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Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age

Neurosignaling Laboratory (C.D.M., C.L.W.), Diabetes Research Laboratory (Z.W., W.T.C.), and Adipose Signaling and Nutrient Sensing Laboratory (T.W.G.), Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; Institute of Chemical Biology and Drug Discovery (S.-Y.L.), State University of New York at Stony Brook, Stony Brook, New York 11794; Department of Biochemistry (D.S.L.), Albert Einstein College of Medicine, Bronx, New York 10461; and Department of Biochemistry and Molecular Biology (Z.-Y.Z.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Christopher D. Morrison, Ph.D., Neurosignaling Laboratory, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: morriscd{at}pbrc.edu.

Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 µg) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.

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