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

Abstract

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.

Leptin mediates postprandial increases in body temperature through hypothalamus–adrenal medulla–adipose tissue crosstalk

“…Similarly, ob/ob mice, which lack the ability to secrete leptin, showed no catecholamine or temperature response to refeeding, but both increased in response to injection with recombinant leptin, again directly implicating leptin in postprandial increases in body temperature (Figure 3, B-D). However, blocking leptin action with a small molecule antagonist reversed the feeding-induced increases in catecholamines and body temperature while increasing food intake and preventing the reversal of hypercorticosteronemia with refeeding (Figure 3, F-H) (54). Taken together, these data indicate that an increase in plasma leptin concentration is both necessary and sufficient to cause increases in body temperature under postprandial conditions and of leptin on the hypothalamus-adrenal medulla-adipose tissue axis in mediating this effect.…”

<p>Glucocorticoid-Induced Fatty Liver Disease</p>

“…22 However, studies in humans and experimental animals suggest that supra-physiological levels of glucocorticoids cause hyperphagia and obesity perhaps by reducing sensitivity to leptin. 21,23,24 Leptin acts via the leptin receptor (OBRb) expressed in hypothalamic nuclei. Based on studies in vitro in a human hepatoma cell line and in vivo in rats, it has been shown that formation of leptin-OBRb complex leads to activation of tyrosine phosphorylation through JAK/STAT pathway.…”

Zinc Finger Transcription Factor Zbtb16 Coordinates the Response to Energy Deficit in the Mouse Hypothalamus

“…The fact that Zbtb16 expression is induced by GC signaling bears significant implications in Zbtb16's involvement in energy homeostasis. In addition to their function in the periphery, GCs centrally control feeding behavior, energy expenditure, and autonomic output to peripheral organs (Zakrzewska et al, 1999;Cusin et al, 2001;Kellendonk et al, 2002;Bernal-Mizrachi et al, 2007;Veyrat-Durebex et al, 2012;Yi et al, 2012;Laryea et al, 2013;Solomon et al, 2015;Perry et al, 2019). More importantly, GCs are required for the development of both genetic and dietinduced obesity and interact with leptin signaling (Yukimura and Bray, 1978;Saito and Bray, 1984;Bray et al, 1992;Makimura et al, 2000;Perry et al, 2019).…”