This was a rather cool study mouse study suggesting that the deleterious effects of cortisol depend far more on disturbed rhythmicity of cortisol than on absolute levels itself. When cortisol was injected around the time that blood levels normally peak, even when it massively increased increased plasma levels about 40-fold higher than the normal peak, leading to dramatically increased total 24h levels of cortisol, it had no long-term effect on obesity. (Figure 7)
In contrast, when cortisol was chronically infused at a low dose that kept plasma levels constant, but total 24h levels still the same or even lower than normal - the result was increased weight gain and fat mass over time. In studies on cells they found that constant exposure to cortisol caused preadipocytes to differentiate into adipocytes, but spikes of cortisol occurring at the natural time had no effect on preadipocyte differentiation.
It suggests that trying to keep cortisol levels chronically low may actually be worse than having elevated cortisol at the appropriate time - which for humans would be in the morning.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30190-6
Flattening the Circadian Glucocorticoid Oscillations in Mice Results in a Striking Increase in Fat Mass
While previous studies had shown that increased glucocorticoid levels can increase fat mass in rodents and humans (Campbell et al., 2011,Lee et al., 2014), our goal here was to test if and how oscillating versus continuous levels of glucocorticoid stimuli affect fat mass and adipogenesis. To generate flattened, sustained levels of Cort, we implanted 8-week-old C57BL/6J male mice with pellets that released Cort continuously over 21 days (scheme in Figure 7A and data in Figure 7B). The Cort dose released per day from the pellet was chosen based on previous studies using Cort pellets in mice (Hodes et al., 2012) such that mean Cort levels would not exceed normal mean physiological levels. As shown in Figure 7B, we confirmed that animals with sham pellets showed the normal diurnal Cort oscillations with a nadir between 08:00 and 11:00 and peak levels between 17:00 and 20:00. Mice implanted with Cort pellets showed significant elevated Cort levels in the nadir of the diurnal pattern, and also showed lower peak Cort levels, effectively flattening the level of circulating glucocorticoids without significantly changing the total amount of circulating glucocorticoids in the mice compared to mice implanted with sham pellets. Flattening of circadian glucocorticoid oscillations by implanted Cort pellets has also been demonstrated in rats (Campbell et al., 2011,Dallman et al., 2000). Notably, due to the nocturnal waking of mice, the timing of circadian glucocorticoid oscillations in mice is shifted, peaking at approximately 19:00 (7 p.m.) instead of at approximately 7 a.m. as in humans.
Confirming previous results in which Cort pellets were implanted in rats (Campbell et al., 2011), the mice we had implanted with Cort pellets initially showed a small decrease in body weight before increasing their weight over the next 3 weeks at a faster rate compared to animals with sham pellets and ending up weighing approximately 5% more than sham animals on day 26 (Figure 7C). Since our in vitro data had shown that daily glucocorticoid pulses with durations less than 12 hr do not result in differentiation independent of their amplitude within a 12-fold amplitude range (Figure S2B), we next tested whether this was also the case in vivo.
We generated a 40-fold increase in daily peak amplitude of glucocorticoids compared to sham-injected mice by injecting Cort into mice at 17:00 (5 p.m.) every day for 21 days (Figures 7D and 7E). Strikingly, despite the greatly increased daily peak levels of Cort, we did not observe a significant difference in weight between the Cort- and sham-injected animals (Figure 7F), arguing that peak amplitude and total dose of glucocorticoids can change over wide ranges and still not cause an increase in weight as long as the increase in glucocorticoids occurs during a short time window and leaves a sufficiently long time period each day with low Cort. Together, these results raise the question of whether the weight gain we observed in the Cort pellet experiments is a reflection of an increase in fat mass.
Markedly, when we dissected animals in the four groups after 26 days, we found that the animals with implanted Cort pellets—and flattened glucocorticorticoid levels—had significantly greater amounts of both inguinal (subcutaneous) and epidydimal (visceral) adipose mass compared to the mice with sham pellets and normal circadian glucocorticoid oscillations (Figures 7G and 7H). Furthermore, despite experiencing daily 40-fold greater peak levels of glucocorticoids for 21 days, the Cort-injected animals showed indistinguishable increases in inguinal and epididymal adipose mass compared to sham-injected animals. A summary of the Cort pellet and injection experiments is presented in Table S7.
