Glucocorticoid excess alters metabolic rate and substrate utilisation via 11β-HSD1

Abstract

Systemic glucocorticoid excess causes several adverse metabolic conditions, most notably Cushing's syndrome. These effects are amplified by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Here, we determined the less well-characterised effects of glucocorticoid excess, and the contribution of 11β-HSD1 amplification on metabolic rate in mice. Male and female C57BL/6J (wild type, WT) and 11β-HSD1 knockout (11β-HSD1 KO) mice were treated with high-dose corticosterone or a vehicle control for 3 weeks. Indirect calorimetry was conducted during the final week of treatment, with or without fasting, to determine the impact on metabolic rate. We found that corticosterone treatment elevated metabolic rate and promoted carbohydrate utilisation primarily in female WT mice, with effects more pronounced during the light phase. Corticosterone treatment also resulted in greater fat accumulation in female WT mice. Corticosterone induced hyperphagia was identified as a likely causal factor altering the respiratory exchange ratio (RER) but not energy expenditure (EE). Male and female 11β-HSD1 KO mice were protected against these effects. We identify novel metabolic consequences of sustained glucocorticoid excess, identify a key mechanism of hyperphagia, and demonstrate that 11β-HSD1 is required to manifest the full metabolic derangement.

Keywords: 11β-HSD1; glucocorticoid excess; metabolic rate; substrate utilisation.

Figure 1

Corticosterone induced a phenotype typical of glucocorticoid excess in WT mice whilst 11β-HSD1 KO prevented it. (A) Male body weight pre- and post-treatment. (B) Female body weight pre- and post-treatment. (C) Male gonadal fat weight normalised to body weight. (D) Female gonadal fat weight normalised to body weight. (E) Male quadriceps weight normalised to body weight. (F) Female quadriceps weight normalised to body weight. Bar graphs are presented as mean ± s.e.m., n = 8–16. *Significant difference between treatments. # Significant pre and post treatment difference *P < 0.05, **P < 0.01, ***P < 0.001, ****/####P < 0.0001.

Figure 2

Corticosterone treatment increased food and water intake in WT mice whilst 11β-HSD1 KO prevented it. (A) Average male food intake. (B) Average female food intake. (C) Average male water intake. (D) Average female water intake. Scatter plots represent average day and night values and are resented as mean with individual values ± s.e.m., n = 5–12. *Significantly different. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 3

Glucocorticoid excess elevated energy expenditure in female WT mice, whilst 11β-HSD1 KO prevented this. (A) Male energy expenditure. (B) Female energy expenditure. Line graphs represent hourly change and are presented as mean ± s.e.m., n = 12. Scatter plots represent average day and night values and are presented as mean with individual values ± s.e.m., n = 12. *Significantly different. *P < 0.05, **P < 0.01.

Figure 4

Glucocorticoid excess altered the respiratory exchange ratio in female WT mice, whilst 11β-HSD1 KO prevented this. (A) Male respiratory exchange ratio. (B) Female respiratory exchange ratio. Line graphs represent hourly change and are presented as mean ± s.e.m., n = 12. Scatter plots represent average day and night values and are presented as mean with individual values ± s.e.m., n = 12. *Significantly different. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 5

Glucocorticoid excess decreased physical activity (locomotor activity) levels in female WT mice. The line graph represents hourly changes and are presented as mean ± s.e.m., n = 8. The scatter plot represents average day and night values and are presented as mean with individual values ± s.e.m., n = 8. *significantly different. ***P < 0.001.

Figure 6

Fasting during the light phase prevented an altered respiratory exchange ratio but did not prevent elevated energy expenditure in female WT mice. (A) Energy expenditure. (B) Respiratory exchange ratio. Line graphs represent hourly change and are presented as mean ± s.e.m., n = 8. Scatter plots represent average day and night values and are presented as mean with individual values ± s.e.m., n = 8. *Significantly different. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Figure 7

Proposed mechanism by which glucocorticoid excess elevates energy expenditure and the respiratory exchange ratio in C57BL/6J mice. Excess corticosterone treatment forces mice into a continuous state of hyperphagia, which, alongside corticosterone excess itself, causes a pronounced increase in adipose tissue. This increases body weight, which likely elevates energy expenditure. Alteration of the respiratory exchange ratio is driven directly by glucocorticoid excess-induced hyperphagia.