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Leptin's hunger-suppressing effects are mediated by the hypothalamic-pituitary-adrenocortical axis in rodents

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Under conditions of starvation, reduced leptin and elevated glucocorticoid signaling both function to promote appetite. In this paper, Perry et al. evaluate the relationships between suppression of leptin and elevations in corticosterone and how they affect feeding. It has been known for several years that corticosterone (the rodent version of cortisol) can promote leptin production (Berneis et al. 1996; Masuzaki et al. 1997), and that leptin can suppress corticosterone signaling (Pralong et al. 1998; Rosmond et al. 2000; Malcher-Lopes et al. 2006), suggesting an intimate relationship between these signaling pathways. Although considered in these previous papers, the role of these pathways in relation to each other has not been thoroughly examined.

The authors performed a series of experiments including fasting, experimental hypoinsulinemia or hypoglycemia, and inhibition of GR signaling along with stabilizing infusions of corticosterone or leptin. By doing this, the authors show that reductions in leptin only increases food intake when accompanied by corticosterone signaling. In three settings of altered glucocorticoid signaling - whether corticosterone is held stable, its signaling is antagonized, or it is inhibited by HSD11B2 over-expression - reduced leptin does not increase food intake. Similarly, if hypercorticosteronemia is induced experimentally, leptin is unable to suppress food intake. They go on to show that it is GR signaling in AgRP/NPy neurons that is critical to the hyperphagic effects of glucocorticoid signaling. These data support the contention that reduced leptin signaling is dependent on glucocorticoid signaling, and has important implications for our understanding of the relationships between obesity, stress and eating behaviors.

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