Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Leprneo/neo mice). Similar to Leprdb/db mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Leprneo/neo mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity.
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The authors would like to thank Drs. Mineko Fujimiya, Clifford Saper and Christian Bjorbaek for helpful advice. This work was supported by grants from the NIH (PO1 DK56116 to B.B.L. and J.K.E., DK57621 and DK26687 to S.C.C., Jr., MH61583 and DK53301 to J.K.E.) and by Takeda Chemical Industries, Ltd., Japan. We thank NIDDK’s National Hormone & Peptide Program and A.F. Parlow for providing recombinant mouse leptin.