Leptin deficiency is known to promote hyperphagia, but the mechanism for this is unknown. Here we show that hypoleptinemia-driven hypercorticosteronemia promotes hyperphagia in fasting (40.3±4.9 kcal consumed in 2 hour after a 48 hour fast vs. 2.4±1.0 kcal after a 6 hour fast, P<0.0001) and poorly-controlled type 1 diabetes (T1D) (28.4±2.5 vs. 13.3±2.9 kcal, P<0.01) in rats. Correcting hypoleptinemia with a 6 hour leptin infusion reversed hypercorticosteronemia and reduced food intake to control rates in both models (48 hour fast+leptin 5.2±2.2 kcal, P<0.0001; T1D+leptin 8.1±1.9 kcal, P<0.0001), while restoring hypercorticosteronemia abrogated the anorexic effect of leptin (48 hour fast+leptin+corticosterone 29.5±3.1 kcal, T1D+leptin+corticosterone 30.0±2.7 kcal, both P<0.001 vs. leptin-treated). Treatment with a glucocorticoid receptor antagonist, mifepristone, reversed hyperphagia (48 hour fast 8.8±4.3 kcal, T1D 15.0±2.3 kcal; both P<0.05). In adrenalectomized mice treated with low-dose corticosterone, food intake following a fast was markedly reduced, whereas high-dose corticosterone restored hyperphagia. Hypercorticosteronemia induced by hypoglycemia drove hyperphagia independent of leptin and insulin (hypoglycemic-hyperinsulinemic: 42.5±2.3 kcal, euglycemic-hyperinsulinemic: 1.8±1.9 kcal, euglycemic-hyperinsulinemic-corticosterone-treated: 32.0±4.6 kcal; both P<0.001 vs. euglycemic) which was reversed by mifepristone (14.6±2.3 kcal, P<0.0001 vs. hypoglycemic).

Finally, we show that hypercorticosteronemia increases feeding behavior through corticosterone-mediated stimulation of AgRP neuron activity: overexpression of 11β-hydroxysteroid dehydrogenase 2 in AgRP neurons abrogated the hyperphagic effect of corticosterone. Together these data provide new insights into hypoleptinemia-induced hyperphagia and reveal that corticosterone-driven AgRP neuron activity drives hyperphagia during starvation, T1D, and hypoglycemia.


R.J. Perry: Research Support; Self; AstraZeneca. J. Resch: None. A.M. Douglass: None. J. Madara: None. J.D. Song: None. C. Wu: None. B. Lowell: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.


National Institutes of Health (R01DK113984, P30DK059635, T32DK101019, K99/R00CA215315, R01NS087568, UL1TR000142, T32DK007058, R01DK075632, R01DK089044, R01DK096010, R01DK111401)

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