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Leptin is a critical regulator of energy balance in mammals and has served as a launch point for innumerable studies examining the regulation of food intake and energy expenditure (1). At high physiological concentrations, leptin causes a decrease in food intake, an increase in energy expenditure, and a shift to increased fatty acid oxidation. These physiological shifts lead to a decrease in body weight and body fat content. Conversely, a lack of leptin leads to obesity due to hyperphagia and increased lipogenesis. In leptin signaling deficiencies, brown adipose tissue, a major thermogenic organ in small rodents, loses its thermogenic capacity due to diminished sympathetic nervous system activity. In this issue of Diabetes, Rahmouni et al. (2) present a new molecular mechanism by which leptin stimulates anorectic and thermogenic responses in rodents.
Given that most of leptin's actions with regard to energy balance occur within the central nervous system, it is currently accepted that a distributed network of leptin receptor- bearing neurons within the hypothalamus are responsible for mediating a concerted response to fluctuations of energy stores within adipose tissue (3). Leptin receptor- bearing neurons are found throughout the hypothalamus, and some of them are chemically defined: arcuate nucleus (proopiomelanocortin [POMC] neurons and agouti-related peptide/neuropeptide Y neurons), ventromedial nucleus (SFl neurons), and lateral hypothalamus (neurotensin neurons). Other types still must be identified and characterized thoroughly. Analysis of the workings of this distributed network has led to the finding of intriguing and (maddeningly) idiosyncratic properties of the system. For example, leptin is known to cause phosphorylation of signal transducer and elevator of transcription (STAT)3 by the activation of janus kinase (JAK)2 for all cell types studied to date (4)....