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. 1997 Aug 5;94(16):8878-83.
doi: 10.1073/pnas.94.16.8878.

Physiological response to long-term peripheral and central leptin infusion in lean and obese mice

J L Halaas  1 , C Boozer, J Blair-West, N Fidahusein, D A Denton, J M Friedman
Affiliations

Physiological response to long-term peripheral and central leptin infusion in lean and obese mice

J L Halaas et al. Proc Natl Acad Sci U S A. .

Abstract

Recent data have identified leptin as an afferent signal in a negative-feedback loop regulating the mass of the adipose tissue. High leptin levels are observed in obese humans and rodents, suggesting that, in some cases, obesity is the result of leptin insensitivity. This hypothesis was tested by comparing the response to peripherally and centrally administered leptin among lean and three obese strains of mice: diet-induced obese AKR/J, New Zealand Obese (NZO), and Ay. Subcutaneous leptin infusion to lean mice resulted in a dose-dependent loss of body weight at physiologic plasma levels. Chronic infusions of leptin intracerebroventricularly (i.c.v.) at doses of 3 ng/hr or greater resulted in complete depletion of visible adipose tissue, which was maintained throughout 30 days of continuous i.c.v. infusion. Direct measurement of energy balance indicated that leptin treatment did not increase total energy expenditure but prevented the decrease that follows reduced food intake. Diet-induced obese mice lost weight in response to peripheral leptin but were less sensitive than lean mice. NZO mice were unresponsive to peripheral leptin but were responsive to i.c.v. leptin. Ay mice did not respond to subcutaneous leptin and were 1/100 as sensitive to i.c.v. leptin. The decreased response to leptin in diet-induced obese, NZO, and Ay mice suggests that obesity in these strains is the result of leptin resistance. In NZO mice, leptin resistance may be the result of decreased transport of leptin into the cerebrospinal fluid, whereas in Ay mice, leptin resistance probably results from defects downstream of the leptin receptor in the hypothalamus.

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Figures

Figure 1
Figure 1
Dose–response of wild-type C57BL/6J mice (n = 8 per group) to recombinant murine leptin delivered by 14-day subcutaneous infusion pumps (Alzet). (A) Maximum body mass change in response to leptin as a percentage of initial mass. (B) Fold increase in serum leptin levels achieved by each dose. Blood was collected at time of pump implantation by retro-orbital bleeding and again 10 days later at the time of maximum body mass change. Leptin levels were measured by RIA (Linco).
Figure 2
Figure 2
Response of wild-type C57BL/6J mice to i.c.v. leptin infusion. The third ventricle was stereotaxially cannulated with a 30-guage needle connected to an osmotic pump. The animals were infused with aCSF for 1 week, after which they were infused with either recombinant murine leptin at a dose of 8 ng/hr (n = 6) or PBS vehicle control (n = 6). The animals were then followed for 30 days and body mass (A) and food intake (B) were measured. At the end of the 30-day experimental infusion the pumps were changed back to aCSF and the animals were followed for 14 more days. ∗, Significantly (P ≤ 0.05 different from PBS control.
Figure 3
Figure 3
Effect of i.c.v. leptin infusion vs. pair-feeding on 24-hr energy expenditure. Three groups of mice were cannulated as before and placed in metabolic chambers (n = 6 per group). One group was infused with leptin at 8 ng/hr, a control group was infused with PBS, and a final control group was infused with PBS and pair-fed to the leptin-infused group. Food intake was measured daily and energy expenditure was measured at four different times: baseline, 3 days following leptin infusion or PBS control, 2 weeks after beginning leptin infusion or PBS control, and 10 days following infusion with aCSF during the recovery phase. Energy expenditure and food intake are graphed as a percentage of the PBS control group. Mass change refers to the mass change relative to the baseline mass at day 0. ∗, P < 0.05 vs. PBS; #, P < 0.005 vs. PBS; +, P < 0.005 vs. leptin; ×, P < 0.05 vs. leptin.
Figure 4
Figure 4
Dose–response of wild-type C57BL/6J to i.c.v. leptin. The animals’ maximal body mass change in response to i.c.v. infused leptin at doses ranging from 0 to 500 ng/hr was measured and is shown as a percentage of the initial body mass at the beginning of leptin infusion (n = 6 for all doses but 500 ng/hr, where n = 4).
Figure 5
Figure 5
Effect of peripheral and central leptin in different murine models of obesity. (A and B) NZO mice (A) and Ay (B) mice were administered recombinant leptin or PBS control (P) by three different methods: (i) high-dose intraperitoneal (IP) injection (12.5 mg/kg twice daily) (n = 8; female, 20 weeks); (ii) subcutaneous (SC) infusion pump (n = 5 for each dose; female, 12 weeks); and (iii) i.c.v. (ICV) infusion (n = 5 at each dose; female, 12 weeks) at the doses indicated. (C) AKR/J mice were tested for their sensitivity to peripheral recombinant leptin at a high dose of 12.5 mg/kg twice daily. One group of mice (n = 16; female, 14 weeks) was lean on a standard chow diet and half this group received leptin intraperitoneally while the other half received vehicle PBS control intraperitoneally. Another group (n = 16; female, 14 weeks) was obese after being on a high-fat diet (45% calories from fat; Teklad, Madison, WI) for 10 weeks. Half of this group received leptin intraperitoneally at a dose of 12.5 mg/kg twice daily, while the other group received vehicle PBS control intraperitoneally.
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