Leptin, the "you have enough" signal

Leptin is produced by adipose tissue in proportion to how much of it there is.C-II-01 The signal travels to the brain, where it is read as a statement about reserves: there is enough.

When you lose fat, leptin falls, and the brain reads low leptin the way it has always read low leptin, as a shortage worth responding to. Hunger rises, energy expenditure falls, and the system orients toward restoring what has been lost. In practical terms, the weight-reduced state behaves like relative leptin insufficiency.C-II-01

The key detail about this particular fuel gauge is that it reports a change more than an absolute quantity, and it responds to a fall far more urgently than to a rise.

The cleanest evidence comes from giving the signal back rather than from observation. In the weight-reduced state, restoring leptin reverses much of the adaptation: the metabolic changes, the hormonal shifts and the pressure toward regain all move back toward their pre-loss levels.C-II-02

That is about as direct as mechanistic evidence gets in human physiology. When the signal is removed, the defense appears; when it is replaced, the defense recedes.

Importantly, this is a demonstration of mechanism rather than a treatment. Leptin replacement is experimental, and it is not available or appropriate as therapy for common obesity.C-II-02

Leptin does not quietly return to baseline once weight stabilizes at a lower level. A year after a diet, in a study published in the New England Journal of Medicine, leptin was still around 35% below where it started, ghrelin was still elevated, and subjective hunger was significantly greater than before the diet began.C-II-04

Ghrelin says eat and leptin says enough. Weight loss tips both the wrong way at once, one turned up and the other turned down, and a year later both were still displaced.

There is an apparent contradiction in this account. If leptin reports stored energy, then someone with a great deal of stored energy should have a great deal of leptin, and correspondingly little hunger.

They do have a great deal of leptin. The appetite suppression does not follow.C-III-16

The usual shorthand is that the brain tunes the signal out. Recent work suggests something more specific: less leptin gets across the blood-brain barrier, so the brain is not ignoring the message so much as receiving a quieter version of it.C-III-16