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. 2007 Jan;148(1):433-40.
doi: 10.1210/en.2006-0672. Epub 2006 Oct 12.

Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age

Christopher D Morrison  1 , Christy L White, Zhong Wang, Seung-Yub Lee, David S Lawrence, William T Cefalu, Zhong-Yin Zhang, Thomas W Gettys
Affiliations

Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age

Christopher D Morrison et al. Endocrinology. 2007 Jan.

Abstract

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 microg) 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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Figures

Fig. 1
Fig. 1
Changes in leptin sensitivity with age and fasting. Male chow-fed Sprague Dawley rats at 8, 12, and 20 wk of age (five to eight rats/group) were treated with a single icv injection of leptin (3 μg), and 24-h food intake was recorded. In addition, a separate group of 20-wk-old rats was fasted for 24 h, injected with leptin after the fast, and 24-h food intake recorded. Leptin treatment significantly suppressed food intake in 8- and 12-wk-old rats (*, P < 0.05) but had no effect on food intake in 20-wk-old rats. However, when 20-wk-old rats were fasted for 24 h, leptin blocked fasting-induced increases in food intake (*, P < 0.05).
Fig. 2
Fig. 2
Effects of age on leptin activation of Stat3 within the medio-basal hypothalamus. Eight and 20-wk-old Sprague Dawley rats were treated icv with vehicle (Veh) or 1 or 3 μg leptin. Twenty minutes after leptin administration, rats were rapidly decapitated and mediobasal hypothalamus collected for analysis of Stat3 phosphorylation via Western blot. Intracerebroventricular leptin induced a significant increase in Stat3 phosphorylation in 8-wk-old rats at both doses tested (P < 0.05) but had no effect on Stat3 phosphorylation 20-wk-old rats.
Fig. 3
Fig. 3
Effects of age and fasting on hypothalamic PTP1B protein expression. Levels of PTP1B protein were determined on small punches of mediobasal hypothalamus collected from 8- and 20-wk-old Sprague Dawley rats by Western blot (five rats/group). Blots were probed with a specific PTP1B antibody, and levels are expressed relative to β-actin content. The 20-wk-old rats exhibited significantly greater levels of PTP1B protein, compared with 8-wk-old rats (P < 0.05). A separate group of 20-wk-old rats were fed or fasted for 24 h and levels of PTP1B protein in mediobasal hypothalamic punches determined via Western blot. Fasting decreased hypothalamic levels of PTP1B in these mature rats (P < 0.05).
Fig. 4
Fig. 4
Pharmacological inhibition of PTP1B improves leptin sensitivity in mature, leptin-resistant rats. Twenty-week-old rats bearing third cerebroventricular cannula (eight to 10 rats/group) were injected with a selective, cell-permeable PTP1B inhibitor (0.3 nmol icv) previously described by Xie et al. (24). One hour after the inhibitor injection, rats were treated with leptin (3 μg icv) or vehicle, and 4- and 24-h food intake was recorded. Neither leptin nor the inhibitor alone significantly affected food intake in these 20-wk-old rats. However, pretreatment with the PTP1B inhibitor markedly improved leptin-dependent suppression of food intake (*, P < 0.05).
Fig. 5
Fig. 5
Pharmacological PTP1B inhibition reduces food intake. Twenty-week-old rats bearing icv cannula were treated with higher doses of the PTP1B inhibitor (1 and 3 nmol, icv) than used to enhance sensitivity to exogenous leptin. Intracerebroventricular administration of the PTP1B inhibitor at these higher doses resulted in a dose-dependent inhibition of food intake (P < 0.05) at both 4 and 24 h, consistent with an increase in sensitivity to endogenous leptin.
Fig. 6
Fig. 6
Effects of a Jak2 inhibitor on regulation of food intake by leptin and MTII. Sprague Dawley rats (16 wk old, six to eight/group) bearing third cerebroventricular cannula were fasted for 24 h and subsequently pretreated with a cell-permeable Jak2 inhibitor (AG490, 1 nmol) or vehicle 1 h before treatment with leptin (3 μg, icv) or vehicle, and 4 and 24 h food intake was measured. Leptin alone significantly suppressed 24-h food intake (*, P < 0.05); however, pretreatment with the Jak2 inhibitor AG490 completely blocked leptin’s ability to suppress food intake. A separate group of Sprague Dawley rats were fasted for 24 h and pretreated as above with AG490 (1 nmol icv) or vehicle 1 h before treatment with the melanocortin agonist MTII (0.3 nmol icv) or vehicle. MTII significantly reduced 4 and 24-h food intake (P < 0.05), but AG490 pretreatment had no effect on MTII-dependent suppression of food intake.
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