Okay. I have an apology to make. I'm not sure there will be an MCQ test on the FIRKO mouse to parallel that on the LIRKO mouse. At this stage of the proceedings I'm not sure that I can muster the motivation which is needed to do justice to such an Herculean task of applied sarcasm. The difficulty is compounded by the loss of my trowel somewhere between Berkshire and Norfolk via Glasgow. You really do need a trowel. I know, excuses, excuses. Mea culpa.
With that apology, I think it's time to discuss this paper.
So now we have the FIRKO mouse. This mutant mouse has been cleverly engineered to fail to express insulin receptors on its adipocytes. Everything else is normal. Functionally the adipocytes are severely insulin resistant. It does not matter how much insulin the pancreas secretes, adipocytes will not, cannot, listen to it. You know the rules. The function of insulin is to store dietary fat in adipocytes. In the almost complete absence of any insulin receptors on any adipocytes, this just ain't gonna happen. So FIRKO mice stay slim, slightly slimmer than a control mouse, and live a bit longer. All on CIAB and without cutting calories of course.
They also fail to develop age related insulin resistance. Please note as a complete aside; those mice on F9, boring old low fat CIAB, do develop age related insulin resistance and glucose intolerance. Wanna stay as healthy as a mouse on F9 with age acquired insulin resistance? Go ahead and eat low fat, about 10% of your calories will do. Try not to get too bored.
I could stop here with this comment from the authors:
"Our data further show that insulin signalling in adipocytes is crucial for triglyceride storage and the development of obesity and its associated metabolic abnormalities"
It would be fun to just thumb your data at those fixated on the central effects of insulin but that would be leaving a whole can of worms unopened. You know how it ticks you off to get partial information on a given study. The selective information rationing typical an obesity researcher. The data are actually quite complex.
Let's get a tin opener.
Sooooooo, what if you take a FIRKO mouse and inject it with gold thioglucose? Obviously you will bust its VMH. You could equally use a electrical ice-pick or a big meal at a Chinese restaurant (jk).
To summarise the last post: This injury increases the ability of adipocytes to divert calories away from metabolism and in to storage, by an increase in their sensitivity to insulin. Fat should simply pour in to the adipocytes of a VMH injured rodent and they should start eating big time. You could be forgiven for thinking you had removed their brain satiety centre or upped their fat set-point.
But the FIRKO mouse has very few insulin receptors on its adipocytes. The brain can scream, shout and have a temper tantrum to demand fat storage. Adipocytes stay cool as a cucumber and don't even give the finger to the brain. Pure ignore-ance. The brain has lost its tool for fat storage. You know the one, the tool which stops you being hungry (snigger) and helps you lose weight (sigh). Insulin.
Now let's look at some of the graphs. We'll start with the supportive one:
We can ignore the middle two columns, they're from different knockout mice. FIRKO mice with a gold thioglucose brain injury (right hand column) weigh the same as, or even a non significant smidge less than, WT mice (or FIRKO mice) without a gold thioglucose injury. Now that's no surprise. Brain:Adipocyte:Insulin.
But there is a shock in store. Here's the next graph, the columns are the same:
FIRKO mice eat MORE if they are injured by gold thioglucose than if they aren't. They eat almost exactly the same extra food as a wild type gold thioglucose injured mouse. While staying slim, of course. But they do eat more.
Does this mean that the VMH really controls appetite rather than the ability to divert calories to fat storage?
FIRKO mice have markedly reduced insulin receptors on both white and brown adipose tissue. The consequence of this on white adipose tissue is simple, insulin causes fat storage, lack of receptors limits fat storage. BAT is more complex. We do have a BATIRKO mouse which has had the insulin receptors knocked out on its brown adipose tissue only. This leads to combined atrophy of BAT (the normal lipid droplets in BAT never form) with marked up regulation of UCP1 production. They stay slim compared to controls while being fed CIAB (aside: although slim they do eventually become diabetic, the reasons for which are utterly unclear to anyone, see the discussion). As the authors comment on "normal" BATIRKO mice:
"Interestingly, the lack of IR leads to the over expression of the UCP-1 and also UCP-2 in the remnant BAT from BATIRKO as compared with controls. These data could be interpreted as a form of compensatory mechanism for the brown fat lipid content and mass loss observed in BATIRKO and may result in a potential increase in the thermogenic capacity of the remnant BAT that may account for the lean phenotype of BATIRKO mice compared with controls"
A lack of insulin receptors on your BAT up regulates thermogenesis. This has nothing to do with the brain and everything to do with the periphery. Why should thermogenesis be increased by VMH injury? I don't know. The control of BAT is complex and I don't think the work has been done yet. There are hints that insulin reduces UCP1 production in mice, bringing us back to changes in insulin signalling and thermogenesis. You might expect a system which activates fat storage might turn off fat burning and vice versa.
At the moment, for FIRKO mice, it looks like an open question as to whether gold thioglucose VMH lesions really increase appetite directly or increases thermogenesis in BAT causing a calorie loss, with compensatory hyperphagia. You can imagine which option I think may be the case, but I do have certain biases.
It's frustrating that there is no information to follow through on this. The group's last publication on the FIRKO mouse was in 2007 and was interesting in its own right.
The FIRKO mouse has white adipose tissue which, with age, gets to have better and better mitochondria. Probably more of them too. The authors talk about increased whole body oxidative metabolism but don't seem to consider BAT seperately from WAT... But having your adipocytes live in [what to them is] an hypoinsulinaemic environment seems to be rather good for them. And the mouse
Remember what is special about FIRKO mouse is that its adipocytes never see insulin, whatever the blood insulin level. Lacking IRs on all of your adipocytes keeps you slim, keeps your insulin levels low and extends your life expectancy by about 18%. It gives you shiny new mitochondria in your adipocytes as you age. If you are a mouse.
It it possible to mimic this state in non-FIRKO mice?
Perhaps it's time to revisit ketogenic diets in mice. Oh, and cirrhosis too.