Circumventing leptin resistance for weight control.

I 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 hypothalamus (5), and the serendipitous finding that ciliary neurotrophic factor (CNTF) treatment of amyotropic lateral sclerosis patients for neurotropic benefits produced severe anorexia and weight loss (6), an outcome later replicated in rodents (7, 8), presented a new avenue for therapeutic exploration. The paper by Lambert et al. (9) in this issue of PNAS has extended these findings by demonstrating the efficacy of a CNTF derivative, CNTFAx15, in correcting obesity and dependent metabolic disorders in mice. Results show that in leptin-deficient obyob mice and normal mice rendered obese and leptin-resistant by consumption of a high fat diet, CNTFAx15 treatment normalized the obese phenotypes. Furthermore, it is apparent that CNTFAx15 mobilizes intracellular signal transduction pathways in the hypothalamus that are similar to those activated by leptin, and not by interleukin-1, the prototype cytokine. This explains why the weight-reducing effects of CNTFAx15 are free of side effects, such as fever, taste aversion, and metabolic abnormalities that are generally evoked by cytokines.