Leptin resistance in overweight humans is primarily at the hypothalamic level, leading to high leptin levels that fail to signal fullness.

“the leptin resistance is at the hypothalamic level so people who are overweight almost always have very high leptin levels and the leptin is not signaling is not working”

“so in the same way that people can develop insulin resistance where it takes more insulin to do the physiological jobs in the body people with obesity require more leptin for the hypothalamus to be satisfied so another way to say that they require more leptin to avert the starvation response that the brain has that where alarm bells start going off because it thinks you don't have enough body fat so they require more more leptin to achieve that state and so we call that leptin resistance”

“it seems like the only thing we know is it's not too low an amount of circulating leptin as evidenced by two things one the high circulating levels of leptin and the fact i think more importantly that when you give exogenous leptin it doesn't improve the condition suggesting that that's not the defect”