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Ryan, K.K.* ; Packard, A.E.B.* ; Larson, K.R.* ; Stout, J.* ; Fourman, S.M.* ; Thompson, A.M.K.* ; Ludwick, K.* ; Habegger, K.M.* ; Stemmer, K. ; Itoh, N.* ; Perez-Tilve, D.* ; Tschöp, M.H. ; Seeley, R.J.* ; Ulrich-Lai, Y.M.*

Dietary manipulations that induce ketosis activate the HPA axis in male rats and mice: A potential role for fibroblast growth factor-21.

Endocrinology 159, 400-413 (2018)

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Endocrine Society. In response to an acute threat to homeostasis or well-being, the hypothalamic-pituitary-adrenocortical (HPA) axis is engaged. A major outcome of this HPA axis activation is the mobilization of stored energy, to fuel an appropriate behavioral and/or physiological response to the perceived threat. Importantly, the extent of HPA axis activity is thought to be modulated by an individual’s nutritional environment. In this study, we report that nutritional manipulations signaling a relative depletion of dietary carbohydrates, thereby inducing nutritional ketosis, acutely and chronically activate the HPA axis. Male rats and mice maintained on a low-carbohydrate high-fat ketogenic diet (KD) exhibited canonical markers of chronic stress, including increased basal and stress-evoked plasma corticosterone, increased adrenal sensitivity to adrenocorticotropin hormone, increased stress-evoked c-Fos immunolabeling in the paraventricular nucleus of the hypothalamus, and thymic atrophy, an indicator of chronic glucocorticoid exposure. Moreover, acutely feeding medium-chain triglycerides (MCTs) to rapidly induce ketosis among chow-fed male rats and mice also acutely increased HPA axis activity. Lastly, and consistent with a growing literature that characterizes the hepatokine fibroblast growth factor-21 (FGF21) as both a marker of the ketotic state and as a key metabolic stress hormone, the HPA response to both KD and MCTs was significantly blunted among mice lacking FGF21. We conclude that dietary manipulations that induce ketosis lead to increased HPA axis tone, and that the hepatokine FGF21 may play an important role to facilitate this effect.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Pituitary-adrenal Axis; Medium-chain Triglycerides; Low-fat Diet; Chronic Stress; Ketogenic Diet; Low-carbohydrate; C-fos; Psychological Stress; Glucose-homeostasis; Energy-expenditure

ISSN (print) / ISBN 0013-7227

e-ISSN 1945-7170

Journal Endocrinology

Quellenangaben Volume: 159, Issue: 1, Pages: 400-413

Publisher Endocrine Society

Publishing Place Chevy Chase, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)