Dietary Manipulations That Induce Ketosis Activate the HPA Axis in Male Rats and Mice: A Potential Role for Fibroblast Growth Factor-21

• Published in: Endocrinology (Philadelphia) Vol. 159; no. 1; pp. 400 - 413
• Main Authors: Ryan, Karen K, Packard, Amy E B, Larson, Karlton R, Stout, Jayna, Fourman, Sarah M, Thompson, Abigail M K, Ludwick, Kristen, Habegger, Kirk M, Stemmer, Kerstin, Itoh, Nobuyuki, Perez-Tilve, Diego, Tschöp, Matthias H, Seeley, Randy J, Ulrich-Lai, Yvonne M
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.01.2018; Oxford University Press
• Subjects: Adrenal glands; Adrenocorticotropin (ACTH); Animals; Atrophy; Behavior, Animal; Biomarkers - blood; c-Fos protein; Carbohydrates; Corticosterone; Corticosterone - blood; Depletion; Diet; Diet, Ketogenic - adverse effects; Endocrinology; Fibroblast growth factors; Fibroblast Growth Factors - administration & dosage; Fibroblast Growth Factors - blood; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fibroblasts; Glucocorticoids; Growth factors; High carbohydrate diet; High fat diet; Homeostasis; Humans; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - pathology; Hypothalamo-Hypophyseal System - physiopathology; Hypothalamus; Infusions, Intraventricular; Internal energy; Ketogenesis; Ketosis; Ketosis - blood; Ketosis - etiology; Ketosis - pathology; Ketosis - physiopathology; Low carbohydrate diet; Low fat diet; Male; Markers; Menopause; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - metabolism; Neurons - pathology; Nutrient deficiency; Organ Size; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - pathology; Paraventricular nucleus; Pituitary; Pituitary-Adrenal System - pathology; Pituitary-Adrenal System - physiopathology; Rats, Long-Evans; Recombinant Proteins - administration & dosage; Recombinant Proteins - metabolism; Rodents; Stress; Thymus; Thymus Gland - pathology; Triglycerides
• ISSN: 1945-7170; 0013-7227; 1945-7170
• DOI: 10.1210/en.2017-00486

Abstract 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. Inducing dietary ketosis by two distinct mechanisms (one acute and one chronic) results in HPA axis activation, and these HPA effects are attenuated in mice that lack FGF21.