Scientists at Indiana University and international collaborators have found a way to link two hormones into a single molecule, producing a more effective therapy with fewer side effects for potential use as treatment for obesity and related medical conditions.

The studies were carried out in the laboratories of Richard DiMarchi, the Standiford H. Cox Distinguished Professor of Chemistry and the Linda & Jack Gill Chair in Biomolecular Sciences in the IU Bloomington College of Arts and Sciences, and of Matthias Tschöp, professor of medicine and director of the Institute of Diabetes and Obesity, Helmholtz Center Munich, Germany.

Results were published online this week by the journal Nature Medicine.

Researchers combined a peptide hormone from the digestive system, GLP-1, with the hormone estrogen and administered it to obese laboratory mice. While both GLP-1 and estrogen have demonstrated efficacy as therapy for obesity and adult-onset diabetes, the combination was more effective in producing weight loss and other beneficial results than using either compound on its own. And it produced fewer adverse effects, such as excessive tissue growth linked to tumor formation.

"We find that combining the hormones as a single molecule dramatically enhanced their efficacy and their safety," DiMarchi said. "The combination improves the ability to lower body weight and the ability to manage glucose, and it does so without showing the hallmark toxicities associated with estrogen."

The researchers believe GLP-1 acts as a "medicinal chaperone," targeting estrogen to the hypothalamus and pancreas, which are involved with metabolic processes. The precise targeting reduces the likelihood that the estrogen will produce negative effects, such as cancer and stroke.

Brian Finan, a former doctoral student in DiMarchi's lab, is the lead author of the paper, "Targeted estrogen delivery reverses the metabolic syndrome." Co-authors include Bin Yang and Vasily Gelfanov, research scientists in the IU Bloomington Department of Chemistry, and DiMarchi. Finan is now a post-doctoral researcher at the Helmholtz Zentrum München in Germany, directed by Tschöp, who is DiMarchi's longtime collaborator and a corresponding co-author. Affiliations of the other 20 co-authors include the University of Cincinnati where, also led by Tschöp, many of the in vivo pharmacology and molecular mechanism studies were conducted; Northwestern University; and research laboratories in Germany and China.

Associated with what health authorities are calling a global epidemic of obesity, the metabolic syndrome consists of obesity associated with other factors such as high blood pressure, high triglycerides, hyperglycemia and low HDL cholesterol. The International Diabetes Federation estimates that as much as 20 percent of the world's adult population has some form of the metabolic syndrome and that they are three times as likely to have a heart attack or stroke and five times as likely to develop adult-onset diabetes as people without the syndrome.

DiMarchi said investigation continues in the optimization of the peptide-based hormone conjugates with an emphasis on determining the specific mechanism of biological action and identification of an optimal drug candidate suitable for human study. The combination of other peptides and nuclear hormones for targeting other medical conditions holds considerable promise and opportunity for future research.

Partial funding of the research was provided by Marcadia Biotech and more recently Roche Pharma. Marcadia is a company that DiMarchi co-founded and was acquired in 2010 by Roche Pharma, to which he remains a research consultant.

Two recent studies by CRG researchers delve into the role of chromatin modifying enzymes and transcription factors in tumour cells.

In one, published on September 9 in Genes & Development, it was found that the PARP1 enzyme activated by kinase CDK2 is necessary to induce the genes responsible for the proliferation of breast cancer cells in response to progesterone. In addition, extensive work has been undertaken to identify those genes activated by the administration of progesterone in breast cancer, the sequences that can be recognised and how these genes are induced. This work will be published on November 21 in the journal Molecular Cell.

Cancer is a complex set of diseases and only thanks to advances in genomic techniques have researchers begun to understand, at a cellular and molecular level, the mechanisms which are disrupted in cancer cells, a prerequisite for developing effective strategies to treat these diseases.

One clear example of this is breast cancer. It has long been known that hormones such as estrogen and progesterone encourage the proliferation of cancer cells. Because of this, one of the most common treatments is the administration of hormone receptor blockers. The block, however, affects all the cells of the body not only the cancer cells, and causes a number of side effects in patients. Additionally, most cancers develop resistance after a time and continue to grow despite anti-hormone therapy. To treat these patients it is necessary to understand the mechanisms that trigger the proliferation, which will allow their direct inhibition.

The scientists from the Cromatin and Gene Expression lab at the CRG, led by Miguel Beato, are dedicated to understanding how hormones activate cell division in breast cancer, focusing on regulating the expression of the genes that control the cell cycle.

Hormone receptors are transcription factors that bind to DNA sequences in the vicinity of the genes they regulate. But the DNA of the genes is packed into a dense structure known as "chromatin," which is considered a barrier preventing the access of transcription factors to genes. Therefore the chromatin must be decompacted for the transcription factors to activate the target genes expressed in RNA and subsequently translate them into proteins that stimulate cell proliferation. This is where the progesterone, via its receptor, activates various enzymes initiating chromatin opening.

In the study published on September 1 in the journal Genes & Development, the researchers looked at the role of an enzyme, PARP-1, which is primarily responsible for the repair of cuts in DNA. "It was not known how PARP-1 is activated and we found that it happens via the activation of another enzyme, CDK2, which phosphorylates and activates PARP-1, which in turn modifies the histone H1 and the chromatin displacement. And if PARP1 does not do this, many of the progesterone's target genes are not regulated," explains Roni Wright, first author of the study. Wright is a postdoctoral researcher in Beato's lab. She believes that much remains to be discovered in this area of research. "This experiment was conducted on cell lines, but now we have to do it on real, patient cells to see if their behaviour is the same," adds the researcher.

