Re: Is hunger the fundamental basis of CR benefits?

[Guest guest]

Hi :

Gosh that is interesting. And if it turns out to be true then eating

non-caloric 'fillers' to make CR easier will negate the hoped for

benefits. And " all-you-can-eat-CR " is a contradiction in terms - at

least if the term CR is meant to imply benefit.

Hmmmmm.

Rodney.

--- In , T <pct35768@y...>

wrote:

> I think a recent study featured in Hypertension is a " jaw-

dropper " . You can take the most messed up group of rats from an

endocrinological standpoint (hyperinsulinemia, hyperleptinemia,, and

if they don't have melanocortin-4 receptors, they don't develop

hypertension...

>

> So what does this receptor do? Well, it regulates food intake.

Specifically, it makes you feel " full " .

>

> What's more, the well known Agouti-related peptide, which

antagonizes melanocortin signalling, is a potent inducer of meals in

test organisms, indicating that it mediates part of the experience of

hunger.

>

> If it is antagonizing melanocortin signalling, and melanocortin

signalling is implicated in hypertension development, it may be that

such signalling is extremely fundamental to the constellation of

pathologies associated with overexuberant phosphoinositol-3-kinase

signalling seen with insulinemic/leptinemic signalling.

>

> This all is beginning to point to the somewhat " spooky " notion

being explored by some at the moment that " satiety " itself may be

the " fundamental " pro-aging influence!

>

> An individual by the name of Bruce , along with De Cabo,

Ingram, and R. Anson (among many others) presented an

abstract at the recent American Aging Association that describes this

perspective. [ http://tinyurl.com/9pemm ]

>

> =-=-=-=-=-=-=-=-=

>

> Hypertension. 2005 Jul 18; [Epub ahead of print]

>

>

> Melanocortin-4 Receptor-Deficient Mice Are Not Hypertensive or Salt-

Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia.

>

> Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE.

>

> Department of Physiology and Biophysics, University of Mississippi

Medical Center, .

>

> The purpose of this study was to test whether the melanocortin-4

receptor (MC4R) is critical in the development of hypertension

associated with obesity and its metabolic disorders. MC4R-deficient

homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J

mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with

telemetry devices for monitoring 24-hour mean arterial pressure (MAP)

and heart rate (HR). After 3-day stable control measurements on

normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet

(HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-

/-) mice were severely obese compared with MC4R (+/-) and WT mice

(body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively).

On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm

Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-)

was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not

different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not

> significantly alter MAP or HR in any of the groups. Epididymal and

retroperitoneal fat weights and plasma leptin levels were several-

fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice.

Plasma insulin and glucose levels were also significantly greater in

MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that

despite obesity, visceral adiposity, hyperleptinemia, and

hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt

sensitive, indicating that a functional MC4R may be necessary for the

development of hypertension associated with obesity and its metabolic

abnormalities.

>

> PMID: 16027245 [PubMed - as supplied by publisher]

>

> =-=-=-=-=-=-=-=-=-=-=-=-=-

>

> Endocrinology. 2005 Jun 2; [Epub ahead of print]Related Articles,

Links

>

>

> The effect of the melanocortin agonist, MT-II, on the defended

level of body adiposity.

>

> Seeley RJ, Burklow ML, Wilmer KA, s CC, Reizes O, McOsker

CC, Trokhan DP, Gross MC, Sheldon RJ.

>

> Department of Psychiatry, Genome Research Institute, University of

Cincinnati and Procter & Gamble Pharmaceuticals, Mason, OH 45040.

