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

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.

Codon-optimized FAM132b prevents diet-induced obesity by modulating adrenergic response and insulin action

“…2D). High-fat diet was reported to enhance HPA axis activity (8,9), leading to hyperglycemic response to EPI (28). In this study, we further found that FAM132b gene therapy reduced serum levels of corticosterone, ACTH, norepinephrine (NE), and EPI ( Fig.…”

“…Thus, chronic stress is associated with a higher risk of type 2 diabetes (6), while regular exercise is helpful for glycemic control in the previous cohort studies (7). High-fat feeding not only causes glucose intolerance, insulin resistance and metabolic disorders, and also enhances HPA axis tone in a manner that resembles HPA hyperactivity in chronic stress exposure (8,9). Evidence from chronic stress suggests lowering glycemic response to HPA axis by some means contributes to glycemic control in patients with diabetes or hyperglycemia.…”

Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges

“…Mice fed a ketogenic diet (KD) show significant increase in FGF21 expression and serum levels [96,97,98] required for the activation of hepatic lipid oxidation, triglyceride clearance, and ketogenesis induced by KD [36]. However, unlike the murine model, in obese patients, a KD does not increase FGF21 serum levels [99] and even decreases its levels when a KD is combined with low calorie intake [100].…”

Neuro-Behavioral Status and the Hippocampal Expression of Metabolic Associated Genes in Wild-Type Rat Following a Ketogenic Diet

“…This may be explained by the increased BHB levels following dietary treatment. A recent study by Ryan et al found that the low carbohydrate and high fat ketogenic diet (KD) in male rats and mice resulted in an increase in hypothalamic-pituitary-adrenal (HPA) axis tone (25). Thus, we speculate that the increased activation of HPA axis associated with an absence of carbohydrates and increased levels of BHB may be associated with the observed behavioral changes in current study.…”