.8%
w1118
3% 317 63.2 (0.80) 328 69.1 (0.72) 6.0 9.5%
5% 314 63.9 (0.77) 322 69.5 (0.77) 5.6 8.7%
7.5% 322 63.6 (0.80) 324 73.6 (0.74) 10.0 15.7%
10% 317 65.2 (0.77) 310 74.6 (0.77) 9.4 14.5%
15% 317 64.4 (0.80) 305 73.8 (0.71) 9.4 14.5%
==========================================================
Mean life spans of Or83b2 homozygous mutant and wild-type control males.
The Or83b2 allele was backcrossed into each of three genetic backgrounds.
For all comparisons, longevity extension in the mutant was calculated with
respect to the wild-type background to which it had been backcrossed.
All increases are statistically significant (P < 1 ? 10-6), determined by
means of a log-rank test and Cox regression.

Expression of a rescuing Or83b transgene (15) under the control of an
Or83b-Gal driver (14) restored normal life span to the Or83b2 mutant flies
(Fig. 2C). The effectiveness of this construct was verified by genomic
polymerase chain reaction and visually (fig. S6), and it rescues most (but
not all) olfactory phenotypes (14, 15). The Or83b-Gal4 driver and the
upstream activating sequence-green fluorescent protein Or83b transgene
(UAS-GFP:Or83b) were inserted into different genomic positions and none
affected life span on their own (Fig. 2C and fig. S7). These rescue data and
the persistence of the longevity phenotype through extensive backcrossing to
three different genetic backgrounds provide compelling evidence that loss of
function in Or83b is the cause of increased life span in these animals.

Olfactory signaling modulates life span primarily by altering the onset of
demographic senescence (Fig. 3). Mortality analysis suggests that olfaction
shifts the mortality curve to earlier (in the case of yeast odorants) or
later (in the case of Or83b mutation) ages. In females, the rate of increase
in mortality with age was largely unaffected (Fig. 3, A and B, and fig. S8),
an effect that is similar to diet restriction (1, 5). In males, the impact
of olfaction on mortality rate was reduced later in life; mortality
trajectories converge at the oldest ages (Fig. 3C).

Fig. 3. Olfaction modulates the onset of demographic senescence. (A)
Age-specific mortality rates for flies exposed to yeast odorants … for
Or83b mutant ( females and (C) males and their controls … Corresponding
survival data are presented in Fig. 2, A and B. …

We next investigated whether olfactory function was required for longevity
extension through diet manipulation. We measured male and female life span
in different nutritional regimes ranging from severe nutrient restriction
[3% sugar/yeast (SY) media] to nutrient-replete conditions (15% SY media).
Flies homozygous for the Or83b2 mutation were consistently longer-lived than
those of appropriate control stocks (Tables 1 and 2). Despite their
exceptional longevity, life span was further increased in the Or83b2 mutants
by dietary restriction. Or83b is therefore not required for diet-mediated
longevity. Consistent with the yeast odorant results, however, we do find
evidence for interaction between the olfactory and diet pathways. The
relative increase in median and mean longevity in Or83b2 flies was
significantly greater when flies were maintained in well-fed conditions
(Tables 1 and 2), and mutant animals were partially resistant to changes in
diet (fig. S9). Thus, the Or83b mutation extends longevity largely, but not
exclusively, through a diet-independent pathway.

Reduced early reproductive output is not required for extended longevity in
Or83b2 mutants. We observed the largest life-span extension in very high
nutrient conditions where flies were provided access to live yeast paste
(see Table 1), and, under these conditions, homozygous Or83b2 mutant females
had equal or greater reproductive output than control females (Fig. 4A). We
consistently observed that Or83b2 mutants showed moderately reduced egg
production from 24 to 48 hours post-eclosion, but the reason for this is
unclear. Feeding rates are not reduced in mature flies (fig. S10), but
reduced reproduction may be due to a delay in the onset of adult feeding,
because the chemotaxis ability of mutant flies is compromised.

