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

Rachel Perry, Jon Resch, Amelia Douglass, Joseph Madara, Aviva Rabin-Court, Hakan Kucukdereli, Chen Wu, Joongyu Song, Bradford Lowell and Gerald Shulman

Proceedings of the National Academy of Sciences 2019. 116: 13670-13679.


Leptin informs the brain about sufficiency of fuel stores. When insufficient, leptin levels fall, triggering compensatory increases in appetite. Falling leptin is first sensed by hypothalamic neurons, which then initiate adaptive responses. With regard to hunger, it is thought that leptin-sensing neurons work entirely via circuits within the central nervous system (CNS). Very unexpectedly, however, we now show this is not the case. Instead, stimulation of hunger requires an intervening endocrine step, namely activation of the hypothalamic–pituitary–adrenocortical (HPA) axis. Increased corticosterone then activates AgRP neurons to fully increase hunger. Importantly, this is true for 2 forms of low leptin-induced hunger, fasting and poorly controlled type 1 diabetes. Hypoglycemia, which also stimulates hunger by activating CNS neurons, albeit independently of leptin, similarly recruits and requires this pathway by which HPA axis activity stimulates AgRP neurons. Thus, HPA axis regulation of AgRP neurons is a previously underappreciated step in homeostatic regulation of hunger.

Our Thoughts on This Paper

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.

Written by Dave Bridges on July 25, 2019.


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