A UV addiction through endorphins?

Ah, summer, with its warm weather and abundant sunshine, is finally here - well, sort of if you live in the UK. Sun worshipers crowd patches of grass at every opportunity, desperate to catch some heat and, with any luck, the lovely, healthy glow of a tan.

Image from https://flic.kr/p/4dnzTq

Apparently, according to a recent Cell paper, the uncontrollable urge to go sit out in the sunshine to catch some rays (or go lie in a tanning 'coffin' if so inclined) can actually be explained by an addiction to UV light.

When we are exposed to UV light, the DNA in our skin cells, or keratinocytes, becomes damaged, which triggers the activation of a pathway that results in the production of a protein known as proopiomelanocortin (POMC). This is processed into a hormone, known as α-MSH, that stimulates the tanning process. It is also processed into β-endorphin, an endogenous opioid that offers similar analgesic effects to exogenous opiods, partly by binding to μ-opioid receptor.

The research group from Harvard Medical School saw that exposing rats to UV light triggered the production of  β-endorphin, as they expected. What was intriguing, however, was that this seemed to correlate with a higher pain threshold, something that could be blocked through treatment with the opioid antagonist naloxone, a drug that is used to counter the effects of opioid overdose.

What is more, treating these rats with naloxone triggered what the researchers describe as "classic murine signs of opioid withdrawal" - apparently that's "wet dog shake, paw tremor, teeth chatter and rearing". This suggests that the rats were developing an addiction, of sorts, to the β-endorphin released after UV exposure.

Notably, the increased pain threshold and withdrawal symptoms were not observed in rats lacking β-endorphin, which highlights it as the 'causative' factor behind these symptoms.

So there you have it - the release of β-endorphin seems to be causing a UV light addiction, complete with withdrawal symptoms. Although the work was carried out in rats, a similar addictive behaviour may apply to humans as well and may explain, in a more biological way, why many of us continue to expose ourselves to high levels of UV light despite knowing that it can give us skin cancer.

Who said beige is boring? The secrets of good fat, and more evidence that the immune system is behind everything

We have all been conditioned to believe that all fat is bad, but this is not actually the case. We are born with what is known as brown fat, which actually burns energy by generating heat, or thermogenesis, to protect us from the cold. But this is gradually replaced with white fat, the fat that we all consider to be bad. However, some white fat can be converted into brown fat when exposed to cold or intense exercise; in this case, the brown fat is called beige, or brite, fat.

Bad but tasty fat!

With obesity in an all-time high, there is obviously great interest in understanding the mechanism behind this conversion process and potentially use it to develop therapeutics. Two independent studies published in Cell now identify a link between the development of beige fat and the immune system.

The first group, led by Professor Bruce Spiegelman, found that the levels of the hormone Metrnl (Meteorin-like) increases in the bloodstream after exposure to cold or exercise, and injection of this hormone in mice resulted in the expression of brown fat genes and reduction of fat content.

Metrnl must somehow trigger the switch to beige fat - this is where the immune system fits in and where the two studies overlap. Using genetically modified mice, the second group, led by Professor Ajay Chawla, saw that interleukin-4 (IL-4) and IL-13, two immune molecules known as cytokines, can also stimulate the conversion of white fat into beige fat. And, as shown by Spiegelman's group, Metrnl stimulates an increase in the levels of these cytokines.

Both groups went on to show that IL-4 and IL-13 in fat tissue are produced by immune cells known as eosinophils, which are famous for their roles in combating parasite infections but are also culprits in the pathology of asthma and allergies.

In this case, eosinophils produce IL-4 and IL-13, which trigger the development of alternatively activated, or M2, macrophages, another immune cell type that is involved primarily in tissue repair. These cells then produce a group of molecules known as a catecholamines that can trigger the expression of the genes that convert white fat to beige fat, ultimately giving rise to beige fat development.

Could targeting the immune system offer a solution to obesity and metabolic diseases such as diabetes? The results of the two studies suggest that targeting this pathway may be promising. Spiegelman's group found that injecting mice with Metrnl decreased their body fat content, and could improve glucose tolerance in obese diabetic mice. Along similar lines, Chawla's group found that injecting obese mice with IL-4 decreased fat mass and could restore insulin sensitivity.

So, once again the immune system is the 'conductor', orchestrating the conversion of beige fat from white in times of stress such as cold, and holding the key to a not-so-boring type of beige, ie the kind that makes us lean!

What makes you you? Day of immunology and fun times learning about diversity

What is the feature that distinguishes us from each other, that makes up unique? Most would immediately think of obvious external characteristics like hair or eye colour, but as Professor Daniel Davis explained in a recent lecture I attended, it is actually our immune genes.

Taking us on a whirlwind tour of immunology history, Davis set off by describing the discovery of immune tolerance in 1951 by Medawar and colleagues, who were at the time trying to understand why transplants are rejected. We now know that transplants are rejected because they are recognised as foreign, or 'non-self', by our immune system, and what instructs this recognition are a set of genes known as histocompatibility genes.