Fig. 4. Or83b2 flies exhibited altered physiology and enhanced stress
resistance. (A) Total reproductive output through day 14 is not different
between Or83b mutant and control females. Data represent average daily egg
production per female … Or83b2 mutants had significantly lower egg
production over the first observation period … P = 0.0005) and higher
levels of egg production at age 8 and 12 days … P = 5.7 x 10-5 and P =
0.009, respectively). (B and C) Or83b2 homozygous mutant flies are
starvation resistant. … (D) Or83b2 homozygous mutant flies have increased
triglyceride levels. Triglyceride levels are presented after normalization
to total weight. … (E and F) Weight and CO2 production for Or83b2
homozygous mutant and wild-type flies. …

Or83b2 flies exhibited a range of phenotypes indicative of altered
physiology and enhanced stress resistance. Females were more resistant to
hyperoxia (mean longevity = 110 ? 2.04 hours and 123 ? 1.0 hours for control
and Or83b2 mutant females, respectively; P <1 x 10-6, determined by means of
a log-rank test). Mutants are resistant to starvation (Fig. 4, B and C), and
females have significantly elevated levels of triglyceride, the primary
lipid-storage molecule in Drosophila (Fig. 4D), despite their similar
overall size and weight (Fig. 4E). Mutant males have higher but
statistically indistinguishable levels of triglyceride, which suggests that
life span and fat content are separable in this sex. The observed increases
in longevity and stress resistance do not result from decreased metabolic
rate (Fig. 4F).

Aging and longevity in Caenorhabditis elegans are regulated by sensory
function through antagonistic effects of specific gustatory and olfactory
neurons (18, 19). Although the specific environmental cues that regulate
longevity in C. elegans are unknown, sensory regulation of aging largely
involves insulin/IGF (insulin-like growth factor) signaling (18). Modulation
of aging by gustatory neurons is entirely insulin signaling (i.e.,
daf-16)-dependent, whereas longevity extension by the ablation of olfactory
neurons has a large daf-16-independent component (18).

Sensory systems and insulin-mediated longevity regulation are evolutionarily
conserved (20, 21). Thus, as in C. elegans, olfaction may affect aging in
Drosophila through altered insulin signaling and subsequent modulation of
transcription factor dFOXO (the fly ortholog to daf-16). However, expression
levels of Drosophila insulin-like peptides show no consistent differences in
Or83b2 mutant flies (fig. S11). Consistent with normal levels of insulin
signaling, we found that expression of Thor-the Drosophila homolog of
mammalian 4E-BP and a primary target of dFOXO (22)-is not elevated in the
body of mutant animals (fig. S11). Olfactory regulation of aging in
Drosophila may therefore contain a substantial component that is independent
of insulin signaling.

We have identified a nutrient-related olfactory cue (odorants from live
yeast) and a gene involved in olfaction (Or83b) that limit fly life span.
Olfactory-receptor function constrains the beneficial effects of dietary
restriction, indicating that consumption is not the only way that nutrient
availability modulates longevity (4). Genetic dissection of the roles of
conventional odorant receptors in the life span of Drosophila may reveal
additional candidate odors and neural circuits for longevity regulation.

Filed under: scientific study , longevity, calorie restriction, lifespan, smell, stress

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Filed under: 1 , deals

Alternation between foods within a meal: Influence on satiation and consumption in humans.

Brondel L, Lauraine G, Van Wymelbeke V, Romer M, Schaal B.
Appetite. 2009 Jun 22. [Epub ahead of print]
PMID: 19555729

Food habituation/dishabituation has been observed in non-human primates in
neurophysiological investigations of feeding, and in humans, through
salivation or hedonic responses to food.

The objective of the study was to evaluate in humans the effect of
disruption of habituation by alternation between foods in a meal.

Sixteen volunteers (8 males, 8 females; age: 21?1 yr; BMI: 21.5?0.5kg.m(-2))
ate a 2-course meal [meatballs (M) and fries (F), then vanilla cream (C) and
brownies (B)] during three randomized sessions. Sessions differed by the
alternation of these foods: No-Repetition session with M-F-C-B;
Single-Repetition session with F-M-F-B-C-B; Multiple-Repetition session with
M-F-M-F-M-F-C-B-C-B-C-B. Final intakes of F and B were ad libitum.
Quantities consumed (g, kJ) and ratings of hunger, pleasantness and desire
to eat each food were evaluated.

Compared to the No-Repetition session, subjects ate 18% more fries and 16%
more brownies in the Single-Repetition, and 13% more fries but 20% less
brownies in the Multiple-Repetition session. Pleasantness for the food
decreased from before to after intake for both fries and brownies with no
significant difference between the sessions.

It therefore appears that moderate alternation between foods at lunch
increases intake, but multiple alternations of foods at the end of the meal
may decrease consumption. These differences in intakes could result from
differences in sensory-specific satiety via disruption of habituation.

