Young and Old Mice Differ in Energy Regulation: Implications for Childhood Obesity?

An obese mouse unable to produce leptin compared to a normal mouse

The fat-busting molecule, leptin, appears to work in different regions of the brain in young compared with old mice.

In the mid 90’s, the way scientists think about what causes obesity was revolutionized with the discovery of leptin, an appetite-suppressing hormone.

Leptin is made by fat tissue and binds receptors in the brain to reduce energy intake by suppressing appetite and increasing activity to burn off energy, essentially regulating energy balance, or ‘homeostasis’.

Understanding how energy homeostasis is regulated is an area of intense research because of the current obesity epidemic. Importantly, childhood obesity is rising worldwide, together with associated conditions such as type 2 diabetes and heart disease. However, ways of treating childhood obesity remain mainly ineffective.

Leptin contributes to the regulation of energy homeostasis by acting on neurons in different brain regions, but exactly what effects each region mediates has not been clearly determined.

To address this question, Ring and Zeltser from Columbia University in New York, created mice in which leptin signaling was disrupted in only the hypothalamus of the brain (LeprNkx2.1 KO mice). When they compared the characteristics of these mice at a young age (<8 weeks) to mice lacking leptin signaling in all body cells (Leprdb/db mice), they found they were similar showing increased weight gain and increased amount of fat tissue. In contrast, after 8 weeks they found that mice with disrupted leptin signaling in the hypothalamus maintained consistent levels of fat tissue, whereas the mice lacking leptin in all body cells, became more and more obese. These findings suggest that leptin signaling in the mouse hypothalamus is needed to stop the development of fat tissue in young mice, whereas leptin signaling limits the development of fat tissue in older mice occurs through other regions of the brain.

The authors highlight that ‘these observations are consistent with the idea that the regulation of phenotypes related to energy homeostasis may be different (and less complex) in immature animals.’

The authors conclude ‘If this notion proves true, manipulations of critical components of circuits that establish metabolic profiles in young animals would represent a promising strategy to combat childhood obesity.’


Bone Drugs May Thwart Development of Cancer ‘Seeds’

What do cancer cells and seeds have in common? The way that they spread to a new site and germinate it seems.

When a plant goes to seed, its seeds are carried in lots of different directions, but they can only grow and develop if they land on soil which is conducive to growth. Similarly, it is now well known that when cancer spreads secondary tumors (or metastases) do not develop by chance, as some organs provide a more fertile soil for tumor growth than others. These ideas form a long-running hypothesis in cancer research called the ‘seed and soil’ hypothesis.

A recent editorial in the Journal of Clinical Oncology this week by Dr Michael Gnat, further reinforces this hypothesis for cancer development, and that a certain group of bone cancer drugs, bisphosphonates, might create an “unfavorable soil” in which the development of cancer cells is thwarted.

Bisphosphonates are the treatment of choice for preventing bone loss and fractures in postmenopausal women with osteoporosis. They are also being investigated as treatment for preventing cancer-induced bone loss in women with early-stage breast cancer. Importantly, they have demonstrated anti-cancer activity in the lab and in clinical studies, which have shown that they:  block the release of factors that promote tumor growth and angiogenesis (growth of the tumors blood supply), induce cancer cell death (or apoptosis), prevent cancer cells sticking to each other, reduce the ability of cancer cells to spread via blood vessels, and activate the immune system to attack cancer cells. 

Based on this background information, several studies have been set up to determine whether bisphosphonates given to women with postmenopausal osteoporosis may reduce the risk of breast cancer, including two studies reported in the same issue of the Journal of Clinical Oncology.

In the first study by Chlebowski et al., approximately 150,000 women who received bisphosphonates for osteoporosis had a 32% reduction in the risk of breast cancer versus those who did not receive bisphosphonates. In a separate study by Rennert et al., a 28% reduction in the risk of breast cancer was reported in women receiving bisphosphonates for more than 1 year.