>

> A wide range of experimental evidence implicates a critical role

for melanocortin signaling in the control of food intake and body

adiposity. Melanocortin receptor agonists such as MT-II potently

reduce food intake and body weight making such agonists potential

therapeutics for obesity. The critical concept addressed by the

present experiments is whether the homeostatic effects of

melanocortin agonists is to directly regulate food intake or whether

the effects on food intake are secondary, with the primary effects

being the regulation of body weight and adiposity. To investigate

this, we compared the effect of various doses of MT-II given via

osmotic minipump for 28 days to alter food intake, body weight and

body fat in dietary-induced obese rats. In addition, before the

implantation of the minipump, dietary-induced obese rats were weight

reduced by differing amounts using varying levels of food

restriction. The results show that in food restricted rats, MT-II-

treated rats consume

> significantly more calories than those receiving MT-II after ad

lib access to food. More importantly, regardless of the widely

differing levels of body fat among the different dietary treatments

employed, body fat at the end of the study was determined exclusively

by the dose of MT-II with MT-II-treated rats having less body fat

than vehicle-treated rats. These experiments support the hypothesis

that melanocortin signaling primarily regulates total body adiposity

and that food intake is adjusted as necessary to achieve a specific

level of body adiposity.

>

> PMID: 15932932 [PubMed - as supplied by publisher]

>

> =-=-=-=-=-=-=-=--=-=-=-=-

>

> Nat Neurosci. 2005 May;8(5):571-8.Related Articles, Links

>

>

> Anatomy and regulation of the central melanocortin system.

>

> Cone RD.

>

> Vollum Institute and the Center for the Study of Weight Regulation,

Oregon Health and Science University, 3181 SW Sam Park Road,

Portland, Oregon 97239, USA. cone@o...

>

> The central melanocortin system is perhaps the best-characterized

neuronal pathway involved in the regulation of energy homeostasis.

This collection of circuits is unique in having the capability of

sensing signals from a staggering array of hormones, nutrients and

afferent neural inputs. It is likely to be involved in integrating

long-term adipostatic signals from leptin and insulin, primarily

received by the hypothalamus, with acute signals regulating hunger

and satiety, primarily received by the brainstem. The system is also

unique from a regulatory point of view in that it is composed of

fibers expressing both agonists and antagonists of melanocortin

receptors. Given that the central melanocortin system is an active

target for development of drugs for the treatment of obesity,

diabetes and cachexia, it is important to understand the system in

its full complexity, including the likelihood that the system also

regulates the cardiovascular and reproductive systems.

>

> Publication Types:

>

> Review

>

>

> PMID: 15856065 [PubMed - indexed for MEDLINE]

>

> =-=-=-=-=--=-=-=-

>

> Nutrition. 2005 Feb;21(2):269-79.Related Articles, Links

>

>

>

> Neuropeptide Y, alpha-melanocyte-stimulating hormone, and

monoamines in food intake regulation.

>

> Ramos EJ, Meguid MM, Campos AC, Coelho JC.

>

> Surgical Metabolism and Nutrition Laboratory, Department of

Surgery, University Hospital, Upstate Medical University, Syracuse,

New York, USA.

>

> Obesity is increasing in severity and prevalence in the United

States and represents a major public health issue. No effective

pharmacologic treatment leading to sustained weight loss currently

exists. The growing interest in the regulation of food intake stems

from the current drug treatments for obesity, almost all of which

interfere with the monoamine system. Our knowledge of potential

interactions between the orexigenic and anorexigenic pathways is

limited and fragmented, making the development of targeted drug

therapy for obesity difficult. The present review of the interaction

of neuropeptides and monoamines emphasizes the complexity of the

central mechanisms that regulate feeding behavior. Two main systems

are implicated in food intake regulation: neuropeptide Y (NPY) and

pro-opiomelanocortin. alpha-Melanocyte-stimulating hormone is a

tridecapeptide cleaved from pro-opiomelanocortin that acts to inhibit

food intake. The predominant NPY orexigenic receptors are NPY-Y1 and

> NPY-Y5, and the two anorexigenic melanocortin receptors involved

in hypothalamic food intake control are MC3-R and MC4-R. Both

neuropeptides interact with monoamines in the hypothalamus to control

physiologic states such as hunger, satiation, and satiety. Serotonin

suppresses food intake and body weight, acting mainly through the

serotonin 1B receptor. Dopamine regulates hunger and satiety by

acting in specific hypothalamic areas, through the D1 and D2

receptors. Noradrenaline activation of alpha1- and beta2-

adrenoceptors decreases food intake, and stimulation of the alpha2-

adrenoceptor increases food intake. A better understanding of the

detailed mechanisms underlying the pathogenesis of hyperphagia and

hypophagia is needed to develop new therapeutic approaches to obesity.

