High Leptin in fat people

OK, its well known fat people have high leptin. But why? Is it because of leptin resistance in the brain, as most people seem to think? OR, is it because of something else? Most scientific papers simply state that "leptin circulates in direct proportion to fat mass", subtly implying that fat mass determines leptin secretion.

hhhhhmmmmm, im suspicious that there is more too it...

Apparently some people are still under the impression that insulin doesnt make you fat. Thats only partially correct, it is insulin sensitivity of fat cells that determines the fattening power of insulin. Having a ton of insulin will indeed not make you fat if there's no insulin receptors on the fat cells. One of the first things discovered about leptin was that its secretion was enhanced dramatically in the presence of insulin. I.E. insulin signalling in fat cells produces leptin.

So, do fat people have high leptin because they generally also have high insulin? Maybe.

But how does insulin cause leptin secretion anyway? Whats the mechanism? Well, one of the things we know that insulin does is promote glucose uptake through increased GLUT4 on the fat cell surface. Right, so is increased glucose uptake responsible for leptin secretion?

Maybe.

Once glucose gets into the adipocyte, there are several fates for it. It can either be converted to lactate and exported, it can be oxidized, or it can enter the lipogenesis pathway. Obviously going down the lipogenesis pathway is not something you want if your trying to stay slim. Im not sure exactly what determines which path the glucose takes, but astonishingly, Metformin enhances glucose uptake into fat cells. ( 1, 2 )

Remember that metformin is much more strongly associated with weight loss, and from these papers we learn that although metformin causes glucose uptake via GLUT4 expression, the pathway for this glucose is lactate production and oxidation, which helps explain why metformin doesn't make you fat, but actually quite the opposite.

In that first paper, the researchers speculated that glucose going down the lipogenesis pathway in adipocytes might be the signal for leptin secretion, and these musings would be confirmed a few years later by a further study that shows glucose incorporation into lipid, at least during insulin-stimulated conditions, leads to leptin secretion. ( 3 )

So we are left with the reasonably strong conclusion that Lipogenesis causes leptin secretion. The corollary to this is that the amount of leptin found floating around in the blood is a direct indication of the amount lipogenesis from carbohydrate going on in your fat cells. This, in turn, I would propose, is a direct indication to the insulin sensitivity of your fat cells.

The fact that lipogenesis is the stimulation for leptin secretion should not really be all that surprising, one of the primary jobs of leptin is actually to stimulate lipolysis via the nervous system once its found its binding sites in the brain. Using a crude example, adipocyte takes in 1 triglyceride, in return, 1 molecule of leptin is secreted, it floats around the blood eventually arriving at the brain, where it lets the brain know we have 1 triglyceride in storage ready for energy usage in the future. The brain can then order the mobilization of that triglyceride via the nervous system by stimulation of lipolysis in the adipocyte, thus creating a perfect negative feedback loop system where system stability is maintained.

Summary : The high levels of leptin found in fat people is very likely an indication of elevated insulin sensitivity and lipogenesis in their fat cells.