Editors' ChoiceMetabolic Disease

A new player in hunger games

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaay3569
DOI: 10.1126/scitranslmed.aay3569


Hypoleptinemia-mediated food intake requires the activation of the hypothalamic-pituitary-adrenal axis.

Leptin is a hormone secreted from the adipocytes that plays a critical role in regulating appetite, reproductive function, and immunity. In response to starvation, leptin concentrations fall, which signals the hypothalamus to increase food intake. In contrast, when energy stores are full, leptin concentrations increase and signal to the brain to lower food intake and increase energy expenditure; however, the underlying molecular mechanisms of this regulation are incompletely understood.

A recent study by Perry et al. shows that, as opposed to the conventional theory of leptin signaling pathways working entirely within the central nervous system, leptin’s effects on food intake have an endocrine component and require the suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, during prolonged fasting and in poorly controlled type 1 diabetes, hypoleptinemia activates the HPA axis and increase circulating corticosterone. The authors showed that the resultant hypercorticosteronemia is the primary mechanism responsible for hyperphagia or increased appetite, as increasing plasma corticosterone to fasting concentrations via exogenous corticosterone infusion increased food intake, whereas blocking corticosterone action by mifepristone treatment abrogated corticosterone’s hyperphagic effect. Furthermore, the aforementioned HPA axis activation regulated food intake in insulin-induced hypoglycemia, which suggests that hypercorticosteronemia, independent of leptin deficiency, is also essential for the hypoglycemia-driven feeding. In contrast, elevated leptin upon high-fat diet feeding prevented the fasting-induced increase in plasma corticosterone and the resultant hyperphagia, consistent with the presence of a threshold for plasma leptin below which the HPA axis is stimulated.

To investigate whether corticosterone promotes appetite by directly stimulating the activity of orexigenic agouti-related protein (AgRP) neurons, the authors inhibited glucocorticoid action specifically in AgRP neurons by overexpressing the glucocorticoid inactivating enzyme 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). 11β-HSD2 overexpression in AgRP neurons blunted both the fasting- and corticosterone-induced AgRP neuron firing rate and lowered food consumption. Taken together, this study increases our understanding of the regulation of appetite and demonstrates that hypercorticosteronemia is both necessary and sufficient to trigger hyperphagia during hypoglycemia, poorly controlled type 1 diabetes, and starvation. Given that hypoleptinemia-driven HPA axis activation also promotes adipose tissue lipolysis and contributes to glucose homeostasis, these results further emphasize the importance of leptin signaling in evolutionary survival during times of starvation.

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