‘At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy’

However, these results should be considered with caution as the authors note that several factors may have influenced the results, including age, ethnicity, and tobacco use to name but a few, says Dr Gnat. As a result, he states, ‘these analyses should be viewed as hypothesis generating and not practice changing at this time’…. ‘At this point, it would be premature to recommend the use of oral bisphosphonates to prevent breast cancer in all postmenopausal women. However, it is not unreasonable to consider the potential anticancer benefits of bisphosphonate therapy, in addition to its bone protecting effects’.

‘Bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing cancer’

Dr Gnat also states ‘The statistically significant reductions in breast cancer risk associated with bisphosphonate use “are profound and intriguing, because they suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing breast cancer,”. He goes on to say that these significant results are ‘profound and intriguing’ as they ‘suggest that bisphosphonate-induced changes to the microenvironment surrounding potential cancer cells can be exploited in preventing cancer’. He also suggests that these results support the idea that the seed and soil hypothesis is relevant to both healthy postmenopausal women as well as in preventing recurrence in women with early-stage breast cancer.

In conclusion, Dr Gnat suggests that future anticancer treatments may target the tumor microenvironment in addition to the cancer cells themselves.





All Roads Lead to Blocking Androgen Signaling in Castrate-Resistant Prostate Cancer, But Which Road is Best?

Things are hotting up in the prostate cancer field, with scientists discovering several new targets that may provide hope for patients with late-stage prostate cancer.

Androgens (testosterone and dihydrotestosterone) are known to fuel the growth of prostate cancers as they bind the androgen receptor (AR) driving signaling pathways that driving tumor cell proliferation and tumor development. To halt the effects of androgens binding the AR, androgen deprivation therapy (ADT) is used to try and block the levels of circulating androgens and prevent them from fuelling tumor growth.

Despite ADT reducing androgen levels to very low or ‘castrate’ levels, castrate-resistant prostate cancer (CRPC) typically develops in most patients who initially respond to treatment. The precise mechanisms underlying this resistance are just starting to be worked out, but it seems that that ADT does not fully ablate androgen synthesis in the adrenal glands (where androgen synthesis normally occurs)  nor in the tumor itself where recently it has been discovered that androgen synthesis also occurs.

Once CRPC develops, the time to death is about 2 years and treatment options in this patient population are limited, demonstrating a high unmet need for treatments that prolong survival in these patients.

Androgens are synthesized from cholesterol involving complex enzymatic pathways, which includes the enzyme 3 beta-hydroxysteroid dehydrogenase which takes inactive precursors (DHEA and A5diol) and converts them to the more active androgens, androstenedione and testosterone, which are later converted to dihydrotestosterone. If this enzyme is active in prostate tumors, testosterone and dihydrotestosterone could in theory bind the AR and continue to fuel tumor growth. In a recent study in the journal Endocrinology, Evaul et al., discovered that was the case with 3 beta-hydroxysteroid dehydrogenase being necessary for producing testosterone and dihydrotestosterone in models of CRPC, which then activates the AR, driving tumor cell proliferation. As a result, this enzyme is thought to provide an attractive new target for the treatment of CRPC.

At the moment this is just a hypothesis that needs to be tested in the clinic. However, there are similar agents currently in later stages of development, including abiraterone and TAK700 which inhibit another enzyme in the androgen synthesis pathway (CYP17,20), MDV3100 which blocks androgens binding the AR, and VN/124-1 which both inhibits CYP17,20 and blocks androgens binding the AR. These are indeed exciting times for prostate cancer patients.


Decaying Cellular Waste Disposal Pumps Linked to Cellular Aging

The maternal instincts of yeast cells to protect their offspring from the damaging effects of cellular toxic waste appears to promote their own demise, but this altruistic act also provides new insights in cellular aging and importantly age-related diseases such as cancer.

Most cells appear to have a finite ability to replicate, after which they enter a stage of cell aging, also known as cellular senescence during which toxic agents build up within cells.  Research reported by Li et al. this week in Nature Cell Biology provides further ideas on how and why this occurs.

