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Research Notes: Obesity TreatmentFASEB J. 2007 Jun 21. Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high-fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high-fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38-deficient mice are protected against high-fat diet-induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38-deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet-induced obesity is mediated at least in part via a NAD-dependent activation of SIRT-PGC1alpha axis, a well-established cascade, involved in the regulation of mitochondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet-induced obesity Proc Natl Acad Sci USA. 2007 Apr 30. Maintenance of ATP levels is a critical feature of all cells. Mitochondria are responsible for most ATP synthesis in eukaryotes. We show here that mammalian cells respond to a partial chemical uncoupling of mitochondrial oxidative phosphorylation with a decrease in ATP levels, which recovers over several hours to control levels. This recovery occurs through an increased expression of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (PGC-1alpha) and mitochondrial genes. Cells and animals lacking PGC-1alpha lose this compensatory mechanism and cannot defend their ATP levels or increase mitochondrial gene expression in response to reduced oxidative phosphorylation. The induction of PGC-1alpha and its mitochondrial target genes is triggered by a burst of intracellular calcium, which causes an increase in cAMP-response-element-binding protein and transducer of regulated cAMP-response-element-binding proteins actions on the PGC-1alpha promoter. These data illustrate a fundamental transcriptional cycle that provides homeostatic control of cellular ATP. In light of this compensatory system that limits the toxicity of mild uncoupling, the use of chemical uncoupling of mitochondria as a means of treating obesity should be re-evaluated. Curr Opin Investig Drugs. 2007 Apr. The rising incidence of obesity, as a disorder of energy metabolism, has provoked a search for pharmacological agents that either increase energy expenditure or reduce food intake. The fatty acid oxidation pathway, and its rate-limiting enzyme carnitine palmitoyltransferase (CPT)-1 are potential targets for the treatment of obesity. The modulation of CPT-1 may simultaneously affect energy metabolism and food intake to aid in the management of obesity. Both the inhibition and enhancement of CPT-1 activity are currently under investigation as strategies for the treatment of obesity. In this review, key data on both sides of the 'CPT-1 activity balance' as they relate to obesity therapy are discussed. (10/03/06 - EurekAlert) Promising anti-obesity drug fails to produce clinically meaningful weight loss. A drug designed to target a powerful hunger-stimulating factor that has long been considered a prime target for antiobesity therapy failed to produce clinically meaningful weight loss in obese people in a long-term clinical trial. People taking the drug known as MK-0557 for a year consistently lost about three pounds more than those taking a placebo, researchers reported in the October issue of the journal Cell Metabolism. The results, which are the culmination of a 10 year program of study, suggest MK-0557 alone will not provide a useful weapon in the fight against obesity. The possibility remains, however, that the treatment could potentially play a role in future combination therapies, according to the research team that includes Steven Heymsfield and Ngozi Erondu of Merck & Co., Inc. "The current findings add to a growing sense that you will have to try a lot of different targets or get an even better understanding of the scientific underpinnings in order to unwire the food intake system with some combination of drugs," Steven Heymsfield said. "Finding safe and effective antiobesity drugs is not unlike the challenge and complexity of sending the space shuttle into orbit." MK-0557 blocks brain receptors that respond to the hunger factor called neuropeptide Y (NPY). NPY, whose role in driving appetite Heymsfield likens to an accelerator in a car, is one in a chain of players in the hunger pathway that includes the fat hormone leptin. Leptin hormone sends signals to the brain about the level of energy stores available, information that is then used to gauge metabolism and appetite. Scientists discovered NPY more than two decades ago, making it one of the first identified appetite stimulants, but it was only after the discovery of leptin in 1994 that the neuropeptide's key role and potential as a drug target was fully appreciated. After screening numerous compounds for their safety and ability to specifically bind NPY receptors, MK-0557 emerged as the "survivor," Heymsfield said. In the current study, the researchers first conducted a unique imaging study designed to directly reveal the number of human NPY receptors bound by MK-0557 after people took the drug at various doses. Using this method, they found that it only takes a small amount - 1 mg per day - for almost complete occupancy of the "NPY5R" receptor. A 12 week proof-of-concept and dosing study including 547 participants