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Although most obesity-associated mutations in LepR are distal to the leptin-binding sites and likely act to simply destabilize LepR, two previously identified human obesity-associated LepR mutations ( A409E and Y422H ) 22,23 both occur at the site 3 binding interface and are predicted by our structure to disrupt the key aromatic contacts formed by leptin Tyr119 (Fig

Supporting neurotrophic signaling through lifestyle strategies may help reinforce these pathways

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