>

> Publication Types:

>

> Review

>

>

> PMID: 15723758 [PubMed - indexed for MEDLINE]

>

> =-=-=-=-=-=-=-=-=-=-==--=

>

> Ann N Y Acad Sci. 2002 Jun;967:379-88.Related Articles, Links

>

>

> Leptin signaling, adiposity, and energy balance.

>

> Jequier E.

>

> Institute of Physiology, University of Lausanne, Switzerland.

.Jequier@i...

>

> A chronic minor imbalance between energy intake and energy

expenditure may lead to obesity. Both lean and obese subjects

eventually reach energy balance and their body weight regulation

implies that the adipose tissue mass is " sensed " , leading to

appropriate responses of energy intake and energy expenditure. The

cloning of the ob gene and the identification of its encoded protein,

leptin, have provided a system signaling the amount of adipose energy

stores to the brain. Leptin, a hormone secreted by fat cells, acts in

rodents via hypothalamic receptors to inhibit feeding and increase

thermogenesis. A feedback regulatory loop with three distinct steps

has been identified: (1) a sensor (leptin production by adipose

cells) monitors the size of the adipose tissue mass; (2) hypothalamic

centers receive and integrate the intensity of the leptin signal

through leptin receptors (LRb); (3) effector systems, including the

sympathetic nervous system, control the two main determinants of

energy

> balance-energy intake and energy expenditure. While this feedback

regulatory loop is well established in rodents, there are many

unsolved questions about its applicability to body weight regulation

in humans. The rate of leptin production is related to adiposity, but

a large portion of the interindividual variability in plasma leptin

concentration is independent of body fatness. Gender is an important

factor determining plasma leptin, with women having markedly higher

leptin concentrations than men for any given degree of fat mass. The

ob mRNA expression is also upregulated by glucocorticoids, whereas

stimulation of the sympathetic nervous system results in its

inhibition. Furthermore, leptin is not a satiety factor in humans

because changes in food intake do not induce short-term increases in

plasma leptin levels. After its binding to LRb in the hypothalamus,

leptin stimulates a specific signaling cascade that results in the

inhibition of several orexigenic neuropeptides, while

> stimulating several anorexigenic peptides. The orexigenic

neuropeptides that are downregulated by leptin are NPY (neuropeptide

Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-

related peptide). The anorexigenic neuropeptides that are upregulated

by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which

acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-

regulated transcript); and CRH (corticotropin-releasing-hormone).

Obese humans have high plasma leptin concentrations related to the

size of adipose tissue, but this elevated leptin signal does not

induce the expected responses (i.e., a reduction in food intake and

an increase in energy expenditure). This suggests that obese humans

are resistant to the effects of endogenous leptin. This resistance is

also shown by the lack of effect of exogenous leptin administration

to induce weight loss in obese patients. The mechanisms that may

account for leptin resistance in human obesity include a

> limitation of the blood-brain-barrier transport system for leptin

and an inhibition of the leptin signaling pathways in leptin-

responsive hypothalamic neurons. During periods of energy deficit,

the fall in leptin plasma levels exceeds the rate at which fat stores

are decreased. Reduction of the leptin signal induces several

neuroendocrine responses that tend to limit weight loss, such as

hunger, food-seeking behavior, and suppression of plasma thyroid

hormone levels. Conversely, it is unlikely that leptin has evolved to

prevent obesity when plenty of palatable foods are available because

the elevated plasma leptin levels resulting from the increased

adipose tissue mass do not prevent the development of obesity. In

conclusion, in humans, the leptin signaling system appears to be

mainly involved in maintenance of adequate energy stores for survival

during periods of energy deficit. Its role in the etiology of human

obesity is only demonstrated in the very rare situations of absence of

> the leptin signal (mutations of the leptin gene or of the leptin

receptor gene), which produces an internal perception of starvation

and results in a chronic stimulation of excessive food intake.