In contrast, when cortisol was chronically infused at a low dose that kept plasma levels constant, but total 24h levels still the same or even lower than normal - the result was increased weight gain and fat mass over time. In studies on cells they found that constant exposure to cortisol caused preadipocytes to differentiate into adipocytes, but spikes of cortisol occurring at the natural time had no effect on preadipocyte differentiation.
It suggests that trying to keep cortisol levels chronically low may actually be worse than having elevated cortisol at the appropriate time - which for humans would be in the morning.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30190-6
Flattening the Circadian Glucocorticoid Oscillations in Mice Results in a Striking Increase in Fat Mass
While previous studies had shown that increased glucocorticoid levels can increase fat mass in rodents and humans (Campbell et al., 2011,Lee et al., 2014), our goal here was to test if and how oscillating versus continuous levels of glucocorticoid stimuli affect fat mass and adipogenesis. To generate flattened, sustained levels of Cort, we implanted 8-week-old C57BL/6J male mice with pellets that released Cort continuously over 21 days (scheme in Figure 7A and data in Figure 7B). The Cort dose released per day from the pellet was chosen based on previous studies using Cort pellets in mice (Hodes et al., 2012) such that mean Cort levels would not exceed normal mean physiological levels. As shown in Figure 7B, we confirmed that animals with sham pellets showed the normal diurnal Cort oscillations with a nadir between 08:00 and 11:00 and peak levels between 17:00 and 20:00. Mice implanted with Cort pellets showed significant elevated Cort levels in the nadir of the diurnal pattern, and also showed lower peak Cort levels, effectively flattening the level of circulating glucocorticoids without significantly changing the total amount of circulating glucocorticoids in the mice compared to mice implanted with sham pellets. Flattening of circadian glucocorticoid oscillations by implanted Cort pellets has also been demonstrated in rats (Campbell et al., 2011,Dallman et al., 2000). Notably, due to the nocturnal waking of mice, the timing of circadian glucocorticoid oscillations in mice is shifted, peaking at approximately 19:00 (7 p.m.) instead of at approximately 7 a.m. as in humans.
Confirming previous results in which Cort pellets were implanted in rats (Campbell et al., 2011), the mice we had implanted with Cort pellets initially showed a small decrease in body weight before increasing their weight over the next 3 weeks at a faster rate compared to animals with sham pellets and ending up weighing approximately 5% more than sham animals on day 26 (Figure 7C). Since our in vitro data had shown that daily glucocorticoid pulses with durations less than 12 hr do not result in differentiation independent of their amplitude within a 12-fold amplitude range (Figure S2B), we next tested whether this was also the case in vivo.
We generated a 40-fold increase in daily peak amplitude of glucocorticoids compared to sham-injected mice by injecting Cort into mice at 17:00 (5 p.m.) every day for 21 days (Figures 7D and 7E). Strikingly, despite the greatly increased daily peak levels of Cort, we did not observe a significant difference in weight between the Cort- and sham-injected animals (Figure 7F), arguing that peak amplitude and total dose of glucocorticoids can change over wide ranges and still not cause an increase in weight as long as the increase in glucocorticoids occurs during a short time window and leaves a sufficiently long time period each day with low Cort. Together, these results raise the question of whether the weight gain we observed in the Cort pellet experiments is a reflection of an increase in fat mass.
Markedly, when we dissected animals in the four groups after 26 days, we found that the animals with implanted Cort pellets—and flattened glucocorticorticoid levels—had significantly greater amounts of both inguinal (subcutaneous) and epidydimal (visceral) adipose mass compared to the mice with sham pellets and normal circadian glucocorticoid oscillations (Figures 7G and 7H). Furthermore, despite experiencing daily 40-fold greater peak levels of glucocorticoids for 21 days, the Cort-injected animals showed indistinguishable increases in inguinal and epididymal adipose mass compared to sham-injected animals. A summary of the Cort pellet and injection experiments is presented in Table S7.
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