Link Between Childhood Obesity And Increased Risk Of Adult Cardiovascular And Metabolic Disorders

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Pediatrics / Children's Health;??Heart Disease;??Diabetes
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Mounting evidence linking childhood obesity to an increasing risk of obesity, heart disease, type 2 diabetes, and other cardiovascular and metabolic disorders in adulthood is clearly presented in a comprehensive review article in the current issue of Childhood Obesity, published by Mary Ann Liebert, Inc. The article is available free online.

Authors Megan Moriarty-Kelsey, MD and Stephen Daniels, MD, PhD, Department of Pediatrics, University of Colorado School of Medicine, caution that the rising prevalence of obesity in children will lead to higher obesity rates in the adult population, resulting in a greater health burden caused by obesity-related metabolic and cardiovascular complications. In fact, obese children may already exhibit early signs of disorders such as hypertension, elevated cholesterol levels, and insulin resistance.

In the article entitled "Childhood Obesity is the Fuel That Fires Adult Metabolic Abnormalities and Cardiovascular Disease," the authors emphasize the importance of prevention and early intervention for childhood obesity. This not only minimizes risk of future disease, but also prevents the occurrence of disorders once thought of as conditions of adulthood that have become increasingly common in children, such as type 2 diabetes and fatty liver disease.

Source:
Cathia Falvey
Mary Ann Liebert, Inc./Genetic Engineering News

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First synthetic activator of two critical proteins identified: New approach to treat numerous metabolic disorders?

ScienceDaily (Nov. 19, 2010) ? Scientists from the Florida campus of The Scripps Research Institute have identified a novel synthetic activator of a pair of proteins that belong to a protein family playing key roles in human metabolism and immune function. The discovery could provide new and potentially more effective therapeutic approaches to diseases ranging from diabetes to osteoporosis.

The study was published in the November issue of the journal ACS Chemical Biology.

"This new compound is particularly important because it works in vivo, and it is selective for certain receptors," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "These two properties give it significant potential as a possible therapeutic compound."

The new discovery represents the very first synthetic ligand (binding partner) that functions as an agonist (activator) of retinoid-related orphan (ROR) nuclear receptor. Nuclear receptors are protein molecules that mediate hormone activity inside the cell; they have been implicated in the progress of a number of cancers, and have also become drug development targets for diseases including type 2 diabetes, atherosclerosis, and metabolic syndrome.

Although scientists don't know the full therapeutic significance of the new synthetic ligand, its potential usefulness is clear, Burris noted.

"For example, loss of RORα in animal models renders them resistant to weight gain," he said, "while RORγ has been shown to be involved in development of cells that are implicated in autoimmune diseases -- and loss of RORγ results in animals that are resistant to these types of disease."

RORα has also been shown to be required for normal bone development; animal models lacking this receptor develop osteoporosis, strongly suggesting that RORα agonists may have potential as a treatment of this disease. Osteoporosis affects as many as 44 million Americans, according to the National Institutes of Health. Burris and his colleagues also discovered a pathway stimulating liver secretion of FGF21 -- which has been shown to treat diabetic animals -- via activation of ROR. Diabetes is estimated to affect 23.6 million Americans, according to the National Institutes of Health.

Second Major Discovery

This new agonist is the second that Burris and his Scripps Florida colleagues have identified.

In 2009, Burris and Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, identified a high affinity synthetic inverse agonist of this same pair of nuclear receptors. An inverse agonist, which binds to the same site as an agonist, induces the opposite action of an agonist of that receptor.

For this new study, Burris said they used that first discovery, a compound known as T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORα and RORγ.

The one compound that stood out was SR1078, which displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general.

"Unexpectedly, we found that SR1078 functioned as a ROR agonist," Burris said. "When we treated cells with SR1078 we got a significant increase in RORα transcription. Similarly, with RORγ, SR1078 treatment resulted in a stimulation of RORγ dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so."

The study was supported by the National Institutes of Health.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Scripps Research Institute.

Journal Reference:

Douglas Kojetin, Yongjun Wang, Theodore M. Kamenecka, Thomas P. Burris. Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chemical Biology, 2010; : 101110091929001 DOI: 10.1021/cb1002575

Note: If no author is given, the source is cited instead.

View the original article here

Identification Of First Synthetic Activator Of 2 Critical Proteins Could Lead To New Approaches To Treat Numerous Metabolic Disorders

Main Category: Biology / Biochemistry
Also Included In: Diabetes;??Bones / Orthopedics;??Immune System / Vaccines
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Scientists from the Florida campus of The Scripps Research Institute have identified a novel synthetic activator of a pair of proteins that belong to a protein family playing key roles in human metabolism and immune function. The discovery could provide new and potentially more effective therapeutic approaches to diseases ranging from diabetes to osteoporosis.

The study was published in the November issue (Volume 5, Issue 11) of the journal ACS Chemical Biology.

"This new compound is particularly important because it works in vivo, and it is selective for certain receptors," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "These two properties give it significant potential as a possible therapeutic compound."

The new discovery represents the very first synthetic ligand (binding partner) that functions as an agonist (activator) of retinoid-related orphan (ROR) nuclear receptor. Nuclear receptors are protein molecules that mediate hormone activity inside the cell; they have been implicated in the progress of a number of cancers, and have also become drug development targets for diseases including type 2 diabetes, atherosclerosis, and metabolic syndrome.

Although scientists don't know the full therapeutic significance of the new synthetic ligand, its potential usefulness is clear, Burris noted.

"For example, loss of RORα in animal models renders them resistant to weight gain," he said, "while RORγ has been shown to be involved in development of cells that are implicated in autoimmune diseases - and loss of RORγ results in animals that are resistant to these types of disease."