Keywords: Body-weight regulation; food-intake; food variety; habituation;
sensory-specific satiety.

Filed under: scientific study , food intake

Effect of Estradiol on Food Intake (Studies by the same author from 1983 and 2009)

Behav Neurosci. 1983 Apr;97(2):210-20.// Links

Independent effects of estradiol on water and food intake.

Czaja JA, Butera PC, McCaffrey TA.

Six experiments examined the effects of estradiol on ingestive behaviors of guinea pigs. Estradiol treatment was found to reduce water intake independently of its actions on food intake and body weight. In the first experiment, minimum intake and body weight of intact female guinea pigs coincided with rupture of the vaginal membrane, the estimated time of ovulation. In a second experiment, injections of 3 micrograms of estradiol benzoate per day to ovariectomized females significantly depressed food intake, water intake, and body weight, compared with oil injections. The ratio of water intake per gram of food intake did not change significantly during the estrous cycle or following estradiol injections, results suggesting that the reduced drinking might be a consequence of the reduced feeding. However, reducing food rations to 30% below ad lib levels in Experiment 3 by itself had no significant effect on drinking. In Experiment 4, therefore, ovariectomized females were first placed on a food ration 30% below ad lib levels and then injected daily with either 3 micrograms of estradiol benzoate or oil. Compared with oil injections, these estradiol injections significantly reduced water intake, while food intake did not decline significantly. In these experiments, the reduction in food intake was therefore neither a sufficient nor a necessary condition for the estradiol-induced suppression of water intake. The last two experiments verified that estradiol has independent actions on feeding. The daily water ration was reduced to 30% below ad lib levels in Experiment 5, with no significant effect on food intake. In the sixth experiment, the water ration was first reduced to 30% below ad lib levels, and then the ovariectomized females were injected with either oil or 3 micrograms of estradiol benzoate per day. With this reduced water ration, the estradiol significantly suppressed food intake while producing only minimal and insignificant changes in water intake. These findings established that estradiol can independently influence water intake and food intake in the guinea pig and thereby indicate that estradiol operates through different mechanisms to produce these two effects.

Estradiol and the control of food intake.
Butera PC.
Physiol Behav. 2009 Jun 22. [Epub ahead of print] PMID: 19555704

Gonadal steroids are among the many factors that influence food intake and body weight in mammals. Hormonal effects on these processes are particularly striking in female rats, which show large increases in food intake and body weight after ovariectomy. A key role of estradiol in the control of food intake and energy balance in humans is evidenced by the fact that the incidence of obesity increases greatly after menopause [1]. The actions of estradiol on neural systems that regulate eating may also account in part for sex differences in food intake and eating disorders, which occur much more frequently in young women [65].

This paper presents a minireview of research examining the changes in feeding that occur during the ovarian cycle, the effects of estradiol withdrawal and replacement on food intake and body weight, and the neurobiological mechanisms by which estradiol influences feeding behavior.

A model of hormone action on food intake that emerges from this research views estradiol as an indirect control of eating and meal size, producing changes in feeding behavior by modulating the central processing of both satiating and orexigenic peptides that represent direct controls of eating. Some of the shortcomings of the model and directions for future research are discussed.

1. Introduction

The goal of this review is not to provide a comprehensive analysis of the research on the control of ingestive behavior by ovarian hormones. Instead, the goal is to focus on the ability of estradiol to influence feeding via interactions with peptidergic systems known to be involved in the control of food intake; cholecystokinin (CCK), neuropeptide Y (NPY), and ghrelin, and how that research does or does not fit with Smith?s theoretical model of the direct and indirect controls of meal size. Thus, the pages that follow are not intended to reflect all the work in this area of ingestive behavior, but to show progress and shortcomings in our understanding of how estradiol interacts with the neurobiological controls of food intake. Readers interested in the effects of estradiol on other signaling molecules that affect feeding are referred to the work of Mystkowski and Schwartz [50], Rivera and Eckel [55], and Eckel et al. [31], while readers interested in
the effects of estradiol on energy balance and the availability of metabolic fuels are referred to the work of Schneider [60].

