HDAC4 regulates fasting/feeding states

Many studies have shown that the control of lipid (fat) stores during fasting and feeding states is largely dependent on SIRT1 and FoxO activity. This latest study investigates the role of these proteins in obesity and adds another level of regulation to the mix.

Using a drosophila model, Wang et. al. (Cell 145:596-606) provide evidence that the serine/threonine salt-inducible kinase (SIK) 3 controls lipid storage or lipolysis in a HDAC4/FoxO dependent manner. During feeding, insulin activates SIK3 (its mammalian homolog is SIK2), phosphorylates HDAC4, which prevents its activation and subsequent movement to the nuclear compartment. This inhibits the deacetylation and activation of FoxO and ultimately increases lipid storage. Under fasting conditions, SIK3 activity is inhibited, HDAC4 remains in an active, dephosphorylated state where it can easily translocate to the nucleus. In the nucleus, HDAC4 deacetylates and activates FoxO to increase lipolysis as a mechanism to provide energy to the starving organism. When the organism re-feeds, FoxO is acetylated via the action of p300 and CBP and HDAC4 is re-phosphorylated. Therefore, HDAC4 activity is a critical regulator of fasting or feeding states.

This pathway is not limited to drosophila. Using a mouse hepatocyte cell line, Wang et. al. confirm their findings in mammals, suggesting a universality of this mechanism.

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Nicotine suppresses appetite by activation of neurons of the arcuate nucleus

Many people use smoking as a mechanism to suppresses appetite and control their body weight. Nicotine in cigarettes is the culprit, affecting peripheral energy expenditures, but also affecting the central nervous system to regulate feeding. Mineur et. al.(Science 332:1330-1332) have now uncovered some the of the molecular steps involved in nicotine-induced anorexia. In mouse models, nicotine binds to the nicotinic acetylcholine receptor (nAChR) in the arcuate nucleus (ARC) region of the brain. Here it activates the pro-opiomelanocortin (POMC) neurons that begin to fire more frequently. This stimulates downstream melanocortin 4 receptors, ultimately releasing melanocortin, a known inhibitor of feeding behavior. The hope is that this work can lead to the development of new therapy to treat obesity and other metabolic syndromes.

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A new protein that controls obesity

Obesity is on the rise. Our diets aren’t healthy (or low in calories) and we are increasingly sedentary. Many scientists are researching how to control obesity and how to prevent obesity-related diseases including diabetes, cardiovascular disease and cancers. A new study by Zhang et al (Journal of Biological Chemistry 286:28396 August 12, 2011) identifies another player in the regulation of body mass and obesity. This protein, beta-arrestin 1, appears to regulate the expression of genes involved in metabolism and in inflammation. Since both are linked to many obesity-related diseases, these investigators investigated its role in obesity. Elimination of the gene increases body mass and metabolic dysregulation in mice fed a high fat diet. Conversely, overexpression of beta-arrestin 1 reversed these effects and restored normal weight, even in the presence of excess calories. While this is far from a magic pill to control weight and obesity, it does provide insight into how the body regulates weight and its metabolism.

Access to the internet is changing what we remember

A new study in Science Magazine by Drs. Sparrow, Liu, and Wegner (vol 333: 776, Aug 2011), demonstrates that we are using the internet as an external memory source to provide access to all the information we want to retain. All we have to do is remember how we found it.

Their data show that if we know we can just search for info again, we remember the website where we found the answer. Likewise, if we download the data, we recall the folder where it is stored. In either case, we are not as likely to remember the data itself. However, if we think the information is erased, our own recall of the information is pretty accurate. This study indicates that we are increasingly relying on having constant access as an external memory source (the internet). We just have to remember how we got there to find it!

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A new player in tumor metastasis

Primary tumors metastasize to distant locations through a process called endothelial to mesenchymal transition (EMT). Tumor cells have to move from the primary location, enter the bloodstream, travel to the distant site, enter that tissue and begin to grow in the new environment. In order to accomplish this, tumor cells alter the genes that are expressed. Breast tumor cells, for example, are epithelial cells that have begun to grow uncontrollably. As these cells emerge from the breast and enter into the bloodstream, many genes that define the tumor as a epithelial cell are switched off and genes that allow for movement (mesechymal genes) are turned on. Therefore, due to changes in the gene expression, primary breast tumors emerge from the breast, enter the bloodstream, and migrate to the lung where metastatic disease occurs. Scientists can detect the profiles of genes that change when tumors become metastatic, but how this switch occurs still remains unclear.

