Abstract
To determine the mechanism of weight loss caused by high doses of N-butyldeoxynojirimycin (NB-DNJ) in healthy lean and leptin-deficient obese (ob/ob) mice. Healthy lean and obese mice were treated with NB-DNJ by the following methods: admixed with their diet, delivered by subcutaneously implanted mini-pumps or by intraperitoneal or intracerebroventricular (ICV) injection. Daily changes in body weight and food intake were recorded during the experimental period. The effect of NB-DNJ treatment on subcutaneous adipose tissue and on epididymal fat pads was measured. Lean mice treated with NB-DNJ, admixed with their diet, lost weight in the form of adipose tissue. This resulted in a 40% reduction in skin thickness (control, 358 +/- 11 microm; NB-DNJ treated 203 +/- 6 microm) and a reduction in epididymal fat pad weights after 5 weeks of treatment at 2400 mg/kg/day (control, 0.0154 +/- 0.001; NB-DNJ treated, 0.0026 +/- 0.0005 as ratios of fat pad weight to total body weight). Following the depletion of adipose tissue mass, the mice grew normally and did not have any reduction in lean mass. Obese mice treated with NB-DNJ also lost weight or gained weight at a greatly reduced rate compared with non-treated controls. Body weights at 6 months of age were: lean control, 29.10 +/- 1.15 g; lean NB-DNJ treated, 22.73 +/- 0.29 g; obese control, 63.25 +/- 1.5 g; obese NB-DNJ treated from 5 weeks of age, 35.30 +/- 1.68 g; obese NB-DNJ treated from 12 weeks of age, 38.84 +/- 1.26 g. Both the lean and obese groups of mice treated with NB-DNJ ate up to 30% less than untreated controls. Daily food intake (powder diet) were: lean control, 4.15 +/- 0.54 g; obese control, 4.14 +/- 0.2 g; lean NB-DNJ treated 2.9 +/- 0.37 g; obese NB-DNJ treated, 2.88 +/- 0.47 g. Mice treated with the N-substituted galactose imino sugar analogue, N-butyldeoxygalactonojirimycin (NB-DGJ) did not lose weight. Mice experienced similar weight loss or lack of weight gain when fed a restricted diet that mimics the drug-induced level of food consumption. Delivery of 2 nmol NB-DNJ by ICV injection into lean mice also caused similar reductions in food intake. Food intake: saline vehicle, 4.30 +/- 0.12 g; NB-DNJ, 3.37 +/- 0.19 g; NB-DGJ, 4.03 +/- 0.16 g; 2-deoxyglucose, 4.7 +/- 0.15 g. NB-DNJ causes weight loss as a result of reduced food consumption due to central appetite suppression.
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