Let's start with this quote from Brain insulin controls adipose tissue lipolysis and lipogenesis:
"Insulin is considered the major anti-lipolytic hormone. Its anti–lipolytic effects are thought to be exclusively mediated through insulin receptors expressed on adipocytes (Degerman et al., 2003). Cyclic–AMP (cAMP) signaling represents the major pro–lipolytic pathway in WAT, which is chiefly regulated by the sympathetic nervous system (SNS)."
and then go on to this one from the discussion:
"We draw this conclusion from the finding that denervation of WAT leads to no change in lipogenic protein expression, but completely abrogates Hsl activation leading to increased adipose depot mass (Buettner et al., 2008)".
OK, got that? Brain insulin makes you fat by damping down lipolytic neurotransmission to adipocytes. Turning off your sympathetic nervous system supply to your fat cells allows insulin to go on an obesity spree.
Then there is this quote (MBH is medial basal hypothalamus, better known as VMH, ventro medial hypothalamus):
"Our studies raise several questions. One is which neuronal subtype within the CNS and the MBH mediates the effects of insulin on the regulation of WAT metabolism".
That first one really is an interesting question, one which we can go some way towards answering. We know that the cell type is, as already noted, part of the sympathetic nervous system. In the paper they found either surgical or chemical sympathectomy of adipose tissue increases both lipogenesis and inhibits hormone sensitive lipase in that tissue. I think this is straight forward. The sympathetic nervous system is tonically opposing insulin's lipogenesis effect and insulin's inhibition of hormone sensitive lipase.
The next thing we can say is that these cells sport glutamate receptors. We can safely assume this because, if neonatal rats are injected with the excitotoxin MSG, these are some (among many) of the cells which actually die. That is, the sympathetic nervous system supply to adipose tissue dies. Lipogenesis is unrestrained. Hormone sensitive lipase shuts down. Carbohydrate easily pours in to adipocytes and stays there. Blood glucose levels are low, free fatty acid levels are low, insulin sensitivity is excellent. While ever adipocyte expansion is on going that is. As the adipocytes stretch they eventually become insulin resistant. Here's the table of metabolic parameters from pre-obese MSG injured and control rats, from a previous post:
We know you can do exactly the same by killing these cells with gold thioglucose. This neurotoxin kills those nerve cells which inhibit lipogenesis.
As the authors say: After gold thioglucose injection "systemic insulin sensitivity is preserved [actually it's increased, but these are obesity researchers, so don't quibble] during the early phase of the obesity syndrome, resulting in extensive fat production".
These hypothalamic cells don't seem to take too kindly to the application of an ice pick either:
"In this study, we have measured the expression of the insulin-sensitive glucose transporter, Glut 4 and the activities and expression of key lipogenic enzymes (fatty-acid synthase and acetyl-CoA carboxylase) in white adipose tissue, one and six weeks after the lesion. All these parameters, as well as glucose transport and metabolism determined in white adipocytes, were markedly increased one week after the lesion. They returned to control values within six weeks in VMH-lesioned rats".
All of these interventions allow calories to pour in to adipocytes and stay there. So what does the poor rat do? It's losing a sh*t load of calories in to its adipocytes but, luckily, it has access to a massive hopper of crapinabag in its cage. It simply has to eat enough calories to supply the loss in to adipocytes, plus enough to run its metabolism on. This can be described, by non comprehending people, as hyperphagia. Metabolically it is normophagia.
These rats are calorically neutral or even in mild energy deficit. They have to be running "hyperphagic" just to stand still, metabolically. They are NOT showing "voluntary" overeating. They DO NOT have an injury to any sort of "satiety" centre. They have low insulin, low FFAs and low glucose. They are NOT being paid to over eat! They will NOT be producing a ton of superoxide, despite having a hugely increased caloric intake. Until...
When does this stop? It stops when FFA leakage due to the resistance to insulin induced by adipocyte distention exactly matches the FFA releasing effect which the (now non-existent) sympathetic nervous system would have been having on non distended adipocytes. Sorry for the convoluted sentence, can't simplify it! The distension process was complete by six weeks in the ice pick rat study cited above. Obese rodents then end up with a crudely normal metabolic rate. But this injured system is a complete bodge. We are looking at the replacement of a finely tuned fuel switching system which exactly matches fuel availability to fuel needs with a system where broken adipocytes are simply leaking FFAs at a level which constantly supplements glucose use, without any semblance of fine tuning to metabolic needs. The chronic elevation of fatty acids drives, through the NADH/FADH2 ratio, superoxide production and insulin resistance. Eating glucose then becomes unacceptable because there is inappropriate whole body insulin resistance from excess and inappropriate FFAs. A large amount of insulin is need to control hyperglycaemia under these conditions. Failure to supply adequate insulin to do this, for any reason, is labelled diabetes.
What has this to do with the current obesity epidemic? If you are overweight I would suggest you should take the ice pick out of your brain. No ice pick? Hmmmmm, damn! Back to the drawing board on that one then.
Ah, but maybe you are a C57BL/6J mouse?
Before we can tackle such a stupid question I think we need to go back to superoxide and fatty acids, to about where we were before this digression began.