Circumventing leptin resistance for weight control

Open Access
Publisher Website
Google Scholar
Abstract
In the avalanche of recent information on the brain's control of energy homeostasis and the pathophysiology of obesity, there are two outstanding insights. One is enhanced knowledge of the neuroanatomy and neurochemistry of various components of the appetite regulation and energy expenditure networks in the hypothalamus, and the other is characterization of the neurobiology of leptin in regulating these two hypothalamic networks (1, 2). Leptin, an adipocyte-derived hormone normally transported across the blood brain barrier (BBB), was initially heralded as a major negative feedback signal relaying information of the body's energy stores to these hypothalamic networks on a moment to moment basis to maintain body weight around a set point. However, results of numerous investigations in rodents and humans have been disappointing because circulating leptin levels display marked variations among individuals and rise in direct proportion to the age-related increase in adipose tissue depots. Thus, leptin concentrations are greatly elevated in obese subjects (2). Consequently, despite the promising results of the leptin replacement therapy experiments in leptin-deficient mice and patients, endogenous hyperleptinemia could neither curb appetite nor augment energy expenditure in normal subjects experiencing an increase in the rate of weight gain. It soon became apparent that the ineffectiveness of endogenous leptin, appropriately termed leptin resistance, develops rapidly and that leptin therapy even at supraphysiological concentrations is largely ineffective in reducing the body weight of clinically obese patients (3). Although these revelations dampened the enthusiasm of clinicians and investigators in academia and industry alike, they presented a challenge to devise newer therapeutic strategies that would curtail the environmentally based increase in the rate of weight gain and the epidemic of obesity in most developed countries (4). The knowledge accrued over several years that cytokines readily cross the BBB and induce anorexia and weight loss by an action within the …

This publication has 36 references indexed in Scilit: