Decreased blood-brain leptin transfer in an ovine model of obesity and weight loss: resolving the cause of leptin resistance.

OBJECTIVE: Hypothalamic resistance to the anorexigenic actions of the peripheral adipostat hormone leptin is characteristic of obesity. Here, we use an obese animal model of similar body weight to that of the human to test in vivo whether leptin resistance is due to decreased blood-brain leptin transport or intra-hypothalamic insensitivity, and whether sensitivity to leptin is restored by weight loss. For 40 weeks, adult sheep surgically prepared with intra-cerebroventricular (ICV) cannulae were given a complete natural diet ad libitum ('Obese' group) or in restricted quantities ('Lean' group), and then the dietary amounts were reversed for 16 weeks until mean group body weights converged ('Slimmers' and 'Fatteners', respectively).
RESULTS: ICV leptin injection (0.5 mg) at 8-week intervals acutely decreased voluntary food intake by approximately 35% in the 'Obese' group on each occasion and in 'Slimmers' and 'Fatteners' at the end, providing no evidence of intra-hypothalamic insensitivity. The ratio between endogenous leptin concentrations in ventricular cerebrospinal fluid (CSF) and peripheral blood decreased with increasing leptinaemia in 'Obese' sheep, indicating decreased efficiency of blood-brain leptin transport, whereas leptin concentrations remained low and the CSF:blood ratio remained high in 'Lean' sheep. Compared with 'Fatteners' of similar body weight, 'Slimmers' were hypoleptinaemic, but their CSF:blood leptin concentration ratio remained low. Thus, the obesity-induced impairment of leptin blood-brain transport was sustained despite an approximately 15% weight loss.
CONCLUSION: These results support the hypothesis that central resistance to leptin in obesity with associated peripheral hyperleptinaemia is attributable to decreased efficiency of leptin transport into the brain and not to intra-hypothalamic leptin insensitivity. However, leptin transport efficiency is not restored after weight loss by caloric restriction despite the prevailing hypoleptinaemia.