How do we know how the proliferation of cancer cells is controlled?

Gene regulation (how genes activate and deactivate) is the key to the overall understanding of how our genome works and when this function is altered. "It is important to discover the mechanism by which genes are activated around chromatin," explains Miguel Beato, head of the Chromatin and Gene Expression group. The chromatin packs the DNA at several levels, the first being the "nucleosomes," which help stabilise the DNA chain. "It was thought that the chromatin structure was not relevant to explaining how genes turn on and off, but we have discovered that it is crucial," adds Beato.

The second study, published online on November 21, 2012 in the journal Molecular Cell, addresses this issue. Firstly, all the genes that progesterone activates or represses in breast cancer cells were identified. Then the researchers identified which DNA sequences recognise the progesterone receptor in the genome. They found that these represented only a small proportion of the possibilities, making them think that interaction with DNA was not sufficient. It was necessary for the sequences which bind to the receptor to be incorporated into nucleosomes, which also provide interaction sites. "It seems that chromatin has a lot to do with determining which genes are activated and which are not," says Cecilia Ballaré, first author of this second paper.

The researchers believe that the only way to create increasingly specific and effective cancer treatments is by studying the role of all the elements that regulate gene expression and cell proliferation in response to hormones. "Knowing the exact way progesterone affects the proliferation of cancer cells may help develop more specific treatments that fight only cancer cells and thus produces fewer side effects," adds Ballaré.

Scientists at Karolinska Institutet in Sweden, in collaboration with colleagues in Germany and the Netherlands, have identified a previously unknown group of nerve cells in the brain. The nerve cells regulate cardiovascular functions such as heart rhythm and blood pressure. It is hoped that the discovery, which is published in the Journal of Clinical Investigation, will be significant in the long term in the treatment of cardiovascular diseases in humans.

The scientists have managed to identify in mice a previously totally unknown group of nerve cells in the brain. These nerve cells, also known as 'neurons', develop in the brain with the aid of thyroid hormone, which is produced in the thyroid gland. Patients in whom the function of the thyroid gland is disturbed and who therefore produce too much or too little thyroid hormone, thus risk developing problems with these nerve cells. This in turn has an effect on the function of the heart, leading to cardiovascular disease.

It is well-known that patients with untreated hyperthyroidism (too high a production of thyroid hormone) or hypothyroidism (too low a production of thyroid hormone) often develop heart problems. It has previously been believed that this was solely a result of the hormone affecting the heart directly. The new study, however, shows that thyroid hormone also affects the heart indirectly, through the newly discovered neurons.

"This discovery opens the possibility of a completely new way of combating cardiovascular disease," says Jens Mittag, group leader at the Department of Cell and Molecular Biology at Karolinska Institutet. "If we learn how to control these neurons, we will be able to treat certain cardiovascular problems like hypertension through the brain. This is, however, still far in the future. A more immediate conclusion is that it is of utmost importance to identify and treat pregnant women with hypothyroidism, since their low level of thyroid hormone may harm the production of these neurons in the fetus, and this may in the long run cause cardiovascular disorders in the offspring."

The study has been financed with grants from the European Molecular Biology Organisation, Deutsche Forschungsgemeinschaft, the Fredrik and Ingrid Thuring Foundation, Karolinska Institutet Foundation, the American Thyroid Association, the Swedish Research Council, the Swedish Cancer Society, the Söderberg Foundations, the Swedish Heart-Lung Foundation, the Netherlands Organization for Health Research and Development, and the Ludgardine Bouwman Foundation.

Heart failure is one of the most debilitating conditions linked to old age, and there are no specific therapies for the most common form of this condition in the elderly. A study published by Cell Press May 9th in the journal Cell reveals that a blood hormone known as growth differentiation factor 11 (GDF11) declines with age, and old mice injected with this hormone experience a reversal in signs of cardiac aging. The findings shed light on the underlying causes of age-related heart failure and may offer a much-needed strategy for treating this condition in humans.

"There has been evidence that circulating bloodstream factors exist in mammals that can rejuvenate tissues, but they haven't been identified. This study found the first factor like this," says senior study author Richard Lee of the Harvard Stem Cell Institute and Brigham and Women's Hospital.

Heart failure is a condition in which the heart can't pump enough blood to meet the body's needs, causing shortness of breath and fatigue, and it is becoming increasingly prevalent in the elderly. The most common form of age-related heart failure involves thickening of heart muscle tissue. But until now, the molecular causes and potential treatment strategies for this condition have been elusive.

To identify molecules in the blood responsible for age-related heart failure, a team led by Lee and Amy Wagers of the Harvard Stem Cell Institute and Joslin Diabetes Center used a well-established experimental technique: they surgically joined pairs of young and old mice so that their blood circulatory systems merged into one. After being exposed to the blood of young mice, old mice experienced a reversal in the thickening of heart muscle tissue. The researchers then screened the blood for molecules that change with age, discovering that levels of the hormone GDF11 were lower in old mice compared with young mice.

Moreover, old mice treated with GDF11 injections experienced a reversal in signs of cardiac aging. Heart muscle cells became smaller, and the thickness of the heart muscle wall resembled that of young mice. "If some age-related diseases are due to loss of a circulating hormone, then it's possible that restoring levels of that hormone could be beneficial," Wagers says. "We're hoping that some day, age-related human heart failure might be treated this way."