2. Changes in food intake during ovarian cycles

In rats, the release of estradiol and progesterone from the ovaries occurs cyclically, with a period of 4-5 days and, along with neuroendocrine events in the hypothalamus and anterior pituitary, comprises the estrous cycle. Apart from changes in female sexual behavior seen during the estrous cycle, food intake also fluctuates in response to these ovarian rhythms. Female rats show cyclic changes in eating during its 4- to 5-day estrous cycle, with reduced food intake occurring during the night of proestrus, following the rise of estradiol secretion that begins during diestrus and continues into the afternoon of proestrus [8, 11, 72]. Cyclic changes in food intake have also been reported to occur in mammals that have long ovarian cycles accompanied by a prolonged luteal phase such as the sheep [70], guinea pig [22], and rhesus monkey, with reduced food intake occurring around the time of ovulation in these animals [21]. Similar data have also been obtained
in human females. In an analysis of 19 separate studies addressing the relationship between ovarian hormones and food intake, Buffenstein et al. [10] reported a mean decrease of 250 kcal per day during the periovulatory phase of the menstrual cycle, with some studies finding a decrease of more than 600 kcal per day. In rats, the decrease in food intake that occurs during proestrus is accomplished by a decrease in meal size without a compensatory increase in meal frequency [8, 35]. Comparable analyses of changes in meal size and number across ovarian cycles in the other species cited above have not, to the best of my knowledge, been conducted.

3. Effects of ovariectomy and estradiol replacement

The research described above suggests that food intake and meal size are significantly reduced at a periovulatory point in estrous and menstrual cycles following the rise of estradiol secretion. Experiments examining the effects of ovariectomy and hormone replacement have provided direct evidence that estradiol is the hormone responsible for the changes in feeding behavior seen during the ovarian cycle. Ovariectomy of adult rats causes a significant increase in food intake and meal size, and a concomitant increase in body weight [2, 8, 40, 77]. In rhesus females, bilateral removal of the ovaries also causes hyperphagia that persists for approximately 3 weeks, along with increased weight gain [66]. The prevalence of obesity also increases in postmenopausal women compared with age-matched controls [67], and estrogen replacement therapy (ERT) has been shown to blunt the increases in body weight and adiposity [71]. Thus, human and animal studies demonstrate
that withdrawal of estradiol via ovariectomy or menopause leads to increases in body weight and fat accumulation. Whether the effects of ERT on body weight gain in postmenopausal women results from a decrease in food intake (as has been shown in rhesus females), a direct action on adipose tissue, or both remains unclear. Treating ovariectomized rats and guinea pigs with physiological doses of estradiol decreases food intake and body weight [2, 69, 77, 22]. Similar effects of estradiol replacement on food intake have also been reported in ovariectomized rhesus monkeys [23]. Progesterone treatment alone has no significant effects on feeding behavior in ovariectomized rodents or rhesus females, although pharmacological doses of progesterone have been shown to antagonize the effects of estradiol on food intake [34, 77, 24]. In ovariectomized rats, estradiol decreases eating by causing a decrease in meal size [2, 8]. Although it is likely that estradiol decreases food intake in ovariectomized guinea pigs and rhesus monkeys by influencing meal size, experimental tests of this hypothesis have not been conducted. The fact that the inhibitory effect of estradiol on food intake appears to result from changes in meal size suggests that estradiol may influence feeding by advancing the onset of satiety, an idea that will be developed in subsequent sections.

