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Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fa^k/fa^k) Rats

Department of Medicine (G.J.M., K.D.N., M.W.S.), Harborview Medical Center and University of Washington, Seattle, Washington 98104; Pacific Northwest Research Institute and Department of Pharmacology (C.J.R.), University of Washington, Seattle, Washington 98112; Research Division (M.G.M.), Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215; Veterans Affairs Puget Sound Health Care System (J.E.B., D.G.B.), Seattle, Washington 98108; and Departments of Medicine and Biological Structure (D.G.B.), University of Washington, Seattle, Washington 98104

Address all correspondence and requests for reprints to: Professor Michael Schwartz, Department of Medicine, Harborview Medical Center, University of Washington, 325 Ninth Avenue, Box 359757, Seattle, Washington 98104. E-mail: mschwart{at}u.washington.edu.

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, lepr^b, in the ARC of leptin receptor-deficient Koletsky (fa^k/fa^k) rats. Successful expression of adenovirus containing lepr^b (Ad-lepr^b) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-lepr^b into the ARC restored low hypothalamic levels of lepr^b mRNA to values approximating those of wild-type (Fa^k/Fa^k) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fa^k/fa^k rats injected with a control adenovirus (Ad-lacZ) (P < 0.05 for each comparison). In contrast, Ad-lepr^b delivery to either the lateral hypothalamic area of fa^k/fa^k rats or to the ARC of wild-type Fa^k/Fa^k rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

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