taking either a placebo or the drug at doses ranging from 0.2-25 mg/day supported the imaging study's findings, the researchers reported. MK-0557 was found to be well tolerated and to induce modest weight loss in obese individuals. The amount of weight loss and proportion of receptors bound by the drug reached a plateau at doses greater than 1 mg. The results led the researchers to proceed with a year long clinical trial including 1661 patients randomized into placebo or 1 mg MK-0557 groups, in order to test whether the drug would support continued weight loss. Of the 832 participants who successfully completed the trial, those in the placebo group lost an average of about 4 pounds, while those taking MK-0557 lost about 7.5 pounds. While the weight loss difference between groups was found to be statistically significant, the results "strongly suggest that a highly selective NPY5R antagonist" on its own is insufficient treatment for curbing obesity, Heymsfield reported. The findings in some ways mirror earlier studies that looked to leptin as a "magic bullet" for weight loss therapy, Heymsfield said. "Most obesity was found to be insensitive to leptin," he said. "It appears the same is true for the NPY5R pathway. When you hit this receptor as a single target, it doesn't generally appear to change energy balance profoundly." Med Hypotheses. 2006 Sep 29. Anecdotal evidence links the initial phase of fasting or a low-carbohydrate diet with feelings of well-being and mild euphoria. These feelings have often been attributed to ketosis, the production of ketone bodies which can replace glucose as an energy source for the brain. One of these ketone bodies, beta-hydroxybutyrate (BHB), is an isomer of the notorious drug of abuse, GHB (gamma-hydroxybutyrate). GHB is also of interest in relation to its potential as a treatment for alcohol and opiate dependence and narcolepsy-associated cataplexy. Here I hypothesize that, the mild euphoria often noted with fasting or low-carbohydrate diets may be due to shared actions of BHB and GHB on the brain. Specifically, I propose that BHB, like GHB, induces mild euphoria by being a weak partial agonist for GABA(B) receptors. I outline several approaches that would test the hypothesis, including receptor binding studies in cultured cells, perception studies in trained rodents, and psychometric testing and functional magnetic resonance imaging in humans. These and other studies investigating whether BHB and GHB share common effects on brain chemistry and mood are timely and warranted, especially when considering their structural similarities and the popularity of ketogenic diets and GHB as a drug of abuse. Intern Med. 2006 Sep 15. Since first cloned and reported by Zhang et al in 1994 (Nature 372:425), the obese gene and its product - leptin - has been studied profoundly. Our knowledge in body weight regulation and the role played by leptin has increased substantially. Leptin serves as an adiposity signal to inform the brain of the adipose tissue mass in a negative feedback loop regulating food intake and energy expenditure. Many articles have reported weight loss at high altitude, but the explanation has been limited to loss of appetite. New ideas were highlighted after studies by Grosfeld et al and Ambrosini et al on the obese gene under hypoxia condition. Cells with hypoxia treatment upregulated obese gene transcription and suggested that enhancement of leptin secretion in vivo under hypoxia environment may be one of the potential therapeutic methods for obesity treatment. (09/13/06 - Yahoo/Reuters Health) Anti-obesity compound found in wakame Studies in animals suggest that brown seaweed, also known as wakame - commonly used to flavor Asian soups and salads - contains a compound that promotes weight loss. The compound, called fucoxanthin, also has anti-diabetes effects. At the 232nd American Chemical Society National Meeting in San Francisco today, Dr. Kazuo Miyashita from Hokkaido University reported seeing significant reductions in fat tissue in rats and obese mice fed the edible seaweed carotenoid fucoxanthin. "The mechanism for this effect is a new one," Dr. Miyashita points out in a statement, explaining that fucoxanthin induces expression of the fat-burning protein UCP1 that accumulates in fat tissue around the internal organs. Mice fed fucoxanthin showed clear signs of UCP1 expression in fat tissue, whereas mice fed a control diet showed little expression of this protein. The studies suggest that fucoxanthin-induced expression of UCP1 in fat tissue fuels the oxidation of fatty acids and production of heat energy in fat tissue mitochondria. Mitochondria, found in every cell, convert sugar and fatty acids into energy and play a key role in regulating metabolism. Miyashita and colleagues also found that fucoxanthin has "strong" anti-diabetes effects by promoting the synthesis of decosahexaenoic acid (DHA) in the liver. DHA is an important fatty acid found in fish oil supplements. Animals fed fucoxanthin plus soybean oil showed an increase in DHA levels in the liver, comparable to that seen with fish oil supplementation, they note. [...] Physiol Behav. 