>

> Publication Types:

>

> Review

> Review, Tutorial

>

> PMID: 12079865 [PubMed - indexed for MEDLINE]

>

> =-=-==-=-===-=-

>

> IS LIMITING CALORIC INTAKE NECESSARY FOR REAPING THE REWARDS OF

DIETARY

>

> RESTRICTION – OR IS IT JUST A GUT FEELING?

>

> B. (P), K. Duffy, S. Ramaswamy, R. Anson, P. Pistell, M.

Chachick, E, Spangler, R. Spencer, D.

>

> Ingram, R. de Cabo

>

> Laboratory of Experimental Gerontology, Gerontology Research

Center, National Institute on Aging, 5600

>

> Shock Drive, Baltimore, MD

>

> Dietary restriction (DR) is the only environmental intervention

scientifically proven to increase longevity,decrease the incidence

and onset of age-related disease as well as prevent age-related

functional declinesin various species. However, the mechanism of the

DR effect remains unknown. Two popularly studied forms of DR include

limited daily feeding, also known as calorie restriction (CR), and

every-other-dayfeeding (EOD). DR studies involve the manipulation of

caloric intake, but cannot control or eliminate theinduction of

hunger. Inability to control for hunger in DR experiments becomes

more critical as evidencetowards a neuroendocrine hypothesis

accumulates as the primary mechanism driving the beneficial effects

of DR. Thus, examining the effects of DR under appetite suppression

would provide a means for observingthe role of hunger in the DR

mechanism. With the use of hypothalamic manipulation, by post-natal

injectionof monosodium glutamate (MSG), the evaluation of hunger

> suppression on the benefits of DR can be examined. MSG chemically

lesions leptin receptors of the arcuate nucleus in the medial

hypothalamus, a neural locus involved in appetite control. Loss of

leptin receptors results in decreased production of orexogenic

neuropeptide-Y (NPY) causing a reduction of appetite displayed by

hypophagic behavior. Mice treated with MSG consumed less per unit

body mass with the exception of those on CR, however, they exhibited

a significant delay in consuming all of their allotted food. The DR

related decrease in fasting serum leptin, insulin, and glucose levels

as well as the related increase in fasting serum corticosterone was

attenuated by appetite suppression. The effects of hunger suppression

suggest dietary restriction ismediated by a gut feeling.

>

> =-=-=-=-=-=-=-=-==-=-

>

> T. pct35768@y...

>

> __________________________________________________

>

[Guest guest]

Rodney and/or : Could you put this finding in terms that we all can understand easily? Are you saying that it is necessary to be hungry to get any benefit? And if we eat to satiety we may be missing the point?

on 7/22/2005 6:42 AM, Rodney at perspect1111@... wrote:

Hi :

Gosh that is interesting. And if it turns out to be true then eating

non-caloric 'fillers' to make CR easier will negate the hoped for

benefits. And " all-you-can-eat-CR " is a contradiction in terms - at

least if the term CR is meant to imply benefit.

Hmmmmm.

Rodney.

--- In , T <pct35768@y...>

wrote:

> I think a recent study featured in Hypertension is a " jaw-

dropper " . You can take the most messed up group of rats from an

endocrinological standpoint (hyperinsulinemia, hyperleptinemia,, and

if they don't have melanocortin-4 receptors, they don't develop

hypertension...

>

[Guest guest]

Hi Francesca:

I should probably leave to answer this question. He posts a

lot of fascinating stuff, but much of it, unfortunately, is above my

pay grade : ^ (((

Based on what I think I understand of that post .......... Yes, that

study seems to be suggesting that hunger is necessary to obtain the

benefits. Indeed, if I got it right, the suggestion appears to be

that the factors which cause the sensation of hunger may also be

responsible for the benefits. But I say this tentatively, subject to

correction by .

