Time for me to blast you with some more biochemistry, with an emphasis on the bio side of that chemistry. Today lets have a discussion about another Nature Scientific Reports article titled "The DNA Repair Protein OGG1 Protects Against Obesity by Altering Mitochondrial Energetics in White Adipose Tissue." In this article the authors discuss the protein OGG1 (8-oxoguanine glycosylase) and its effects on mitochondrial ('the powerhouse of the cell' - everyones high school biology teacher) metabolic functions in fat (adipose) cells. A fairly complex topic yet again (LOTS GOING ON!!), but worry not, in this case we can generalize a bit more and hopefully make a pretty good take away! That is, if you can survive the length of this post. I have tried my best to make this understandable, but its going to be a LONG read! Challenge accepted?
OGG1
One of the first things we should discuss is the protein OGG1 (8-oxoguanine glycosylase) in general. What does it do? Why is it important? To understand that, you must take a look at its name. It contains the word 8-oxoguanine, which is a mutated DNA nucleotide. It forms due to oxidation of a standard guanine (the G in DNA), and it results in an interesting effect during DNA replication.
Normally guanine forms a base pair with its partner cytosine (C in DNA). However if a DNA polymerase is replicating along and it encounters an 8-oxoguanine base, it has a tendency to put an adenosine there (A in DNA). Upon subsequent rounds of DNA replication this results in the change of a G/C pair to an A/T pair. That's bad from the context of maintaining the integrity of the DNA's sequence and can result in the change in a codon (3 base sequence required for indicating what amino acid to incorporate into a protein) and result in a change in a protein's sequence as well. If the amino acid was important for the proteins function... well you get the picture! It can lead to protein malfunction reduced activity, or worse! OGG1 is a protein which cuts the 8-oxoguanine base out of DNA allowing it to be correctly replaced with a G preventing that whole downstream issue we just discussed.
Okay Okay... But What Does a DNA Repair Protein Have to do With Obesity?
Hmm, not a bad question, doesn't seem like it would be intuitively connected. However the available literature paints an interesting picture. Dysfunction of OGG1 has been implicated in a whole host of issues ranging from cancer [2] to Alzheimers [3] but the one we are concerned with has to do with its ability not to participate in cellular DNA repair but rather a activity it has in mitochondria. It is in the mitochondria, that a cells metabolic activity the ability is located, and interestingly this DNA repair protein is found to sit in both the cells nucleus (where the cells's DNA is) but also in the mitochondria. OGG1 has been found to actually reside in the inner mitochondrial membrane, and a deficiency in this protein has been results in malfunctioning metabolism in mice and the development of obesity. [4, 5]. (Ah ha! There is a link!) Furthermore our evidence for this OGG1/Metabolism/Obesity link is not limited to mouse model systems. Rather researchers have identified mutations in OGG1 which also link this protein to both diabetes and obesity in humans as well. [6].
This Research Articles Question Given the link between decreased OGG1 expression levels/ malformed proteins and obesity, does increased mitochondrial expression of this protein have the opposite effect? Can we protect against obesity by pumping out more OGG1?
So Thats What They Did
The authors generated a mouse line which overexpressed OGG1. Specifically they over-expressed the human form of this enzyme, and the over expression was confirmed to occur in the mitochondria. They weren't the first to create this mouse line, there have been a variety of publications looking at them. [7 , 8] However studying the mice in general wasn't what these authors were interested in, rather they were focused on the ability of these mice to become little fatty mice. This was achieved by putting these mice on a very high calorie diet of mcdonalds and milkshakes. I kid of course, they fed them a high fat mouse chow diet and monitored their body weights over a period of weeks.
Above, we see the body weight data from the mice. In the first plot to the left we are looking at male mice which were fed the high fat diet. The data points in red depict the mice over-expressing OGG1 while the data in black are just normal mice. We can see that the normal mice are putting on the lbs... well grams... putting on the grams! While the mice over-expressing OGG1... just aren't, to a statically significant degree. We can then shift our attention to the plot in the middle. Here we are looking at the two mouse varieties (WT and OGG1 over-expressing) eating normal food. There the weight gain is similar. Nice to see. Finally we look to the plot to the right, this is of female mice. The data we observe here mirrors that seen for the male mice. So there is no difference in sex with regards to effect (which is often the case with mice, as metabolism for female mice is slightly different than male mice). All subsequent experiments discussed were performed with male mice.
Are There Metabolic Differences?
The authors studied a variety of metabolic parameters for the mice and found that the OGG1 over expressing mice had better glucose tolerance (ie. they weren't diabetic), lower blood insulin levels, and significantly reduced fat accumulation in their livers. Why is this?
One of the reasons the authors considered was that the OGG1 over expressing mice were just eating less food. However, food intake was monitored (figure to the left) and compared to the wild type mice (black), they were either eating the same amount or perhaps even slightly more (red). This was consistent for both the normal feed (left set) and the high fat feed (right set).