The collective work of numerous scientists in the past 60 years has uncovered the shear diversity of histocompatibility genes in the population, how this diversity is integral to our susceptibility to diseases, and the checks and balances present to ensure that this recognition system is working correctly.

But the effects of histocompatibility genes go beyond immunity: more recent work has uncovered fascinating roles for these genes in sexual attraction, with a study finding that women are more likely to be attracted to men with histocompatibility genes that are different from theirs, and even in pregnancy.

The lecture, organised by my old friends at Nature Reviews Immunology, was part of the international Day of Immunology, which first took place on April 29th 2005. Its aim is to celebrate this exciting discipline and raise awareness of its applications, in particular with regard to wellness, to the lay public.

And this is sadly not an easy feat - as Davis noted, there is a dearth of popular science books or TV programmes on immunology, despite it being a subject that has the potential to be of interest to scientists and lay public alike. There is of course a lot of jargon, like any specialist field, and numerous basic concepts that are necessary to understand any new ideas, which has resulted in this crazy idea that immunology is a scary, complicated subject, even among other scientists. Davis urges all immunologists to take steps to become involved and present this exciting discipline to the public (see his Comment piece on Nature Reviews Immunology, which is free for registered users).

His recent book, The Compatibility Gene, will hopefully spur others to explore this field and write more broadly about it. I can't wait to read it! 

PGE2 as a baddie during influenza infection

One of the things that bugs me a lot, in an entirely geeky way, is when people tell me they have the flu - most of the time, they really just have a cold, caused by a completely different pathogen. Influenza, the real cause of flu, can actually cause very serious disease, much more debilitating than a cold virus, and can even lead to death. Case in point: the Spanish flu is thought to have killed more than 20 million people during the first world war, many believe that was responsible for more deaths than the war itself.

Villains
Image from
https://www.flickr.com/photos/kaptainkobold/6900425981/

But I digress. The rant was triggered by a very interesting paper that I spotted in this week's Immunity, which identified a new potential therapeutic target for influenza A: a group of molecules known as prostaglandins.

An involvement for prostaglandins, a group of lipid molecules with many roles including inflammation and immunity, in influenza infection is not new. A quick search in PubMed revealed that members of the prostaglandin family have previously been shown to block influenza replication and limit inflammation, and deficiency in the enzymes responsible for generating the prostaglandin PGE2 (COX1 and COX2) has revealed conflicting results.

Serpins offer survival advantage to metastatic cancer cells

Cancer cells manage to get away with a lot - they evade recognition by cells of the immune system, they hijack oxygen and nutrients from normal cells and tissues, and travel and successfully establish themselves into new parts of the body. The later, known as metastasis, is considered the main cause of death in cancer, and despite this the factors driving it have remained fairly enigmatic. But today I came across a slightly older study from Cell that identified a  'duel' between cancer cells and cells from the brain microenvironment involving the molecule plasmin.

Plasmin is an enzyme that is released by the body to break down naturally occurring blood clots, and in the brain is expressed in high levels by one type of cell known as an astrocyte. While looking for factors involved in metastasis, the authors of this study found that metastatic lung and breast cancer cells express high levels of molecules known as serpins, a subset of which (NS, serpin B2, serpin E1 and serpin E2) are known to inhibit the function of plasmin.

Its good to talk, especially in the case of fat cells and skin cells

To get anywhere, you need effective communication, be it between say construction workers building a bridge (as a human example), worker bees making honey or bats out in the dark hunting for food. The same applies in the micro scale - the cells in our body need to communicate at different stages of development so that they know what to become, where to go, whether to grow or die, among other things.

Its good to talk.
 Image from https://www.flickr.com/photos/danielcoy/4175199668

And just like many other cells in the body, adipocytes (or fat cells; a slight obsession of mine in my previous life!) communicate with a type of skin cell known as a keratinocyte, sending signals to regulate the growth of hair follicles and, ultimately, hair growth (a very complicated cycle of growth and death that you can read about here if you have access). It turns out that this line of communication actually goes both ways, as a new study published in PNAS shows that molecular signals from epidermal cells also regulate the growth of the underlying adipocyte layer.

CMPF could offer a new target for diabetes

A potential culprit for diabetes in pregnancy (gestational diabetes) and type 2 diabetes has been identified in a recent study published in Cell Metabolism.

Gestational diabetes can affect up to 5% of pregnant women, at least in the UK, and can develop in the absence of any previous history of intolerance to glucose. Women with this condition have higher than normal levels of glucose in their blood, usually because their bodies do not produce enough insulin to transport glucose into the cells. The mechanism underlying the development of this condition has remained a mystery, although it has been linked with a decline in the function of pancreatic β cells, the cells that produce insulin.

An imbalance of metabolites

When the authors screened the blood plasma of women with gestational diabetes, they found a significant change in metabolites compared with women without this disease, in particular in the levels of a range of fatty acids. Among this was the furan fatty acid metabolite CMPF, which was greatly increased in those with gestational diabetes. Interestingly, levels of CMPF were also increased in patients with type 2 diabetes compared with controls, and in both cases this was independent of BMI or age.