Rodney.

> > I think a recent study featured in Hypertension is a " jaw-

> dropper " . You can take the most messed up group of rats from an

> endocrinological standpoint (hyperinsulinemia, hyperleptinemia,, and

> if they don't have melanocortin-4 receptors, they don't develop

> hypertension...

> >

[Guest guest]

Hi Francesca:

I think the abstract was poorly worded (ambiguous about what they

meant to say) in a couple of important respects. For example near

the end it says: " The DR related decrease in fasting serum leptin,

insulin, and glucose levels as well as the related increase in

fasting serum corticosterone was attenuated by appetite suppression.

The effects of hunger suppression suggest dietary restriction

ismediated by a gut feeling. "

I think it would have been stated more clearly if they had said (and

assuming this is what they had meant): " The effects of hunger

suppression suggest THAT THE BENEFITS DERIVED FROM dietary

restriction is (ARE) mediated by a gut feeling. " Now if that is not

what they meant then it proves (!) it was poorly worded, because that

is the impression I had gotten from what they wrote, but it is

somewhat ambiguous.

As to what the significance of the study may be ........ in the

earlier part of my quote above, they seem to be saying that the

benefits of CR (reduced leptin, insulin and glucose, and increased

corticosterone) are reduced when appetite is suppressed. I.E. the

benefits are reduced is there is less hunger.

Anyway that is what I think they were trying to say. As I said,

can correct me if necessary.

Rodney.

> > > I think a recent study featured in Hypertension is a " jaw-

> > dropper " . You can take the most messed up group of rats from an

> > endocrinological standpoint (hyperinsulinemia, hyperleptinemia,,

and

> > if they don't have melanocortin-4 receptors, they don't develop

> > hypertension...

> > >

[Guest guest]

My "gut feeling" is the English in this paper is overwhelming.

I don't "attenuate" appetite or hunger, by eating less food, rather by eating the right foods. That just happens to turn out less than what is "thought" to be a "reasonable" intake for someone else.

"Two popularly studied forms of DR include limited daily feeding, also known as CR and every-other-day (EOD)." implies he doesn't think of CR as I do.

A suppression of hunger using MGS? How's that work?

Regards.

----- Original Message -----

From: Rodney

Sent: Friday, July 22, 2005 7:40 AM

Subject: [ ] Re: Is hunger the "fundamental basis" of CR benefits?

Hi Francesca:I think the abstract was poorly worded (ambiguous about what they meant to say) in a couple of important respects. For example near the end it says: "The DR related decrease in fasting serum leptin, insulin, and glucose levels as well as the related increase in fasting serum corticosterone was attenuated by appetite suppression. The effects of hunger suppression suggest dietary restriction ismediated by a gut feeling."I think it would have been stated more clearly if they had said (and assuming this is what they had meant): "The effects of hunger suppression suggest THAT THE BENEFITS DERIVED FROM dietary restriction is (ARE) mediated by a gut feeling." Now if that is not what they meant then it proves (!) it was poorly worded, because that is the impression I had gotten from what they wrote, but it is somewhat ambiguous.As to what the significance of the study may be ........ in the earlier part of my quote above, they seem to be saying that the benefits of CR (reduced leptin, insulin and glucose, and increased corticosterone) are reduced when appetite is suppressed. I.E. the benefits are reduced is there is less hunger.Anyway that is what I think they were trying to say. As I said, can correct me if necessary.Rodney.> > > I think a recent study featured in Hypertension is a "jaw-> > dropper". You can take the most messed up group of rats from an> > endocrinological standpoint (hyperinsulinemia, hyperleptinemia,, and> > if they don't have melanocortin-4 receptors, they don't develop> > hypertension...> > >

[Guest guest]

Heh, I appreciate the fact that one of my posts was actually interesting to someone other than me! [ T.----> ]

This perspective was *strictly* theoretical until I saw [ PMID: 16027245 } out of the University of Mississippi, which is a truly remarkable discovery, in my opinion. Metabolic "reductionists" have been prone to reducing the attendent problems with obesity to simply "too much" of fats, energy, inflammation, and more recently serological hormones, otherwise known as adipokines.

