Our in-depth molecular and functional analysis of the EEC lineage reveals mechanisms of EEC dysfunction in obesity that include (1) higher abundance of Ngn3+ EEPs owing to increased proliferation, (2) lower abundance of serotonergic Reg4+ EC cells and lower plasma serotonin levels, (3) higher abundance of peptidergic Ghrl+ SILA cells but lower ghrelin plasma levels, (4) increased numbers of ileal Gcg+ cells and increased Glp-1 levels and (5) lower abundance of Lgr5+ EECs. Here, GHRL is linked to obesity due to melanocortin 4 receptor deficiency.