4. Central effects of estradiol

Several lines of evidence indicate that the effects of estradiol on food intake are mediated by its actions on estrogen receptors within the brain. In the early 1970?s, Wade and Zucker [75] were the first to report that direct stimulation of the ventromedial hypothalamus (VMH) by estradiol influenced feeding behavior in female rats. They found that central implants of undiluted estradiol benzoate (EB) in the VMH decreased food intake in ovariectomized rats during a 3-day period of hormonal stimulation. Implants of EB in the preoptic area (POA) had no significant effects on feeding [75]. Those findings were replicated by other investigators [5, 42] and incorporated into a set point model of food intake which hypothesized that estradiol?s effects on feeding behavior were secondary to the reduction of a body weight set point via the actions of estradiol in the VMH [42, 76]. Data from our lab and from other investigators indicate that the effects of estradiol on food intake may be mediated by its actions on estrogen receptors in hypothalamic regions other than the VMH, and that estrogenic effects on feeding aren?t necessarily secondary to a lowering of a body weight set point. In these experiments, estradiol implants in the paraventricular nucleus of the hypothalamus (PVN), a brain region involved in the control of feeding behavior [7, 46] decreased food intake in ovariectomized rats and guinea pigs [12, 53, 14]. Direct placement of estradiol in other brain regions (posterior hypothalamus, POA, VMH) had no significant effects on food intake [12]. The fact that PVN implants of estradiol suppressed eating in the absence of changes in lipoprotein lipase activity in adipose tissue suggest that peripheral metabolic changes are not responsible for the changes in feeding seen after estrogenic stimulation of the PVN [53]. In addition, the findings that estradiol implants in the PVN can inhibit food intake without inducing significant levels of lordosis behavior indicates that steroid spread from the PVN to the VMH did not underlie the observed effects on feeding [12]. Although the results of these studies suggest that the PVN is an important site of action for estrogenic effects on feeding, other experiments have failed to replicate these findings [25, 41]. More recent findings suggest that the effects of estradiol on food intake are not limited to the hypothalamus but also involve actions on estrogen receptors in the hindbrain. In this experiment, surgical placement of an estradiol-containing haemostatic cloth onto the surface of the hindbrain (over the caudal region of the nucleus of the solitary tract) in ovariectomized rats decreased food intake 72 hours after hormone application [78]. These authors also reported that hindbrain placement of estradiol increased CCK-induced Fos activity in the caudal nucleus of the solitary tract (NTS). It is possible that the effects of estradiol on feeding involve actions in an estrogen-sensitive, PVN-hindbrain pathway that participates in the neural control of food intake and autonomic functions [43, 59, 68]. Neuroanatomical evidence in support of this hypothesis comes from research showing that estrogen-sensitive PVN neurons in the parvocelluar portion of this brain region form reciprocal connections with neurons in the dorsal vagal complex of the medulla (NTS, dorsal motor nucleus of the vagus) [19]. It will be important for future studies to further explore the central sites at which estradiol acts to inhibit food intake.

The central effects of estradiol on feeding behavior depend upon its ability to bind to and activate estrogen receptors (ER) in the brain regions described above. However, the subtype of the receptor responsible for estrogenic effects on eating (ERalpha, ER?) is still not clear. In one study, intracerebroventricular (icv) infusions of anti-sense oligodeoxynucleotides for ER? but not ERalpha blocked the effects of systemic estradiol on food intake and body weight, suggesting that central ER? receptors are involved in the anorectic effects of estradiol in ovariectomized rats [47]. In ovariectomized mice with null mutations of ERalpha (alphaERKO), systemic estradiol treatment did not produce the expected decrease in food intake, suggesting that perhaps in mice activation of ERalpha is responsible for the effects of estradiol on feeding [36]. To extend this latter observation to the female rat, investigators have examined the effects of selective ER
agonists on food intake and body weight. In these studies, systemic injections of the ERalpha agonist PPT produced both a chronic [56] and an acute [58] suppression of food intake and body weight in ovariectomized rats. These investigators also found that peripheral administration of the ER? agonist DPN had no significant effects on feeding or body weight. The fact that PPT mimicked the effects of estradiol on food intake by producing a decrease in nocturnal meal size [58] provides additional support for the idea that estradiol?s actions in ovariectomized rats involve the activation of ERalpha? However, the hypothesis that activation of ERalpha is necessary for the effects of estradiol on feeding behavior is not consistent with the results of experiments showing that direct placement of estradiol in the PVN [9, 14, 53] or VMH [5, 42, 75] reduces food intake in ovariectomized rats and guinea pigs. Although the PVN contains estrogen-sensitive neurons, the subtype of the estrogen receptor found in the PVN is ER? not ERalpha?[61]. In addition, selective silencing of ERalpha expression in the VMH did not attenuate the effects of systemic estradiol treatment on feeding behavior in ovariectomized rats [49]. It will be important for future studies to further explore the involvement of these subtypes of the ER by utilizing icv infusions of ER agonists in specific brain regions and/or RNA silencing of ER expression to gain a better understanding of the involvement of these ER subtypes in the anorectic action of estradiol.