However, this most recent inquiry featured a protocol where you remove a receptor that makes you stop eating, and then watch as the animal balloons up to massive obesity, with its associated hyperinsulinemia and hyperleptinemia is interesting. But what is astounding is that these animals do not get hypertensive, when their buddies who *can* experience "true melanocortin-4 mediated satiety" do experience hypertension!

Now, this is only one problem seen in obesity, but, what is significant here is that one of the most pathologic cardiovascular changes of "obesity" was abrogated by the removal of a cellular receptor thought to be mediating the reduction in food intake associated with longitudinal weight manintenance.

The authors in the paper concede that this effect may be a "peripheral" manifestation of this experimental intervention, as melanocortin receptors are expressed in many tissues around the body. Even this notion does not necessarily dispel the possibility that the "central" (brain) experience of hunger is correlated with cardiovascular protection, as it has been shown that even circulating levels of "endogenous" melanocortin receptor agonists are positively correlated to resting metabolic rate [ PMID: 15591028 ], as well as body fat, although this latter concept has an equivocal evidence base [ PMID:15212642 vs. PMID: 15546902 ]. Interestingly, circulating levels of a "melanocortin antagonist", the Agouti-related peptide, has less equivocal support for its elevation in states of nutritional deprivation. [ PMID: 15212642 *and* PMID: 15546902 ].

I know that "metabolic rate" is something of a "flashpoint" for many investigators studying obesity and "weight management", and my only point in bringing it up in the context of melanocortin receptor agonists is that I just want to emphasize that this hormone can affect *many* significant variables of the cell, and so it may have a rather strong bearing on the benefits one might associate with "calorie restriction". I understand that the differences in metabolic rate, or "lack thereof", observed in many calorie restriction studies have their experimental backing, and am not discounting those, as such findings may represent the "net total" physiologic manifestation of an organism accomodating nutritent withdrawal stress, with melanocortin "tone" representing only "one cog" from the "larger machine".

However, this does not yet "prove", of course, that hunger is necessary for "benefits". But it does move my own personal "take" on the "contribution" to "total benefit" from the 10% range to the 30-50% range. If more findings continue to support this perspective, that could drift higher very rapidly, but, I suppose I should give thermodynamics some credit. [ ]

=-=-=-=-=-=-=-=-=-

J Clin Endocrinol Metab. 2005 Feb;90(2):1047-54. Epub 2004 Nov 16.

Related Articles,

Links

Circulating melanin-concentrating hormone, agouti-related protein, and alpha-melanocyte-stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration.Gavrila A, Chan JL, LC, Heist K, Yiannakouris N, Mantzoros CS.Division of Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.We evaluated whether circulating levels of melanin-concentrating hormone (MCH), agouti-related protein (AGRP), and alpha-MSH could serve as useful markers of energy homeostasis in humans. We first assessed correlations of serum MCH, AGRP, and alpha-MSH with anthropometric, dietary, and hormonal variables in a cross-sectional study of 108 healthy humans. We then performed interventional studies to evaluate the effects of fasting and/or leptin administration. In eight healthy, normal weight men, we measured serum MCH, AGRP, and alpha-MSH levels at baseline, after 2 d of fasting alone (a low leptin state), and after 2 d of fasting with

replacement dose recombinant methionyl human leptin (r-metHuLeptin) administration to normalize circulating leptin levels. In a separate group of five lean and five obese men, we measured MCH levels in response to increasing circulating leptin levels to the pharmacological range by administration of one r-metHuLeptin dose in the fed state. In the cross-sectional study, serum MCH levels were independently and positively associated with body mass index and fat mass and were higher in women than in men. Furthermore, in our interventional studies, fasting for 2 d significantly decreased leptin levels and increased serum MCH levels. Administration of replacement dose r-metHuLeptin during fasting prevented the fasting-induced increase in MCH levels, but administration of a pharmacological r-metHuLeptin dose in the fed state did not further alter MCH levels. Serum AGRP levels tended to change in directions similar to MCH, but this change was less

