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OBJECTIVE-Leptin is an adipocyte hormone that plays a major role in energy balance. Leptin receptors in the hypothalamus are known to signal via distinct mechanisms, including signal transducer and activator of transcription-3 (STAT3) and phosphoinositol-3 kinase (PI 3-kinase). Here, we tested the hypothesis that extracellular signal-regulated kinase (ERK) is mediating leptin action in the hypothalamus.
RESEARCH DESIGN AND METHODS-Biochemical, pharmacological, and physiological approaches were combined to characterize leptin activation of ERK in the hypothalamus in rats.
RESULTS-Leptin activates ERK 1/2 in a receptor-mediated manner that involves JAK2. Leptin-induced ERK1/2 activation was restricted to the hypothalamic arcuate nucleus. Pharmacological blockade of hypothalamic ERK 1/2 reverses the anorectic and weight-reducing effects of leptin. The pharmacological antagonists of ERK1/2 did not attenuate leptin-induced activation of STAT3 or PI 3-kinase. Blockade of ERK1/2 abolishes leptin-induced increases in sympathetic nerve traffic to thermogenic brown adipose tissue (BAT) but does not alter the stimulatory effects of leptin on sympathetic nerve activity to kidney, hindlimb, or adrenal gland. In contrast, blockade of PI 3-kinase prevents leptin-induced sympathetic activation to kidney but not to BAT, hindlimb, or adrenal gland.
CONCLUSIONS-Our findings indicate that hypothalamic ERK plays a key role in the control of food intake, body weight, and thermogenic sympathetic outflow by leptin but does not participate in the cardiovascular and renal sympathetic actions of leptin. Diabetes 58:536-542, 2009
Leptin is a largely adipocyte-derived hormone that can act in the central nervous system to decrease appetite and increase energy expenditure, thereby leading to decreased body weight (1). Central actions of leptin play an important role in the regulation of several other physiological functions, including reproductive function (2), bone formation (3), and regional sympathetic nerve activity (SNA) subserving thermogenic metabolism and cardiovascular function (4).
Leptin exerts its effects via interaction with specific receptors located in distinct classes of neurons. While several isoforms of the leptin receptor have been identified, the Ob-Rb form that includes the long intracellular domain that has signaling capacity appears to mediate most of the biological effects of leptin (5,6). The signal transducer and activator of transcription-3 (STAT3) pathway was the first signaling mechanism associated with the leptin receptor (7). Neural-specific inactivation of STAT3 leads to hyperphagia and obesity in mice (8). In addition, disrupting the ability of the leptin...