In a recent article in Oncogene (2011, 30:3440-3453) Dr. Xiang and colleagues at the University of Louisville, the University of Alabama, and the Louisville Veterans Administration Medical Center have provided new insight into how these genes are activated or inhibited. Their study shows that a gene regulator, called miR-155, acts as a switch that prevents breast tumor cells from migrating from the breast into the blood. Surprisingly, they also found that miR-155 can promote the formation of lung metastases if the tumor cells have already entered the bloodstream. While miR-155 appears to decrease the expression of genes involved in EMT and movement from the primary site, if tumor cells do manage to migrate, miR-155 can help promote their migration and growth in the lung. This is a bit of a double edged sword. These data do suggest that activation of miR-155 when breast tumor cells are confined only within the breast could be effective to prevent metastasis, however if the breast cells have already left the breast location, then activation of miR-155 will promote metastasis.

Skin cells produce their own cortisol

The ability of our skin to maintain and repair its integrity is crucial to our survival. Upon wounding, an inflammatory response is initiated, followed by wound healing and regrowth of the skin layers, or skin epithelium. This inflammatory response is mediated by proteins including the cytokine interleukin-1 (IL-1) that occurs in the skin at the site of injury. IL-1 stimulates the production of glucocorticoids (cortisol) that are tasked to ward off any infiltrating foreign agents prior to initiation of wound repair.

Cortisol is a glucocorticoid steroid hormone that is released in when the immune response is in full swing. Until now, it has been thought that the adrenals were the only site of cortisol production. In this recent paper, Dr. S. Vukelic and colleagues (Journal of Biological Chemistry 286: 10265-10274, March 25, 2011) clearly demonstrate both in cell based (in vitro) and in animal based (in vivo) models that corticol synthesis occurs within the epithelium itself. This is the first evidence that local production of cortisol by specialized skin cells termed kertinocytes can control the local inflammatory response. Indeed, Vukelic et. al. demonstrate that keratinocytes contain the proper enzymes for corticol conversion from cholesterol precursors including CYP11B1, the cytochrome P450 gene necessary for the final conversion step to cortisol. The production of cortisol in keratintocytes is equivalent to that produced by the adrenals. Production peaks at 48 hours after injury and is followed by wound repair and skin regrowth.

This paper is significant because it suggests that local production of glucocorticoids may have clinical significance by influencing the rate of repair after injury.

CD40 co-activation increases patient survival in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Only a small number of patients qualify for surgery and among those, few survive longer than 5 years. Current standard of care is chemotherapy (gemcitabine treatment), however this treatment, unfortunately, has limited efficacy.

New evidence reported in Science Magazine (Science 331:1612-1616, March 25, 2011) shows that preventing the activation of white blood cells or leukocytes, which are in high concentration in the tissues surrounding the pancreatic tumor, may improve the overall survival rate of patients. Dr. GL Beatty and colleagues are studying in mice how blocking a protein on the leukocytes, called CD40, can prevent the suppression of the immune system. This would allow for the patient’s own immune cells (macrophages) to attack the tumor to destroy it. In their mouse models, the combination of gemcitabine + anti-CD40 treatment helps promote survival cancer ridden mice. These data show promise for developing new therapeutic approaches to treat pancreatic ductal carcinoma.

New mutations found in Head and Neck cancer

Efforts are underway to identify the mutations in tumor cells that may give rise to cancer. Analysis of mutations in tumors from patients with head and neck squamous cell carcinoma (HNSCC) identified some familiar players (TP53, CDKN2A, PTEN, PIK3CA, HRAS ) along with some new faces (NOTCH, IRF6, TP63, CASP8, EZH2).

HNSCC is the 6th most common non-skin cancer. Risk factors that contribute to the development of HNSCC include tobacco, alcohol, and human papilloma virus infection. By comparing the sequence of genes (via a process called exon sequencing) in the tumors of patients with HNSCC with the sequence in normal, non-cancerous cells in their blood, Nicolas Stransky and colleagues have identified new mutations that were not previously known to be altered in HNSCC. These findings, published in Science Express on July 28, 2011 (DOI 10.1126/science.1208130) www.sciencemag.org, offer new insight into the regulation of HNSCC. Further, this data offers potential new targets to attack to prevent continued tumor growth.

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