pronounced and needs to be investigated in larger studies. In contrast, serum alpha-MSH levels did not correlate with body composition parameters, were not associated with caloric or macronutrient intake, and were not significantly affected by fasting or r-metHuLeptin administration. These findings suggest that serum MCH and possibly AGRP levels could serve as useful peripheral markers of changes in energy homeostasis and thus merit additional investigation.PMID: 15546902 [PubMed - indexed for MEDLINE]

=-=-=-=-=-=-=-=-=-

Clin Endocrinol (Oxf). 2004 Jul;61(1):31-9.

Related Articles,

Links

Plasma concentrations of alpha-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance

perturbation.Hoggard N, stone AM, Faber P, Gibney ER, Elia M,

Lobley G, Rayner V, Horgan G, Hunter L, Bashir S, Stubbs RJ.Rowett Research Institute, Aberdeen, UK. nh@...OBJECTIVE: A great deal of attention has focused on the central role of alpha melanocyte-stimulating hormone (alpha-MSH) and its antagonism at the melanocortin-4 receptor (MC4R) by agouti related protein (AgRP) in the regulation of energy balance. However, very little is known regarding the function of circulating AgRP and alpha-MSH in humans. We aimed to determine whether circulating alpha-MSH and AgRP are responsive to long-term perturbations in energy balance, in a manner consistent with their central putative functions. DESIGN AND MEASUREMENTS: Circulating alpha-MSH, AgRP and leptin were measured in both lean (n = 11) and obese (n = 18) male volunteers, some

of whom (lean n = 11, obese n = 12) were then allocated one of two weight-loss dietary strategies to achieve about 5% weight loss. This was achieved by either total starvation (for 4-6 days) for rapid weight loss or a very low calorie diet (VLCD, 2.6 MJ/day) (11-12 days) for less rapid weight loss, in both the lean and obese volunteers. RESULTS: At baseline, prior to any weight loss both plasma alpha-MSH (15.8 +/- 1.2 vs. 5.8 +/- 1.0 pmol/l +/- SEM; P < 0.001) and AgRP (49.4 +/- 2.4 vs. 10.1 +/- 0.9 pg/ml +/- SEM; P < 0.001) were elevated in obese subjects compared with lean. In both cases this correlated closely with fat mass (P < 0.001), percentage body fat (P < 0.001) and leptin (P < 0.05). Plasma AgRP increased significantly during a 6-day fast in lean individuals (11.1 +/- 1.6 vs. 21.6 +/- 3.1 pg/ml +/- SEM; P < 0.05) but not in the VLCD subjects or in the obese, while alpha-MSH was not affected by any changes in energy balance in

either the lean or the obese volunteers. CONCLUSION: We show a difference in alpha-MSH and AgRP in lean and obese subjects that correlates closely with body fat at baseline. We demonstrate an increase in plasma AgRP during a 6-day fast in lean individuals that is coincident with a decrease in plasma leptin. This increase in AgRP was not due to weight loss per se as there was no change in AgRP as a result of the same weight loss in the VLCD intervention in lean individuals. The source of the increase in plasma AgRP and its physiological function in the periphery remains to be elucidated but we suggest that the dynamics of the change in plasma leptin may determine the elevation in fasting plasma AgRP in lean subjects.PMID: 15212642 [PubMed - indexed for MEDLINE]

=-=-=-=-=-=-=-=-=-=-=-=-

Hypertension. 2005 Jul 18; [Epub ahead of print]

Related Articles,

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Melanocortin-4 Receptor-Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia.Tallam LS, Stec DE, Willis MA, da Silva AA, Hall JE.Department of Physiology and Biophysics, University of Mississippi Medical

