Potential Target For Diabetes, Heart Disease Treatments

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Diabetes;??Heart Disease
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Cardiac researchers at UC have found a new cellular pathway that could help in developing therapeutic treatments for obesity-related disorders, like diabetes and heart disease.

This research was presented at the American Heart Association's Scientific Sessions in Chicago.

Tapan Chatterjee, PhD, and researchers in the division of cardiovascular diseases found that action by the enzyme histone deacetylase 9 (HDAC9) can lead to obesity-induced body fat dysfunction and that HDAC9-regulated pathways could be targets for potential treatment options in obesity-related diseases.

"Failure of fat cells to differentiate and properly store excess calories in obesity is associated with adipose tissue (fat) inflammation, fatty liver disease, insulin resistance, diabetes and increased cardiovascular diseases," Chatterjee says. "We know that dysfunctional fat tissue is the underlying culprit in obesity-related diseases; however, we do not know why fat tissue becomes dysfunctional when a person becomes obese."

Chatterjee says researchers in this study first identified HDAC9 regulator of fat cell differentiation within the living organism.

"Caloric intake promotes HDAC9 down-regulation to allow the conversion of precursor fat cells to 'functional' fat cells, capable of efficiently storing excess calories for future use and also maintaining whole body lipid and glucose stability," he says. "Ideally, fat cells should function as a reversible storage site of excess calories and as an endocrine organ to maintain systemic lipid and glucose stability.

"Unfortunately, during chronic over-feeding, we find HDAC9 level is up-regulated in fat tissue, thereby blocking the conversion which leads to adipose tissue dysfunction and the onset of diseases such as diabetes, liver disease, high blood pressure and heart disease - the nation's No. 1 killer."

Researchers examined various members of the HDAC family of proteins and found that only HDAC9 showed a direct correlation to differentiation of precursor fat cells, both from human and mouse fat tissues.

"HDAC9 down-regulation is necessary for the differentiation of precursor fat cells to mature fat cells; forced up-regulation of HDAC9 by genetic manipulation blocks the differentiation of the precursor fat cells," Chatterjee says. "On the other hand, precursor fat cells from HDAC9 genetic knockout mice showed accelerated differentiation.

"We believe that HDAC9 keeps precursor fat cells in the undifferentiated state; metabolic cues trigger HDAC9 down-regulation allowing conversion of the precursor cells to mature fat cells. We are exploring the cellular signaling mechanism that promotes such down-regulation of this enzyme during the normal fat cell differentiation process."

Chatterjee says researchers were really interested in the tie between increased HDAC9 levels in fat tissue of mice and the caloric overload.

"Fat tissues from these obese mice showed dysfunction, with increased expression of pro-inflammatory agents and decreased expression of hormones responsible for maintaining whole body lipid and glucose stability," he says. "The fat tissues of these mice are not capable of efficiently storing excess calories and are not able to perform proper endocrine functions.

"The adaptive response fails for some reason during chronic caloric overload, leading to the generation of fat tissue mass that is dysfunctional."

Chatterjee says the HDAC9 level in fat cells is the underlying molecular culprit for dysfunctional fat tissue during obesity.

"We are currently examining HDAC9 knockout mice subjected to chronic high-fat feeding and think that HDAC9 gene removal will protect mice from obesity-linked adipose tissue dysfunction and associated metabolic disorders," he says.

"Identification of HDAC9 as a novel regulator of fat cell differentiation and the finding that elevated HDAC9 levels are associated with adipose tissue dysfunction in obesity are extremely interesting and novel findings," he continues.

Chatterjee's team is pursuing studies to understand how diet regulates HDAC9 levels in fat tissue and how HDAC9 up-regulation can be prevented during diet-induced obesity through pharmacological means.

"Our findings may help lead researchers to targeted therapies that may prevent the development of obesity-related disorders in humans."

This study was funded by a grant from the National Institutes of Health.

Source:
Katie Pence
University of Cincinnati Academic Health Center

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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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