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Abstract
Leptin has beneficial effects on glucose metabolism via actions in the hypothalamus,
but the roles of specific subgroups of neurons responsible for these antidiabetic
effects remain unresolved. We generated diabetic Lep(ob/ob) or Lepr(db/db) mice lacking
or re-expressing leptin receptors (LepRb) in subgroups of neurons to explore their
contributions to leptin's glucose-lowering actions. We show that agouti-related peptide
(AgRP)-expressing neurons are both required and sufficient to correct hyperglycemia
by leptin. LepRb in pro-opiomelanocortin (POMC) neurons or steroidogenic factor-1
(SF1) neurons are not required. Furthermore, normalization of blood glucose by leptin
is blunted in Lep(ob/ob)/MC4R-null mice, but not in Lep(ob/ob) mice lacking neuropeptide
Y (NPY) or gamma-aminobutyric acid (GABA) in AgRP neurons. Leptin's ability to improve
glucose balance is accompanied by a reduction in circulating glucagon. We conclude
that AgRP neurons play a crucial role in glucose-lowering actions by leptin and that
this requires the melanocortin system, but not NPY and GABA.