Center, .The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders. MC4R-deficient homozygous (-/-) and heterozygous (+/-) and wild-type (WT) C57BL/6J mice 17 to 19 weeks old (n=5 to 7 per group) were implanted with telemetry devices for monitoring 24-hour mean arterial pressure (MAP) and heart rate (HR). After 3-day stable control measurements on normal-salt diet (NSD; 0.4% NaCl), mice received a high-salt diet (HSD; 4% NaCl) for 7 days, followed by 3-day recovery on NSD. MC4R (-/-) mice were severely obese compared with MC4R (+/-) and WT mice (body weight 48+/-1.5 versus 31+/-0.6 and 30+/-0.5 g respectively). On NSD, MAP was similar in all groups of mice (MC4R (-/-) 110+/-3 mm Hg; MC4R (+/-) 109+/-2 mm Hg; WT 114+/-2 mm Hg), and HR in MC4R (-/-) was lower than in WT (604+/-5 versus 645+/-9 bpm; P<0.05) but not

different from MC4R (+/-) (625+/-13 bpm) mice. HSD did not significantly alter MAP or HR in any of the groups. Epididymal and retroperitoneal fat weights and plasma leptin levels were several-fold greater in MC4R (-/-) compared with MC4R (+/-) and WT mice. Plasma insulin and glucose levels were also significantly greater in MC4R (-/-) than in MC4R (+/-) and WT mice. These data suggest that despite obesity, visceral adiposity, hyperleptinemia, and hyperinsulinemia, MC4R (-/-) mice are neither hypertensive nor salt sensitive, indicating that a functional MC4R may be necessary for the development of hypertension associated with obesity and its metabolic abnormalities.PMID: 16027245 [PubMed - as supplied by publisher]

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Physiol Genomics. 2003 Mar 18;13(1):47-56.

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Comment in:

Physiol Genomics. 2003 Mar 18;13(1):11-4. Hyperphagia, not hypometabolism, causes early onset obesity in

melanocortin-4 receptor knockout mice.Weide K, Christ N, Moar KM, Arens J, Hinney A, Mercer JG, Eiden S, Schmidt I.Max-Planck-Institut fuer physiologische und klinische Forschung, W. G. Kerckhoff-Institut, D-61231 Bad Nauheim, Germany.Previous studies on mice with melanocortin-4 receptor gene (MC4r) knockout have focused on obese adults. Because humans with functional

MC4r mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r-/- on day 35 and MC4r+/- on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21 to 35, onset of excessive fat deposition in MC4r-/- is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (POMC) mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not

hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.PMID: 12644632 [PubMed - indexed for MEDLINE]

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Endocrinology. 2005 Jun;146(6):2766-73. Epub 2005 Mar 17.

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The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist.Markison S, AC, Chen C, Brookhart GB, Hesse A, Hoare SR, Fleck BA, Brown BT, Marks DL.Department of Pediatrics, Mailcode CDRCP, 707 Southwest Gaines Road, Portland, Oregon 97239, USA. marksd@...Cachexia is metabolic disorder characterized by anorexia, an increased metabolic rate, and loss of lean body mass. It is a relatively common disorder, and is

a pathological feature of diseases such as cancer, HIV infection, and renal failure. Recent studies have demonstrated that cachexia brought about by a variety of illnesses can be attenuated or reversed by blocking activation of the melanocortin 4 subtype receptor (MC4-R) within the central nervous system. Although the potential use of central MC4-R antagonists for the treatment of cachexia was supported by these studies, utility was limited by the need to deliver these agents intracerebroventricularly. In the current study, we present a series of experiments demonstrating that peripheral administration of a small molecule MC4-R antagonist can effectively stimulate daytime (satiated) food intake as well as decrease basal metabolic rate in normal animals. Furthermore, this compound attenuated cachexia and preserved lean body mass in a murine cancer model. These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of

cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder.PMID: 15774557 [PubMed - indexed for MEDLINE]

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