Let's start with the old Stranglers track, "No More Heros", take an ice pick to a rat's brain and make its ears burn. OK, chew up its ventromedial hypothalamus with an electrolysis needle. This French paper
is a pdf.
Here's the interesting table from the results:
At week one, when weight gain has started but not gone very far, fasting insulin was unchanged but blood glucose was LOWER than that of control rats. These rats, with their brain injury, have increased whole body insulin sensitivity. Mostly prominently in their adipocytes. The paper mentions in the discussion that these rats also hyper secrete insulin in response to secretagogues. Now, as we all know, insulin is both anorexic and unimportant to weight control. But if you just imagined, as I do, for a second that insulin does have something to do with weight gain, what would you expect to happen if you dropped hyper-secreted insulin on to exquisitely insulin sensitive adipocytes? Their job is to store fat under the influence of insulin so...
They would store fat. They would hang on to it. As Taubes might comment, the rats then over-eat
because they are losing calories in to their adipocytes. They over eat because they are becoming fat. How do you check this? Well, let's pair feed ice-picked rats with control rats. Limit their calories. Make them go to uncheatable Weight Watchers in a prison cage. From the discussion:
"However pair-feeding rats with controls does not prevent excessive lipogenesis, fat accumulation and hyperinsulinemia [48, 49], suggesting that the disturbances of metabolism and not hyperphagia are the primary factors leading to obesity."
You injure the brain, alter the adipocytes and they store fat. Hyperphagia is an epiphenomenon of calories lost to adipocytes. They store fat even WITHOUT hyperphagia. This was quite obvious in 1992.
Enough frivolity. Let's get slightly more up to date with some Spanish
MSG rats.
You have to be a bit careful with MSG injured rats. MSG is a potent neurotoxin and kills or injures almost any cell sporting glutamate receptors. This includes large numbers of nerve cells in the VMH, the target of the electrical ice-pick. However it also blunts growth hormone production, shuts down thermogenesis from brown adipose tissue and, very interestingly, adipocytes themselves probably use glutamic acid for cross talk purposes, so it's hard to know exactly what we do to MSG treated rats in addition to busting their VMH. You have to wonder whether the adipocytes themselves are injured by MSG.
Anyway, at a month of age, MSG injured rats have highly insulin sensitive adipocytes. Before the rats have become visibly obese their fat cells are already somewhat swollen and ready for the off in to full blown blobby-ness, come puberty. So again, you bust the VMH, increase adipocyte insulin sensitivity, adipocytes suck in fat and your rat simply has to eat to maintain access to enough energy to stay alive and cart the inaccessible fat around its cage. It probably doesn't dream of going to the gym.
If adipocytes are hypersensitive to insulin, what would you expect fasting FFAs, glucose and insulin look like before obesity developed?
Eyeball the HOMA score! These rats are a picture of glucoregulatory health! Unfortunately you need an energy supply from somewhere and some extra FFAs might just sort that out. You really need to develop some adipocyte distension induced insulin resistance by becoming obese to get the FFAs up to an appropriate level for a fasting rat. That's just what they do...
Look at the numbers from some
Slovakian MSG injured rats as adults.
Cool, huh? Unfortunately we don't have the FFA level in the paper but, looking at the adipocyte size, they will be leaking FFAs in defiance of their double-the-control-rat level of insulin.
Now, are these adult, distended adipocytes insulin sensitive or resistant?
Well, they do bugger all to increase glucose uptake with increasing insulin exposure. So yes, they are insulin resistant. But look at this:
What glucose they do take up is diverted to fat. Might we say they are behaving like muscle cells which lack metabolic flexibility? Mitochondrial injury?
So, as obesity becomes established we end up in the age old situation of insulin resistant distended adipocytes leading to more FFA leakage than appropriate for a given level of insulin and so hyperinsulinaemia develops to try to keep blood glucose normal in the face of chronically elevated FFAs. This is absolutely not the case in the very early days, but rapidly becomes so with time.
This is all quite straight forwards and nothing you wouldn't expect if you accept the importance of insulin in obesity, adipocyte hypertrophy induced insulin resistance and the fact that adipocytes have a nerve supply which regulates their insulin sensitivity. In fact there are interesting papers on the role of adrenal hormones and the vagus as well as the sympathetic nervous system in MSG injury induced obesity. The end result is always increased insulin sensitivity of adipocytes until they become over-distended.
You can, of course, do exactly the same with
gold thioglucose. Getting bored with all this? I'd basically come to the conclusion that VMH injuries give the impression of causing hyperphagia when what they actually do is increase lipid loss in to adipocytes, under the influence of insulin.
Okaaaay.
Let's look at a Long-Evans rat. If you feed it on D12492, which has been described as a high fat diet, for just three days, its brain breaks.
What if it is the fat that breaks the brain?
Well, my brain is then going to be completely f*cked.
I really do think that it might just be the fat that does it. How do I know? God told me. Okay, okay, only kidding. About god.
