What goes wrong while the range is rising

Leptin is the body's readout on stored energy. As fat mass increases, leptin rises, and higher leptin should mean less hunger.C-II-01 In obesity, leptin levels are high, often very high, and yet appetite is not suppressed to match. The signal is being sent loudly, yet it is not having its expected effect.C-III-16

The usual shorthand is that the brain tunes the signal out. Recent work suggests something more specific: that 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

This is the step that converts an upward drift into a new setting rather than a temporary excursion. It also explains why the defense is asymmetric: the machinery that should object to further gain is the same machinery whose signal has been turned down.

In a healthy system, metabolism switches fuels according to what is available, burning fat between meals and after fasting and turning to carbohydrate when it arrives. That capacity is known as metabolic flexibility, and it is impaired in obesity and insulin resistance.C-III-14

Importantly, this is not a question of metabolism being "fast" or "slow." The change is in how readily the body moves from one fuel to the other.

Adipose tissue is not inert storage but an endocrine organ, and in obesity it becomes inflamed: immune cells infiltrate it, and it produces a more inflammatory signaling profile. The result is a state of chronic, low-grade inflammation, one that has been demonstrated in human adipose tissue rather than inferred from animal models.C-III-15

Whether inflammation drives obesity or follows from it remains contested, and nothing described here settles the question.

In obesity, fat can accumulate outside adipose tissue, in the liver and in muscle. This ectopic fat drives insulin resistance in both tissues, and it is the link between obesity, fatty liver disease, and metabolic syndrome.C-III-17

This is also where the assumption that weight and illness are the same thing breaks down. At the same body weight, people with less ectopic fat show preserved insulin sensitivity.C-III-17 Weight on its own is not a sufficient description of metabolic health; where the fat is stored matters as much as how much of it there is.

There is a mechanism you will encounter constantly: the intestinal barrier becomes more permeable, bacterial products cross into the circulation, and the resulting inflammation drives metabolic disease. The account is compelling and mechanistically plausible.

Nothing described here has stopped working. Leptin is still being produced, and in larger amounts than ever. Adipose tissue is still signaling. The fuel switch still exists. The system is intact and doing what it is designed to do.C-I-02

What has changed is that its outputs now sustain the state that produced them. High fat mass produces high leptin; high leptin arrives at the brain attenuated; appetite stays up; fat mass stays high. The loop closes, and the defended range settles at its new level rather than returning to the old one.