First a little background on gene expression if you didn't implicitly understand what I wrote above. About 1 % or so of your DNA encodes for proteins. To make a protein, the DNA has to be pulled apart and a complementary single-stranded RNA polymer built to match. This is called messenger RNA and it is sent off to an organelle known as a ribosome which actually assembles the protein that the DNA encodes for.
The rest of your DNA is functional with 'dead space' being a common function. DNA, when being unzipped typically folds in on itself, so sections of the DNA well ahead of the protein encoding region often have functions related whether or not that protein encoding region is actively being transcribed or not. Other proteins literally sit on these spaces and their interaction with the enzymes that unzip and transcribe DNA determine whether messenger RNA is produced or not. Foxa2 is one of these gene transcription activators, so it operates at a very basic level of cellular mechanics. However, it can only do this when insulin is bound to foxa2. Presumably the binding of insulin to foxa2 reconfigures the shape of the foxa2 protein; with proteins, function follows structure/shape.
Silva et al. (2009) published in the journal Nature that this same receptor, foxa2, is found in the hypothalamus (of mice) and it directly effects the hunger reflex. What they did was to take normal and genetically obese mice, fast them, and inject some of them with insulin to put them into the 'fed' state. They then sacrificed the mice and dissected their brains, using an antibody-based stain to identify neurons that were positive for foxa2 and orexin and melanin-concentrating hormone (MCH). Orexin and MCH are known to be associated with feeding and, incidentally, sleep behaviour (Willie, 2001). From their results the authors concluded that the production of the neuropeptides orexin and melanin-concentrating hormone (MCH) were promoted by the foxa2 receptor (but only with insulin attached to it). One of the stronger pieces of evidence was that foxa2 was found in the cytoplasm of the mouse neurons when in the fasted state but in the nucleus when in the fed state. Transcription of messenger RNA occurs in the nucleus.
Supplementary Figure 1 (from Silva, 2009): Author's impression on how the foxa2 receptor cycles in and out of the nucleus in response to insulin.
I put mice in parenthesis in the preceding paragraph because there have been significant differences found between how various pieces of molecular machinery are distributed in rodents versus humans. A good example of this is selano-deiondinase type 2 (D2), which converts the inactive form of thyroid hormone, T4, into the active form T3. It's found in the skeletal muscle of humans but not rats ( Heemstra, 2009 and Larsen, 2009). Incidentally, both papers have fascinating implications for fasting in humans as well as sick euthyroid syndrome.
Interestingly the way they found the distribution of the Foxa2 receptor amongst neurons of the hypothalamus was through the use of specific antibodies as a microscopy fluorescence stain. I'm not clear on how these antibodies are fabricated from the supplemental literature, and a search for, "foxa antibod*" on PubMed didn't return any pertinent hits. I'm sure this is a common method as I've seen it before in fluorescence microscopy, but I am curious about the potential for an associated autoimmune disease.
If you read my previous post on leptin and anorexia (01/12/2010), there is additional support in Silva for the notion of hyperactivity in a fasted state:
Interestingly, the Nes-Cre/+;Foxa2T156Aflox/flox allele was associated with dramatic increases in spontaneous locomotor activity relative to control mice (Fig. 3i). The difference between the locomotor activity of Nes-Cre/+;Foxa2T156Aflox/flox mice and that of Foxa2T156Aflox/flox or Nes-Cre/+ mice was similar to the increase in movement of fasted wild-type mice relative to fed wild-type mice (Fig. 3j). The types of physical activity induced in Nes-Cre/+;Foxa2T156Aflox/flox mice included searching as well as intense grooming, rearing and face-washing behaviour.If you can get past the ridiculous names of the mice variants, the English here is pretty clear.
Now it's very easy to get lost in minutiae such as this and lose clarity in the process. Of course, minutiae does have value for the task of bamboozlement. If we pull back and look at the big picture, the key point here is that insulin has been directly implicated in the hunger reflex for the first time, to my knowledge. Previously I assumed that only leptin and ghrelin can effect hunger. Now, when I read this article I did ask the question, has insulin been implicated to interact with this receptor at a biochemical level, or perhaps it is stimulating some other intermediate hormone which in turn interacts with foxa2? The answer is, yes, insulin is the actor and it directly binds to foxa2 (Wolfrum, 2003).
It amazes me how much we still have to learn about our metabolisms.
Thanks for yet another fascinating post!
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