RORα has also been shown to be required for normal bone development; animal models lacking this receptor develop osteoporosis, strongly suggesting that RORα agonists may have potential as a treatment of this disease. Osteoporosis affects as many as 44 million Americans, according to the National Institutes of Health. Burris and his colleagues also discovered a pathway stimulating liver secretion of FGF21 - which has been shown to treat diabetic animals - via activation of ROR. Diabetes is estimated to affect 23.6 million Americans, according to the National Institutes of Health.

Second Major Discovery

This new agonist is the second that Burris and his Scripps Florida colleagues have identified.

In 2009, Burris and Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, identified a high affinity synthetic inverse agonist of this same pair of nuclear receptors. An inverse agonist, which binds to the same site as an agonist, induces the opposite action of an agonist of that receptor.

For this new study, Burris said they used that first discovery, a compound known as T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORα and RORγ.

The one compound that stood out was SR1078, which displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general.

"Unexpectedly, we found that SR1078 functioned as a ROR agonist," Burris said. "When we treated cells with SR1078 we got a significant increase in RORα transcription. Similarly, with RORγ, SR1078 treatment resulted in a stimulation of RORγ dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so."

The first author of the study, "Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ," is Yongjun Wang of Scripps Research. Others authors include Naresh Kumar, Philippe Nuhant, Michael D. Cameron, Monica A. Istrate, William R. Roush, and Patrick R. Griffin, also of Scripps Research.

The study was supported by the National Institutes of Health.

Source:
Mika Ono
Scripps Research Institute

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Identification Of New Mechanism Regulating Daily Biological Rhythms Offers Novel Target For Treatment Of Sleep Disorders, Diabetes And Cancer

Main Category: Sleep / Sleep Disorders / Insomnia
Also Included In: Diabetes;??Cancer / Oncology
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Scientists from the Florida campus of The Scripps Research Institute have identified for the first time a novel mechanism that regulates circadian rhythm, the master clock that controls the body's natural 24-hour physiological cycle. These new findings could provide a new target not only for jet lag, shift work, and sleep disturbances, but also for disorders that result from circadian rhythm disruption, including diabetes and obesity as well as some types of cancer.

The study is published in the November 12, 2010 edition (Volume 285, Number 45) of the Journal of Biological Chemistry.

"It's well known that the nuclear receptors RORα and REV-ERBα regulate expression of the gene BMAL1, which is vital to virtually every aspect of human physiology and a core component of the circadian clock," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "BMAL1 functions as an obligate heterodimer (only working as a dimer with a partner) with either CLOCK or NPAS2 so it was unclear how RORa and REV-ERBa could control this complex. In this study, we show that both partners are targets. As we understand more about the relationship between these receptors and their gene targets, we can consider the possibility of modulating the body's core clock, especially as we continue to develop synthetic ligands targeting these two nuclear receptors."

Circadian rhythms are conserved across a wide variety of organisms, from Drosophila (fruit flies) to humans. In mammals, these rhythms respond to light signals and are controlled by the "master clock" in the brain. In the periphery, semi-autonomous clocks can respond to signals from the brain and from other cues including nutrient status. Disorders linked to dysfunctional circadian rhythms can be severe and potentially deadly, Burris said.

"When you're dealing with circadian rhythm, the most obvious disease target is sleep - for people who do shift work, critical jobs like police work, fire fighting, and medicine," he said. "If circadian rhythm is disrupted, you're prone to metabolic disorders like diabetes and obesity and even breast cancer - because the core clock is closely linked to the cell cycle. If your clock goes awry, you run the risk of your cell cycle going awry as well."

The Role of Nuclear Receptors

Nuclear receptors are proteins that recognize and regulate hormones as well as other molecules. As a result, they control an organism's metabolism by activating gene expression.

The study found that oscillations in the expression of RORα and REV-ERBα not only influence the pattern of circadian expression of BMAL1, but also of NPAS2, a protein that is part of the circadian clock. The fact that NPAS2 is a target of both receptors suggests that there is a specific mechanism that coordinates the relative levels of each receptor to maintain correct circadian function..

"Based on the fact that BMAL1 and NPAS2 work together within the circadian clock, it seems highly unlikely that these two nuclear receptors would only regulate one of them," Burris said. "Our study shows for the first time that, like BMAL1, NPAS2 is also a direct target for RORα and REV-ERBα. This discovery makes this complex a very good therapeutic target."

The expression of RORα and REV-ERBα follows a 24-hour circadian pattern (with opposing phases) leading to the correct circadian pattern of gene expression of BMAL1 and NPAS2.

"We think it's something of a competition between these two receptors for binding to promoters of these genes that triggers either the activation (RORα) or repression (REV-ERBα) of the gene," Burris said.

Nuclear receptors make tempting drug targets because they can bind directly to DNA and activate genes through specific ligands - molecules that affect receptor behavior - such as the sex hormones, vitamins A and D, and glucocorticoids, which modulate the body's response to stress. Nuclear receptors have been implicated in a number of cancers, including prostate, breast, and colon cancers, and other diseases as well, including type 2 diabetes, atherosclerosis, and metabolic syndrome.

The other important aspect of nuclear receptors is their practicality. Scientists can design small molecule therapeutics to force them to change their ways. Burris said that he has already identified several new synthetic ligands (drug like molecules) for both receptors.

The first author of the study, "Characterization of the Core Mammalian Clock Component, NPAS2, as a REV-­ERBα/RORα Target Gene," is Christine Crumbley of The Scripps Research Institute. Others authors include Yongjun Wang and Douglas J. Kojetin, also of Scripps Research. This work was funded by the National Institutes of Health.

Source:
Mika Ono
Scripps Research Institute

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