Is hunger the fundamental basis of CR benefits?

[Guest guest]

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 ]

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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]

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Endocrinology. 2005 Jun 2; [Epub ahead of print]

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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]

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Nat Neurosci. 2005 May;8(5):571-8.

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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@...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]

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Nutrition. 2005 Feb;21(2):269-79.

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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]

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Ann N Y Acad Sci. 2002 Jun;967:379-88.

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Leptin signaling, adiposity, and energy balance.Jequier E.Institute of Physiology, University of Lausanne, Switzerland. .Jequier@...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]

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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.

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