Li et al., used bakers’ yeast, Saccharomyces cerevisiae, as a model to for studying aging, in which cells divide asymmetrically producing a ‘mother’ and ‘daughter’ cell which are not identical. Previous studies have shown that during yeast cell division, the mother keeps the damaged proteins which are toxic and could be harmful to the daughter cell. Dr Li and her team discovered that the mother yeast cell keeps an old set of  a specific type of protein called a Multi Drug Resistant (MDR) protein, but gives the daughter cells a completely new set. MDR proteins are well known already, as they have been implicated in resistance to some cancer drugs, by expelling the drug from the cell. However, they also transport compounds in and out of normal cells.

Li et al., found that these MDR proteins decayed and lost their function right at the end of the cells’ life, suggesting that they are limiting the lifespan of cells effectively resulting in the loss of a cell’s fitness. As a result, Li et al., hypothesized that if the loss of MDR proteins contributes to aging, then cells lacking MDR proteins should have a reduced lifespan (measured by the replicative ability of the mother cell), and that is exactly what happened- losing one MDR gene and the resultant lack of a particular MDR protein reduced the replicative ability of the mother cell by up to 66%. Conversely, when extra copies of MDR genes were inserted in the mother yeast cell, which led to over expression of MDR genes, the investigators saw an increase in replicative ability.

How this translates into humans, is not yet clear but the MDR proteins are conserved across organisms suggesting that they may have an important role in aging. This process mayalso explain why cancer cells which contain high levels of MDRs are immortal.


Going Bananas Over a Bug Provides New Insights into How Prostate Cancer Develops

I’ve never been to the French West Indies, and I’ve never heard of the banana root borer (a larvae which tunnels through banana corms- admit it, you were wondering!), but this little critter has sparked some insightful research into what causes prostate cancer.

Unlike other cancers, little is known about the risk factors for prostate cancer with increasing age, ethnicity (Afro-Carribean men have an increased risk of prostate cancer for example) and family history of the disease being the only known risk factors.

The key drivers of prostate cancer development are androgens which bind the androgen receptor (AR) in prostate cancer cells and promote tumor development; however, estrogens are also thought to be involved as estrogen receptors (ERs) have been found in the prostate and in vitro studies have shown that binding of estrogens or estrogen-like molecules (also known as endocrine disruptors) to these receptors (ER alpha and beta) can result in prostate cancer development in tumor models.

Chlordecone (also known as Kepone) is an insecticide which has estrogenic-like properties in that it can bind ER alpha and beta and therefore has similar physiological properties to estrogen. Notably, the incidence of prostate cancer is particularly high in the French West Indies, where chlordecone was used for over 30 years to kill the banana root borer larvae.

Based on these findings, Luc Multigner and colleagues from Universitaire de la Guadeloupe in the French West Indies, measured exposure to chlordecone by measuring it’s concentration in the serum of 623 prostate cancer patients and 721 control patients exposured to this agent for over 30 years and found that it was consistently associated with an increased risk of prostate cancer. Prostate cancer risk was higher in subjects with a family history of prostate cancer, suggestive of similar patterns of exposure to chlordecone possibly through genetic susceptibility to the toxic effects of this agent. In addition, prostate cancer risk was increased for those men who had lived in Western countries, possibly attributed to lifestyle and nutritional changes which could increase the risk of developing prostate cancer.

The authors hypothesise that chlordecone acts as an ERalpha agonist and an ERbeta antagonist in the prostate. It is unclear how chlordecone exactly causes prostate cancer, but it is thought that the balance between the bad cancer causing effects mediated through ERa (increasing cell proliferation and inflammation) and the good anti-cancer effects (antiproliferative and ant inflammatory) mediated by ERbeta may be tipped in favor of the bad estrogen- ERalpha.

This is the first epidemiologic study to demonstrate a link between between environmental exposure to endocrine disruptors and prostate cancer development, and will heighten the debate surrounding the use of these agents and their potential risks for humans.

Reference: Journal of Clinical Oncology: