For all of you out there who have resolved to lose some weight, we will continue with this “know thy enemy” theme and talk once again about fat. Losing weight is hard. I was salivating over some light weight mountaineering equipment and my wife intelligently suggested that if I lost 10 pounds it would far exceed the ounces I would shave from the weight of my pack and also save us a pile of money. After 3 weeks of watching my weight dip by a pound or four and then pop back up I now have a new respect for those who are successful dieters. What especially surprised me is that I exercise a lot and, living in Colorado, my wife and I spend at least one day a week playing in the mountains. This underscores the observation that exercise alone is not sufficient. I tried cutting alcohol and chocolate but, apparently, I must be compensating by eating more of other things. It seems that several weeks of hunger pangs are in store if I am to achieve my goal.
There exist some people who can eat anything they want and remain thin. This seems like a blessing but, if you think about it, these people would not have survived in ancient times. They remain thin because they have inefficient metabolisms. Those of us who gain weight by just looking at cheese cake have efficient metabolisms and thus can survive on less food. What is the basis for this efficiency or lack thereof?
We can divide the molecules that supply nutritional energy into three broad classes: carbohydrates, fats, and proteins. Carbohydrates are broken down into sugars which are rapidly absorbed into cells such as muscle via the actions of insulin. Fats are broken down into lipids and cholesterol and transported through the blood stream via lipoprotein complexes called chylomicrons. Proteins are broken down into amino acids which are taken up by all cells.
All of these three classes of molecule ultimately share the same fate. They will be burned in the furnace of metabolism via the citric acid cycle (also called the Krebs cycle); that famous bit of biochemistry that is the bane of all biology undergraduates. The gist of the cycle is that enzymes will convert citric acid through 8 different forms until ultimately citric acid is remade. In the process oxygen will be used up, carbon dioxide will be produced and a number of high energy electrons will get produced; the energy of which will be transferred to the high energy phosphate bond of ATP. Sugars such as glucose get broken in two and then each piece gets inserted into the cycle. Proteins, almost always derived from skeletal muscle, get broken down into their amino acid components and these amino acids are secreted into the blood stream. They are slurped up by the liver which then converts them to glucose. This is especially important for diabetics because, as I have written before, this is a major source of high blood sugar. Once this amino acid derived glucose finds its way into a cell, it will also be burned in the metabolic furnace. Fats are broken down into their component fatty acids – long carbon chains which, in turn, are converted into 2 carbon molecules via a process called beta oxidation. These two carbon molecules can then too be burned.
In a sense, our metabolism has a personality. It could be a saver or a spender. It all depends on the balance of signaling molecules that whisper to cells like angels and devils advising from the shoulder. Their names are many. At the top of the list, of course, are the pancreatic signals; insulin and glucagon – the hormones of plenty and famine respectively. Next come the legion of adipocyte hormones: leptin, ghrelin, adiponectin, and visfatin to name just a few. Then come the small bowel neuropeptides: cholecystokinin (CCK), glycogen-like peptide (GLP), and peptide YY (PYY) which try to get us to not eat. There are more…but I think you get the point. These angels and devils are populous enough to form a congress.
We have tried synthesizing large amounts of the “good” signals and using them as drugs to promote weight loss. The results have been disappointing. Perhaps it is because there are so many different signals that manipulating just one signal is ineffective. In the case of insulin it works because insulin is the top dog but insulin has no effect on eating behavior and indeed, promotes fat storage.
Let’s come at this problem from a different direction. Literally. Lets start with beta oxidation (burning fat). There are a bunch of enzymes that perform this task. These enzymes, of course, come from genes and it does seem that those metabolically inefficient people have more of these enzymes. Can these genes be regulated? The answer is yes and many of these whispers do get translated into up or down regulation of the transcription of these genes.
One of the exciting discoveries of the past half century is that our genes are organized into functional groups. The organization is not via location as it is in lower forms such as bacteria. Rather, the organization comes from special proteins that organize genes in an informational context. Genes are simply blueprints for the construction of proteins plus an instruction set for when these proteins should (or should not) be made. One element of this instruction set that we understand fairly well are things called response elements or enhancers. Enhancers are short sequences of DNA that serve as binding sites for special proteins called transcription factors. One gene can have many different enhancers that operate in different combinations. This is a beautiful and subtle system in that now genes can be placed into different groups depending on the physiological response required. Should we be dealing with infection, one class of transcription factors is activated. These proteins scan the entire genome and bind to their sites wherever they may be. The genes that are necessary are turned on. The genes that are in the way are turned off. At some later time, the infection is dealt with and now the situation of the moment involves increased physical activity. Some of the same genes will turn on but they will do so at the behest of a different set of transcription factors that just happen to include some of the enzymes from the immune response for this different purpose. The mechanism by which transcription factors activate genes (turn them on) is to simply sit there and attract other proteins. Like the growth of a crystal the binding of the transcription factor to DNA creates new binding sites for other proteins and these proteins find their way to the complex. Over the course of milliseconds a molecular machine has been built that ultimately recruits the final protein: RNA polymerase. This enzyme is given a figurative kick in the butt and it scoots down the gene, copying it into RNA. The RNA is processed into messenger RNA and shipped off to the ribosome to be made into protein. That’s how it works.
Returning to beta oxidation, there are just a few transcription factors that seem to play the major role in this process. They include the Nuclear Response Factors; NRF-1 and NRF-2, the weirdly named Peroxisome Proliferation Activating Receptors; PPAR alpha, gamma, and delta (I don’t know what happened to beta), and the Farnesoid X Receptor (FXR). This is still a lot of different proteins. Interestingly, however, as they each create their own unique transcription complex, they all just happen to recruit the same protein; PPAR Gamma Coactivator – 1 alpha (PGC – 1 alpha). This has led to the exciting question; can all of this be regulated at this one point? If we could activate PGC – 1 alpha containing complexes could we promote beta oxidation?
Manipulation of a subset of these transcription complexes is actually standard diabetes therapy and has been so for over a decade. It turns out that the major glucose transporter gene has a PPAR gamma responsive element and activation of PPAR gamma turns it on in an insulin independent manner. Actos and avandia are both small molecules that have been designed to activate PPAR gamma and, as you probably know quite well, they lower blood sugar. They do so at the level of gene therapy. They turn on PPAR gamma that, in turn, turns on the gene (GLUT4) that codes for a major glucose transporter (a glucose shaped hole). GLUT4 is expressed on the surface of cells and glucose now has a place to go. Can we do something similar with PGC – 1 alpha? If we did so, the result would be increased beta oxidation. In effect we would be creating an especially strong whisper to the cell to burn fat rather than store it. The result would (hopefully) be a feeling of energy and motivation. If this was combined with modest dieting and exercise the results could be significant. As of 2009 we do not have such a molecule but that does not mean that it cannot exist. The search is on and perhaps 2010 will be the year.
So, for those of you who have resolved to lose some weight, I am afraid that hunger is still in store. Those whispers are intensely strong and you must be vigilant in avoiding the bad ones. Luckily for me, I did not actually make a New Years resolution to lose weight. Instead, my resolution was to always find the time to write at least one blog entry for A Sweet Life every week. So far I am meeting my resolution. I hope that all of you meet yours.