First of all it is important to understand that fat is not simply a reserve tank for excess calories or "potential energy." Fat is an endocrine organ, such as the thyroid or adrenal glands, for example. This means that fat, in this case white adipose tissue secretes hormones and leptin is one of them. Leptin is a polypeptide hormone (made up of 146 amino acids) produced by adipocytes (fat cells). The more fat the adipocytes contain, the more leptin is secreted. Think of leptin as a metabolism controller and a hunger regulator. It links changes in fat deposits with the control of CNS energy homeostasis.
How do we become resistant to leptin?
Reduction of the blood-brain barrier: The idea that leptin levels were higher in obese people was a surprise. When scientists tested the responsiveness to leptin of various animal tissues resistant to it, in vitro. Most of the time, leptin receptors isolated from the hypothalamus were still somewhat sensitive. This was a huge puzzle until it was discovered that part of the body's response to high levels of leptin is to shut off brain access to it. In order for leptin to get from fat cells to the hypothalamus, leptin must travel through the bloodstream, but it has to cross the brain's blood-brain barrier to gain access. The blood-brain barrier is highly selective in what it allows to pass through it, and it was found that an early response to high levels of leptin closes off the passage through the blood-brain barrier. This allows the body to preserve leptin sensitivity in the hypothalamus whenever it can, spreading until leptin levels return to normal again.
Blocking Leptin Receptor Sensitivity:
Like the insulin receptor, when leptin receptors are constantly bombarded with high amounts of leptin, they become resistant. The mechanism of reduced sensitivity of the leptin receptor was discovered in part by accident, when scientists studied the role of protein tyrosine phosphatase 1B (PTP1B) in the regulation of insulin receptor signals. It has been known for some time that the sensitivity of the insulin receptor is controlled by a number of kinases and phosphatases, and in this case, the scientific hypothesis on whether PTP1B is a limiting factor in insulin sensitivity (this would be great news for diabetics) was tested. To test this hypothesis, a group of knockout mice lacking PTP1B was created. As the scientists predicted, these mice became very sensitive to insulin, a fact that was demonstrated by testing them for glucose tolerance. Scientists also noticed something else. These mice obtained considerable definition to increase their loss of body fat. The mice had a very fast and efficient metabolism, the surprising cause was the elimination of the PTP1B gene, which also massively upregulated sensitivity to leptin. The PTP1B protein was later discovered to be a negative feedback inhibitor of leptin receptor signaling. When the leptin receptor is stimulated with high amounts of leptin, PTP1B is activated to reduce receptor sensitivity. The cytokine-3 signaling suppressor protein (SOCS3) is also an inhibitor of negative leptin feedback. When the leptin receptor is activated by large amounts of leptin it increases, SOCS3 reduces the sensitivity of the leptin receptor.