5. Estradiol, CCK and satiety

Another approach we and other investigators have utilized to study the effects of estradiol on food intake has been to evaluate the ability of estradiol to enhance satiety signals that arise during the course of a meal. This research has focused on the interactions between estradiol and cholecystokinin (CCK). CCK is a peptide hormone released by the small intestine during a meal where it acts on CCK1 receptors in the gut whose stimulation activates afferent fibers of the vagus nerve. These vagal fibers stimulate interconnected neural structures in the brain (e.g., NTS, parabrachial nucleus, PVN) resulting in the cessation of food intake accomplished primarily by decreased meal size [62]. Work done in our lab and by other researchers has shown that peripheral treatment with estradiol increases the suppressive effects of intraperitoneal (ip) injections of CCK on food intake in female rats [3, 13, 37, 48]. This effect of estradiol on CCK-induced satiety is not an additive effect of the individual agents. In our hands, combined treatment of estradiol and CCK (5.0 ?g/kg) suppressed intake during a 60 minute feeding test by 36%, whereas treatment with estradiol or CCK alone produced a suppression of food intake of 9% and 12%, respectively [12]. Similar findings have also been obtained in intact, cycling female rats, as ip injections of CCK (2.5 ?g/kg) reliably suppressed one hour food intake during late diestrus-II (when estradiol levels are high) but not during diestrus-I (when estradiol levels are low) [27]. In addition, administration of devazepide, a CCK1 receptor antagonist, attenuated the anorectic effects of estradiol in ovariectomized rats [16]. In this experiment, peripheral treatment with devazepide (.1 mg/kg) significantly increased intake during a 30 minute feeding test in animals treated with estradiol. Devazepide had no significant effects on food intake in untreated, ovariectomized females
[16]. Similar effects of CCK receptor blockade on meal patterns in intact, cycling female rats have also been obtained. Specifically, devazepide (.1 mg/kg) increased nocturnal food intake and meal size during proestrus but had no significant effects on feeding when animals were tested during diestrus [29]. Data from our lab and others indicate that the potentiation of CCK’s effects on food intake by estradiol may involve estrogenic actions in the brain. For example, estradiol implants in the PVN enhanced the satiety action of peripherally administered CCK, whereas cannulae placed in other brain regions (e.g., VMH, lateral ventricles) had no significant effects on CCK-induced satiety [15]. Estradiol has also been shown to increase CCK-induced c-Fos immunoreactivity in both the NTS and the PVN [30]. In addition, estradiol fails to enhance the satiety action of CCK in female ERalphaKO mice [36]. These findings are consistent with the idea that the
anorectic effects of estradiol stem in part from the ability of estradiol to potentiate the satiety action of CCK by activating estrogen receptors (ERalpha? ER??) in hypothalamic and hindbrain sites that process the vagally mediated signal initiated by the actions of CCK in the abdomen.

6. Interactions with orexigenic peptides

Although the effects of estradiol on food intake appear to be mediated in part by interactions with CCK systems that participate in the control of meal size, the observation that CCK antagonists do not completely reverse the anorectic action of estradiol indicates that CCK is not the only factor involved in mediating estrogenic effects on feeding [29]. More recent work in our lab and by other investigators has focused on the ability of estradiol to attenuate the orexigenic effects of ghrelin and NPY. Discovered in 1999 as an endogenous ligand for the growth hormone secretagogue receptor [44], ghrelin is a peptide produced by the stomach that is best known for its effects on hunger [20]. Fasting increases ghrelin levels in rodents and humans whereas eating suppresses ghrelin secretion [6]. Administration of ghrelin also increases eating in animals and humans [44, 74], and peripheral or central administration of antibodies to ghrelin inhibit food intake in
rats [51, 4]. To investigate the role of ghrelin in the decrease in food intake produced by estradiol, we treated ovariectomized rats with EB (5.0 ?g per animal, n = 5) or the sesame oil vehicle (n = 4) for 2 days. Seventy-two hours after the onset of EB and oil treatments, animals were given ip injections of rat ghrelin (6.0 or 12.0 nM/animal, Bachem, Temecula, CA) or the saline vehicle in a repeated measures design during the diurnal period Food intake (NOYES Precision Pellets) was measured during the 4 hour period following ghrelin or saline treatment using computer controlled food dispensers present in the home cage (Med Associates, St. Albans, VT). The procedure was repeated each week until all animals received ip injections of saline and both doses of ghrelin. As shown in Figure 1, compared to the saline condition, ghrelin (12.0 nM) increased cumulative food intake in the oil group but not in EB-treated females (t [3] = 5.12, p < 0.01). These
findings are consistent with a previous report showing that male rats and untreated, ovariectomized females are more responsive to the orexigenic effects of ghrelin (given peripherally or centrally) than intact or EB-treated ovariectomized females [17]. In these studies, estradiol appeared to attenuate ghrelin?s effect on feeding in ovariectomized animals by increasing the latency to eat in feeding tests conducted during the first 2 hours of the nocturnal period. Significant effects of ghrelin on meal size were not observed in EB- or oil-treated females [17]. In our hands, ip injections of ghrelin increased food intake and meal frequency, but not meal size, in female rats during the first 2 hours of nocturnal feeding during diestrus but not during proestrus [18]. Further work is needed to clarify the mechanism by which estradiol reduces the acute effects of ghrelin on feeding behavior.

