Strategies for the delivery of leptin to the CNS

Leptin is the major regulator of body fat. It is a 16 kD protein released by fat cells into the blood and crosses the blood-brain barrier (BBB) to interact with its receptors at the arcuate nucleus to affect feeding, thermogenesis, and other functions. Within normal and obese body weight ranges, serum and cerebrospinal fluid (CSF) levels of leptin directly correlate with body mass index and adiposity. In animals, leptin at high levels exerts effects on appetite and at low levels informs the brain when fat reserves are adequate to switch behavioral, endocrine, and immune functions from starvation mode. Leptin offers a unique therapeutic opportunity for conditions related to body weight control, such as reversal of obesity and anorexia, and as an indirect treatment for diseases related to being over- or under-weight, such as insulin resistant diabetes and the endocrine changes accompanying starvation. In humans and in many rodent models, obesity may be a consequence of leptin resistance. More specifically, resistance likely results from an impaired transport of leptin across the BBB. Peripheral administration of native leptin results in weight reduction in moderately obese individuals and weight loss and reversal of insulin resistance and dyslipidemia in individuals with low leptin levels. The peripheral pharmacokinetic and BBB transport characteristics of native leptin suggests strategies for improving the therapeutic profile of leptin. These strategies include the development of longer lasting and more permeable analogs, development of antagonists, enhancing the activity of the leptin transporter, and delivering leptin by intrathecal administration.