Why the brain stops hearing “I’m full” despite abundant fat stores.
What the evidence says
- Obesity is a state of leptin resistance with defective leptin signal transduction[1]
- In that state, defective leptin signal transduction ”promotes excess energy intake, to maintain normal energy expenditure”[1]
- The relationship between obesity and leptin resistance is bidirectional — each can cause the other — but the review is explicit that the direction is unsettled: ”It is debated to what extent cellular mechanisms of leptin resistance (i.e., impaired LEPR-B and downstream signaling) cause and/or facilitate the obese phenotype in DIO models”[2]
- Obesity promotes cellular processes that attenuate leptin signaling, preventing it from reaching the level it would otherwise attain, facilitating further weight gain[2]
- In the review’s words, leptin resistance developing with obesity ”limits the ability of leptin to control adiposity, thereby magnifying the extent of weight gain”[2]
- Looking back in 2016 on the work cited here, Friedman writes that ”Most obese patients have high endogenous levels of leptin” yet show a ”variable response to exogenous leptin”[3]