Fig. 4

Mechanisms of Leptin resistance. a In animals with normal body weight, circulating leptin crosses the BBB and binds to LepRb, which induces phosphorylation of JAK2 and of multiple tyrosine residues in the LepRb intracellular domain. LepRb also receives inhibitory signals from multiple negative feedback loops, including SOCS3, PTP1B, ensuring that activation of LepRb does not go beyond a physiologically necessary point. b In obesity, circulating levels of leptin increase, which is associated with diminished leptin transport across the BBB and activation of the inhibitory negative feedback systems that eventually lead to diminished LepRb signaling. Many factors, including hyperleptinemia, inflammation, endoplasmic reticulum (ER) stress, inflammatory and defective autophagy, contribute to leptin resistance. ER stress and responses might contribute to a blunted physiological response to leptin in obesity