Taken together, the results of these experiments suggest that the effects of estradiol on feeding behavior may also involve an attenuation of orexigenic signals, possibly by modulating the effects of the peripheral ghrelin signal on hypothalamic neuropeptides involved in the control of food intake (e.g., NPY). Consistent with this hypothesis, estradiol has been shown to attenuate the orexigenic effects of icv infusions of NPY and the release of NPY in the PVN of ovariectomized rats [57, 9].

7. Estradiol as an indirect control of food intake

What theoretical model of feeding behavior best explains how estradiol acts to influence eating? Earlier models characterized the effects of estradiol on food intake in terms of hormonal modulation of long-term controls on feeding [52, 76], or in terms of a hormone-induced lowering of a body weight set point [76]. A more compelling and experimentally testable model, articulated by Smith [64] and Eckel [28], explains the effects of estradiol on feeding in terms of a theoretical framework of direct and indirect controls of meal size. These ideas conceptualize the various stimuli and conditions that change eating as affecting one of two systems: (1) a direct sensory control system responsible for encoding, transmitting, and processing sensory stimuli that accompany ingestion (e.g., the chemical and mechanical receptors that run from the tongue to the end of the small intestine plus their afferent connections) and (2) indirect control systems that do not
have direct sensory contact with food stimuli but instead encode, transmit, and process other stimuli that exert effects on eating and meal size (e.g., foraging experience, circadian rhythms, adiposity levels, gonadal hormones, etc.). This extensive flow of sensory information that occurs during a meal is supplemented by postingestive afferent input arising from vagal afferent fibers and spinal visceral afferents. This pattern of sensory activity provides the brain with feedback about ingested food that is processed by neural networks involved in the control of food intake. Viewed in this way, meal size is determined by the relative strength and central interactions of the positive and negative sensory feedback, produced by food, that ultimately act on the central network for feeding which controls the rate and duration of eating [64]. The indirect controls are not directly affected by food stimuli that activate the receptors mentioned above, and have a
duration of action that lasts beyond a single meal. In the theoretical system outlined by Smith, indirect controls influence meal size by modulating some features of the direct control system (e.g., central processing of the sensory input, changing metabolic or endocrine responses to food stimuli, changing the number or sensitivity of receptors, etc.). Viewing estradiol as an indirect control of eating and meal size is consistent with some of the existing data on estradiol and feeding described in this paper [2, 8]. The research done in our lab and by others on estradiol-CCK interactions discussed in earlier sections [3, 13, 38, 48] is also consistent with this conceptual framework because it identifies a direct control of meal size (e.g., CCK) that is modulated by estradiol.
?
8. Shortcomings of the model and directions for future research
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According to Smith?s original model, the neurology of the direct and indirect controls of meal size was clearly delineated; the hindbrain is responsible for mediating the effects of direct controls of eating whereas the indirect controls require the forebrain for their effects on behavior to be produced [63]. Much of the support for this idea of the neurology of eating comes from the work of Grill and Norgren on the controls of food intake in the chronic decerebrate rat [39]. These studies revealed that the brainstem has the ability to respond to the positive and negative feedback signals from food stimuli to control meal size and food intake in animals with no reciprocal fibers connecting the hindbrain and forebrain. The fact that the chronic decerebrate rat does not increase eating after food deprivation and does not acquire conditioned taste aversions suggests that these (and other) indirect controls of eating require the forebrain. This model has proven to be heuristic during the ten plus years since its publication, but it is becoming clear that the strict interpretation of the neurology of the direct and indirect controls needs to be modified. Defining a neuropeptide or steroid as a direct or indirect control of eating based in part on their site of action in the brain becomes a tautology; indirect controls require the forebrain therefore a chemical that acts in the forebrain to affect feeding is an indirect control. In the years since the publication of Smith?s theory, it has been shown that molecules conceptualized as direct controls of eating (e.g., ghrelin) can influence food intake by acting in the hindbrain [32, 33] and the hypothalamus [45, 51]. Recent findings indicate that estradiol, typically viewed as an indirect control of eating [16, 28, 64], can inhibit food intake and enhance CCK-induced fos expression in the NTS when applied directly to the hindbrain, with no apparent activation of forebrain sites upstream [73]. These findings suggest that the neurology of direct and indirect controls of eating breaks down when one attempts to classify molecules according to that conceptual framework. Relaxing the neurological criteria for these physiological controls of feeding would still make the model useful and experimentally testable, as indirect controls of eating would still require the identification of a direct control that mediates its effect (e.g., estradiol as an indirect control modifying the actions of CCK, ghrelin, and NPY).