Okay, so its not that the mice were eating less. But what then? The answer becomes apparent when you quantitate the activity levels of the mice (seen to the right). The OGG1 over-expressing mice were just a LOT more active then the normal mice. Yes you can point out that the error bar is pretty large (there was a variance in the activity of the mice sampled) and the P value isn't great. However these are living creatures, not subatomic particles ( :P picking on you 
The authors also illustrated that O2 consumption of the OGG1 over-expressing mice was increased, indicative of increased metabolism, which is further coupled with increased CO2 exhalation. The mice were just more metabolically active!
Next the authors turned to some fat tissue (adipose cells), and studied some additional metabolic parameters. These studies included looking at the expression levels of two important proteins called leptin and adiponectin. Leptin is a protein which is produced by fat cells and is supposed to signal to the brain that you have eaten enough. However, counter intuitively obese people have higher blood concentrations of leptin and actually develop a desensitization to the leptin signaling. Further counterintuitively, others have proposed that leptin is actually a starvation indicator, with higher leptin concentrations actually signalling to the body to conserve fat (strange right? telling the brain "don't eat" but yet at the same time "save the fat"). [9]. As for adiponectin, that is another signaling molecule which results in increased fat metabolism and expression levels are typically lower in obese people then in skinny people. [10].
As for the mice in this study (the figure above and to the left, again the black bars are the wild type mice, and red are the OGG1 over expressing mice), we see that the OGG1 over-expressing mice had lower levels of adipose leptin and higher levels of adipose adiponectin. The literature indicates that this should result in the OGG1 over-expressing mice storing less fat (lower leptin), and increasingly utilize fat stores for energy production (higher adiponectin). This data is in line with the increased activity, and resistance to the storage of fat when feeding on the high fat diet previously described/observed.
Isn't this a Mitochondrial Protein? What About Changes To Mitochondrial Protein Expression?
Another place to look at changes, the authors quantified the mRNA expression levels of various mitochondrial proteins and compared these levels in the wild type vs the OGG1 over-expressing mice. They note a few key differences in proteins involved in mitochondrial energy production and transport including Cytochrome b (Cyto B in the figure) and some others which are not discussed, are not involved in fat metabolism (as far as I know at least, correct me if I am wrong here!) and are interesting to me: Cox-3 (involved in inflammatory and pain pathways, possibly the target of Tylenol or paracetamol for you Europeans) [11] and Cox-2 (also involved in inflammatory and pain pathways, this one is targeted by aspirin and ibuprofen).
So we have a lot of mitochondrial protein expression level changes, some of which are involved in electron transport and important for metabolism, and a reduction in weight gain in the mice. Is the weight gain really due to the mitochondrial effect of this protein? Prior research indicated that loss of this protein results in obesity, among other things. What if you knocked out the expression of this protein everywhere but the mitochondria, and in the mitochondria you over-expressed it? What happens there?
To the right we have the final figure I will show you. It addresses just that question, as the authors generated mice under just that state (complete OGG1 knockout, with re-introduced over-expression in the mitochondria specifically). The black data are WT mice, eating a high fat diet and as in prior figures we see an increase in body weight as time progresses. The (tan? light yellow?) data points, those are from a mouse model which has had OGG1 knocked out, and they show a slightly increased weight gain rate over that of the wild type mice, illustrating the phenotype described by past literature. Finally in purple(ish) we have those mice with OGG1 knocked out, however with the protein over-expressed in the mitochondria. Interestingly the mice not only don't show the increased weight gain of the standard knockout mice, they actually completely reverse the phenotype and again gain less weight than the wild type mice. Thus implicating only the mitochondrial activity of the protein on the reduced weight gain phenotype.
Summing Things Up
To summarize, the DNA repair protein OGG1 has been implicated in influencing metabolism, where a reduction in protein expression is thought to contribute to development of obesity. Here authors explored whether over-expression of this protein could provide some protective effect against the development of obesity. They explored this effect in a mouse model and found that indeed yes OGG1 over-expression reduced weight gain of mice eating a high fat diet. They then showed that it is specifically the fraction of this protein active in the mitochondria which provides this phenotype. Protein expressed elsewhere (in the nucleus) was dispensable.
Really cool! This DNA repair enzyme, involved in removing the 8-oxoguanine nucleotide mutation, plays a significant role not only in this repair activity but also in regulation of mitochondrial energy metabolism and subsequent adipose tissue fat storage.
Other Cited Materials
Images
1.) The horizontal rule used throughout this post is provided for free use by syntaxxx.com
2.) OGG1 Available by CC 3.0 license
3.) Lil Fatty Mouse
Text Sources
1.) https://www.nature.com/articles/s41598-018-33151-1
2.) https://www.nature.com/articles/1202096
3.) https://www.sciencedirect.com/science/article/pii/S0047637416300720
4.) https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051697
5.) https://www.molbiolcell.org/doi/10.1091/mbc.10.5.1637
6.) https://www.sciencedirect.com/science/article/pii/S0006291X0901078X
7.) https://academic.oup.com/endo/article/154/8/2640/2423711
8.) http://www.jneurosci.org/content/31/26/9746
9.) https://onlinelibrary.wiley.com/doi/abs/10.1038/oby.2009.228
10.) https://www.ncbi.nlm.nih.gov/pubmed/15655035
11.) https://www.ncbi.nlm.nih.gov/pubmed/15626590
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