2005 May 19. Although metabolites and energy balance have long been known to play roles in the regulation of food intake, the potential role of fatty acid metabolism in this process has been considered only recently. Fatty acid synthase (FAS) catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids in the cytoplasm, while the breakdown of fatty acids (beta-oxidation) occurs in mitochondria and is regulated by carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting step for the entry of fatty acids into the mitochondria. Inhibition of FAS using cerulenin or synthetic FAS inhibitors such as C75 reduces food intake and induces profound reversible weight loss. Subsequent studies reveal that C75 also stimulates CPT-1 and increases beta-oxidation. Hypotheses as to the mechanisms by which C75 and cerulenin mediate their effects have been proposed. Centrally, these compounds alter the expression profiles of feeding-related neuropeptides, often inhibiting the expression of orexigenic peptides. Whether through centrally mediated or peripheral mechanisms, C75 also increases energy consumption, which contributes to weight loss. In vitro and in vivo studies demonstrate that at least part of C75's effects is mediated by modulation of AMP-activated protein kinase (AMPK), a known peripheral energy-sensing kinase. Collectively, these data suggest a role for fatty acid metabolism in the perception and regulation of energy balance. (10/03/06 - EurekAlert) Promising anti-obesity drug fails to produce clinically meaningful weight loss. A drug designed to target a powerful hunger-stimulating factor that has long been considered a prime target for antiobesity therapy failed to produce clinically meaningful weight loss in obese people in a long-term clinical trial. People taking the drug known as MK-0557 for a year consistently lost about three pounds more than those taking a placebo, researchers reported in the October issue of the journal Cell Metabolism. The results, which are the culmination of a 10 year program of study, suggest MK-0557 alone will not provide a useful weapon in the fight against obesity. The possibility remains, however, that the treatment could potentially play a role in future combination therapies, according to the research team that includes Steven Heymsfield and Ngozi Erondu of Merck & Co., Inc. "The current findings add to a growing sense that you will have to try a lot of different targets or get an even better understanding of the scientific underpinnings in order to unwire the food intake system with some combination of drugs," Steven Heymsfield said. "Finding safe and effective antiobesity drugs is not unlike the challenge and complexity of sending the space shuttle into orbit." MK-0557 blocks brain receptors that respond to the hunger factor called neuropeptide Y (NPY). NPY, whose role in driving appetite Heymsfield likens to an accelerator in a car, is one in a chain of players in the hunger pathway that includes the fat hormone leptin. Leptin hormone sends signals to the brain about the level of energy stores available, information that is then used to gauge metabolism and appetite. Scientists discovered NPY more than two decades ago, making it one of the first identified appetite stimulants, but it was only after the discovery of leptin in 1994 that the neuropeptide's key role and potential as a drug target was fully appreciated. After screening numerous compounds for their safety and ability to specifically bind NPY receptors, MK-0557 emerged as the "survivor," Heymsfield said. In the current study, the researchers first conducted a unique imaging study designed to directly reveal the number of human NPY receptors bound by MK-0557 after people took the drug at various doses. Using this method, they found that it only takes a small amount - 1 mg per day - for almost complete occupancy of the "NPY5R" receptor. A 12 week proof-of-concept and dosing study including 547 participants taking either a placebo or the drug at doses ranging from 0.2-25 mg/day supported the imaging study's findings, the researchers reported. MK-0557 was found to be well tolerated and to induce modest weight loss in obese individuals. The amount of weight loss and proportion of receptors bound by the drug reached a plateau at doses greater than 1 mg. The results led the researchers to proceed with a year long clinical trial including 1661 patients randomized into placebo or 1 mg MK-0557 groups, in order to test whether the drug would support continued weight loss. Of the 832 participants who successfully completed the trial, those in the placebo group lost an average of about 4 pounds, while those taking MK-0557 lost about 7.5 pounds. While the weight loss difference between groups was found to be statistically significant, the results "strongly suggest that a highly selective NPY5R antagonist" on its own is insufficient treatment for curbing obesity, Heymsfield reported. The findings in some ways mirror earlier studies that looked to leptin as a "magic bullet" for weight loss therapy, Heymsfield said. "Most obesity was found to be insensitive to leptin," he said. "It appears the same is true for the NPY5R pathway. When you hit this receptor as a single target, it doesn't generally appear to change energy balance profoundly." |