Despite the progress in understanding how estradiol interacts with the neurobiological controls of food intake to influence ingestive behavior, a number of questions remain. To the best of my knowledge, the ability of estradiol to inhibit food intake in the chronic decerebrate rat has not been examined. Should estradiol affect feeding in these animals, then this would lend additional support to the hypothesis that the actions of estradiol in the hindbrain can suppress food intake in the absence of hormonal activation of hypothalamic sites. As discussed in previous sections, the results of experiments in our lab and by other investigators indicate that estradiol attenuates the acute effects of ghrelin on food intake, and that this effect of estradiol on the orexigenic action of ghrelin is not mediated by a change in meal size. This represents a unique effect of estradiol on feeding behavior, as numerous studies have demonstrated that estradiol inhibits
food intake via a decrease in meal size that?s brought about by the enhancement of the satiety action of CCK [see 16 and 28 for a review]. It will be important for future research to elucidate the mechanism and site of action for this estradiol-ghrelin interaction. In addition, although several lines of evidence implicate ERalpha as the subunit of the estrogen receptor responsible for hormonal effects on food intake [56, 58, but see 47], experiments utilizing RNA silencing of ERalpha and ER? subunit expression in specific brain regions can provide additional information on the brain site and estrogen receptor subunit at which estradiol acts to influence feeding behavior. Finally, the involvement of estrogen receptors located on neural membranes (mER) in the anorectic action of estradiol is an area that warrants further investigation. The fact that STX, an ER antagonist that does not bind to ERalpha or ER? but activates mER, reduced weight gain in ovariectomized guinea pigs is intriguing, and suggests that mER may also play a role in the inhibitory effects of estradiol on food intake and body weight [54]. Whether STX can also influence feeding behavior in ovariectomized animals remains to be determined. Gaining a better understanding of the roles that these various subtypes of the ER play in the control of food intake by estradiol may also provide useful information on the factors that lead to increased obesity after menopause and contribute to sex differences in eating disorders, which occur more frequently in young women [65].

Filed under: scientific study , estradiol, food intake, ovaries

Nutrients, not caloric restriction, extend lifespan in Queensland fruit flies (Bactrocera tryoni).

“In general, lifespan was reduced as caloric intake decreased” for the
http://en.wikipedia.org/wiki/Bactrocera_tryoni fruit fly.

Fanson BG, Weldon CW, P?rez-Staples D, Simpson SJ, Taylor PW. Aging Cell. 2009 Jun 24. [Epub ahead of print] PMID: 19558564

Summary

Caloric restriction (CR) has been widely accepted as a mechanism explaining
increased lifespan in organisms subjected to dietary restriction (DR), but
recent studies investigating the role of nutrients have challenged the role
of CR in extending longevity. Fuelling this debate is the difficulty in
experimentally disentangling CR and nutrient effects due to compensatory
feeding behaviour.

We quantified compensatory feeding by measuring the volume of solution
imbibed and determined how calories and nutrients influenced lifespan and
fecundity in unmated females of the Queensland fruit fly, Bactocera tryoni
(Diptera: Tephritidae). We restricted flies to one of 28 diets varying in
carbohydrate:protein (C:P) ratios and concentrations.

On imbalanced diets, flies overcame dietary dilutions, consuming similar
caloric intakes for most dilutions. The response surface for lifespan
revealed that increasing C:P ratio while keeping calories constant extended
lifespan, with the maximum lifespan along C:P ratio of 21:1. In general,
lifespan was reduced as caloric intake decreased. Lifetime egg production
was maximized at a C:P ratio of 3:1. When given a choice of separate sucrose
and yeast solutions, each at one of 5 concentrations (yielding 25 choice
treatments), flies regulated their nutrient intake to match C:P ratio of
3:1.

Our results 1) demonstrate that compensatory feeding can overcome dietary
dilutions, 2) reveal difficulties with methods presenting fixed amounts of
liquid diet, 3) illustrate the need to measure intake to account for
compensatory feeding in DR studies, and 4) highlight nutrients rather than
CR as a dominant influence on lifespan.

Filed under: scientific study , calorie restriction, lifespan, Nutrition