Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men

Beckey Trinh, Merel Peletier, Casper Simonsen, Peter Plomgaard, Kristian Karstoft, Bente Klarlund Pedersen, Gerrit van Hall, Helga Ellingsgaard, Beckey Trinh, Merel Peletier, Casper Simonsen, Peter Plomgaard, Kristian Karstoft, Bente Klarlund Pedersen, Gerrit van Hall, Helga Ellingsgaard

Abstract

Lack of interleukin-6 (IL-6) leads to expansion of adipose tissue mass in rodents and humans. The exact underlying mechanisms have not been identified. In this placebo-controlled, non-randomized, participant-blinded crossover study, we use the IL-6 receptor antibody tocilizumab to investigate the role of endogenous IL-6 in regulating systemic energy metabolism at rest and during exercise and recovery in lean and obese men using tracer dilution methodology. Tocilizumab reduces fatty acid appearance in the circulation under all conditions in lean and obese individuals, whereas lipolysis (the rate of glycerol appearance into the circulation) is mostly unaffected. The fact that fatty acid oxidation is unaffected by IL-6 receptor blockade suggests increased re-esterification of fatty acids. Glucose kinetics are unaffected. We find that blocking endogenous IL-6 signaling with tocilizumab impairs fat mobilization, which may contribute to expansion of adipose tissue mass and, thus, affect the health of individuals undergoing anti-IL-6 therapy (Clinicaltrials.gov: NCT03967691).

Keywords: IL-6 receptor; Interleukin-6; exercise; fatty acids; glycerol; lipolysis; metabolism; obesity; stable isotopes; tocilizumab.

Conflict of interest statement

The authors declare no competing interests.

© 2021 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Schematic overview of the studyNaCl 0.9% was infused on saline day and day 21, and tocilizumab was infused on day 1. IC, indirect calorimetry; Wattmax, peak power output; •, blood sample;°, breath sample.
Figure 2
Figure 2
IL-6 receptor blockade increases IL-6 concentration Plasma concentration of IL-6. Left panel: data from the lean group (n = 13). Right panel: data from the obese group (n = 9). Data are represented as mean ± SEM. ∗p 

Figure 3

IL-6 receptor blockade reduces release…

Figure 3

IL-6 receptor blockade reduces release of palmitate into the circulation but has no…

Figure 3
IL-6 receptor blockade reduces release of palmitate into the circulation but has no effect on palmitate oxidation (A–F) Plasma concentration of palmitate (A), Ra palmitate per kilogram of fat mass (B) and per kilogram of fat free mass (FFM) (C), Rd palmitate per kilogram of FFM (D), palmitate oxidation rate (E), and average plasma concentration of triglycerides in each phase (F). Left panels: data from the lean group (n = 11 for palmitate data, n = 13 for triglycerides). Right panels: data from the obese group (n = 9). Gaps are left at the beginning of each phase because data were calculated based on the average of two consecutive measurements without overlapping phases (see details in the STAR Methods). Data are represented as mean ± SEM. ∗p < 0.05 day 1 versus saline, ∗∗p < 0.01 day 1 versus saline, #p < 0.05 day 21 versus saline, ##p < 0.01 day 21 versus saline using a linear mixed-effects model and Dunnett’s method for many-to-one comparisons. Ra, rate of appearance; Rd, rate of disappearance. See also Figure S2.

Figure 4

IL-6 receptor blockade reduces lipolysis…

Figure 4

IL-6 receptor blockade reduces lipolysis in obese individuals and has no effect on…

Figure 4
IL-6 receptor blockade reduces lipolysis in obese individuals and has no effect on glucose kinetics (A–G) Plasma concentration of glycerol (A), Ra glycerol per kilogram of fat mass (B) and per kilogram of FFM (C), ratio of Ra palmitate to Ra glycerol (D), plasma glucose concentration (E), Ra glucose (F), and Rd glucose (G). Left panels: data from the lean group (n = 12). Right panels: data from the obese group (n = 9). Gaps are left at the beginning of each phase because data were calculated based on the average of two consecutive measurements without overlapping phases (see details in the STAR Methods). Data are represented as mean ± SEM. ∗p < 0.05 day 1 versus saline, ∗∗p < 0.01 day 1 versus saline, #p < 0.05 day 21 versus saline, ##p < 0.01 day 21 versus saline using a linear mixed-effects model and Dunnett’s method for many-to-one comparisons.

Figure 5

IL-6 receptor blockade decreases cortisol…

Figure 5

IL-6 receptor blockade decreases cortisol and glucagon levels (A–E) Plasma concentrations of cortisol…

Figure 5
IL-6 receptor blockade decreases cortisol and glucagon levels (A–E) Plasma concentrations of cortisol (A), insulin (B), glucagon (C), adrenaline (D), and noradrenaline (E). Left panels: data from the lean group (n = 13). Right panels: data from the obese group (n = 9). Data are represented as mean ± SEM. ∗p 
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Figure 3
Figure 3
IL-6 receptor blockade reduces release of palmitate into the circulation but has no effect on palmitate oxidation (A–F) Plasma concentration of palmitate (A), Ra palmitate per kilogram of fat mass (B) and per kilogram of fat free mass (FFM) (C), Rd palmitate per kilogram of FFM (D), palmitate oxidation rate (E), and average plasma concentration of triglycerides in each phase (F). Left panels: data from the lean group (n = 11 for palmitate data, n = 13 for triglycerides). Right panels: data from the obese group (n = 9). Gaps are left at the beginning of each phase because data were calculated based on the average of two consecutive measurements without overlapping phases (see details in the STAR Methods). Data are represented as mean ± SEM. ∗p < 0.05 day 1 versus saline, ∗∗p < 0.01 day 1 versus saline, #p < 0.05 day 21 versus saline, ##p < 0.01 day 21 versus saline using a linear mixed-effects model and Dunnett’s method for many-to-one comparisons. Ra, rate of appearance; Rd, rate of disappearance. See also Figure S2.
Figure 4
Figure 4
IL-6 receptor blockade reduces lipolysis in obese individuals and has no effect on glucose kinetics (A–G) Plasma concentration of glycerol (A), Ra glycerol per kilogram of fat mass (B) and per kilogram of FFM (C), ratio of Ra palmitate to Ra glycerol (D), plasma glucose concentration (E), Ra glucose (F), and Rd glucose (G). Left panels: data from the lean group (n = 12). Right panels: data from the obese group (n = 9). Gaps are left at the beginning of each phase because data were calculated based on the average of two consecutive measurements without overlapping phases (see details in the STAR Methods). Data are represented as mean ± SEM. ∗p < 0.05 day 1 versus saline, ∗∗p < 0.01 day 1 versus saline, #p < 0.05 day 21 versus saline, ##p < 0.01 day 21 versus saline using a linear mixed-effects model and Dunnett’s method for many-to-one comparisons.
Figure 5
Figure 5
IL-6 receptor blockade decreases cortisol and glucagon levels (A–E) Plasma concentrations of cortisol (A), insulin (B), glucagon (C), adrenaline (D), and noradrenaline (E). Left panels: data from the lean group (n = 13). Right panels: data from the obese group (n = 9). Data are represented as mean ± SEM. ∗p 

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