No, James emailed me a link to the latest
Schwartz offering. I suspect that Dr Schwartz does not like Gary Taubes. We can also skip to the blog of the 4th author, who certainly does not like Gary Taubes, load up on ondansetron and have a browse. The blog says:
"Based on previous studies, the dietary fat itself is probably an important component that makes D12492 fattening in rodents"
The man is correct.
If you have quite recovered from that, let's look at the simpler aspects of the study. We can come back to the superb electron micrographs of dying mitochondria some other time. BTW, they are very, very cool pictures. I've been looking for similar photomicrographs all over the place. Who would have thought I would have found them here? Anyhoo:
First off, let's look at
Figure 1, skip to graph H.
Start some ratties on D12492 and they will immediately double their calorie intake, on day 1. After living your whole short life eating CIAB I can understand this. D12492 tastes so good you just can't help yourself and it must be quite easy to eat enough of it to break your brain. It must be very rewarding. Luckily your brain recovers a bit and soon, by day seven, you're not eating any more calories of D12492 than a rat on CIAB and that's how it stays for the full 28 day period. We can tell this from Graph G. Here the average 28d food consumption on D12492 is only just above the 14d average consumed as CIAB. This excess is mostly accounted for by the first seven days of hyperphagia.
The bit of the brain which breaks "in association" with the massive 60% of calories from fat is the good old VMH. If we go back to the ice-pick rats, the MSG rats and the gold thioglucose rats we might just develop the suspicion that breaking the brain of a Long-Evans rat might affect the insulin sensitivity of its adipocytes.
If it does, fat from the diet will simply pour in to the adipose tissue and the unfortunate rattie will then have to eat extra to supply some energy to run its metabolism on in addition to that used for filling its adipocytes. Initially twice the amount it ate on CIAB. As the adipocytes fill they will become intrinsically less sensitive to insulin and fat accumulation, with its necessary compensatory hyperphagia, will slow. But not stop, if they behave anything like adipocytes in other VMH injured rat models.
On a high fat diet there is plenty of fat to pour in to adipocytes, no lipogenesis is needed. Adipocytes can distend quickly and it would be interesting to see if the fasting hypoinsulinaemia seen in the MSG rats (fed on high carbohydrate CIAB) occurs in D12492 injured rats. Probably it would still occur but be very transient, but obviously no one in the Schwartz lab would be interested in insulin.
Of course, one has to wonder which component of the D12492 might injure a rat's VMH. We are all familiar with the
conversation (scroll up to get to the text) between Chris Masterjohn and the good doctor, where the omega 6 PUFA content of D12492 was noted to be 32% of fat and the omega 6:3 ratio was 14 or 16:1. All fascinating background. But my favourite obesity researcher correctly thinks it is the fat, not the type of fat, which breaks the VMH.
You can do exactly the same with butter oil (plus a smidge of soybean oil), which I'm guessing is a bit like ghee. Which I rather like. This is what butter oil at 20g/100g of food does to a Long-Evans rat in
this study:
In particular look at what happened to the group HF. They switched from non purified (NP) diet on day 1 on the graph, spiked their intake to about 50% extra calories by day 5ish and were almost back down to the NP group's caloric intake by day 10. Exactly the same pattern as the D12492 also produces in Long-Evans rats.
It is impossible to emphasise how important both studies are to you if you are a Long-Evans rat.
Does three days of high fat eating break your brain if you are a human being? I have to admit that I appear to have singularly failed to become obese on 80% of my calories as fat over nine years. Possibly because 80% of your calories from fat becomes protective? I dunno. I can't help but recall those chaps in
Aberdeen eating 66% of their calories as fat and refusing to finish off their allotted 2000kcal/d...
I have to be open to the idea that humans may not respond to high fat feeding in quite the same way as Long-Evans rats do. OK, they just don't. Their VMH doesn't acutely break. The rat is in trouble on 60% of calories as any sort of fat. Humans just say "no thank you" to the extra slice of bacon, in Aberdeen anyway. Oh, and in Lowestoft too.
In summary: Injuring your VMH in any way (even by eating butter oil if you are a Long-Evans rat) does nasty things to your adipocytes. They will store fat even if you cut calories. You will then be very hungry and, unless you do eat more, you will chew up your muscles for energy, get cold and move as little as possible. Oh, and still get fat. People will say you lie about your calorie intake.
Now, is it possible to become obese without breaking your VMH? Of course it is. Does it matter? That depends.
I think the chronic changes in both the Long-Evans rats and the C57BL/6 mice are very important and are quite likely different from the initial fat induced injury to the VMH. They appear to be more related to the chronic hyperinsulinaemia and hyperglycaemia which follow on from adipocyte insulin resistance and elevated FFAs especially in the presence of a high dietary carbohydrate intake. That will lead us to back to mitochondrial injury (which is probably where all of this comes from, did I even mention that obesity is a mitochondrial problem?), free radicals and I might even throw in gliosis. Which is interesting.
Peter
