TY - JOUR
T1 - Dietary manipulations that induce ketosis activate the HPA axis in male rats and mice
T2 - A potential role for fibroblast growth factor-21
AU - Ryan, Karen K.
AU - Packard, Amy E.B.
AU - Larson, Karlton R.
AU - Stout, Jayna
AU - Fourman, Sarah M.
AU - Thompson, Abigail M.K.
AU - Ludwick, Kristen
AU - Habegger, Kirk M.
AU - Stemmer, Kerstin
AU - Itoh, Nobuyuki
AU - Perez-Tilve, Diego
AU - Tschöp, Matthias H.
AU - Seeley, Randy J.
AU - Ulrich-Lai, Yvonne M.
N1 - Publisher Copyright:
Copyright © 2018 Endocrine Society.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040721052&partnerID=8YFLogxK
U2 - 10.1210/en.2017-00486
DO - 10.1210/en.2017-00486
M3 - Article
C2 - 29077838
AN - SCOPUS:85040721052
SN - 0013-7227
VL - 159
SP - 400
EP - 413
JO - Endocrinology
JF - Endocrinology
IS - 1
ER -