IL-6 Regulation of Substrate Metabolism and Influence of Obesity

The aim of the study is to investigate the effects of blocking IL-6 signaling with tocilizumab on lipid, glucose and protein metabolism during rest and exercise in healthy and obese humans.

Interleukin-6 is a molecule produced by a variety of cells and impacts on energy metabolism during fasting and fed conditions. Systemic IL-6 levels are low but increase acutely in response to fasting, exercise and infection, and also chronically in response to obesity and other conditions of lowgrade inflammation.Our recent human intervention study showed that IL-6 receptor blockade prevents exercise training from reducing visceral fat mass.

Whether IL-6 receptor blockade directly regulates lipolysis and/or lipid oxidation in humans is however unclear. Therefore, this study will be performed to investigate the physiological role of IL-6 on lipid, glucose and protein metabolism in humans.

Study Overview

• Status: Completed
• Conditions: Healthy; Obesity
• Intervention / Treatment: Drug: Saline 0.9%; Drug: Tocilizumab infusion

Detailed Description

The aim of the study is to assess changes in substrate kinetics, that is, lipolytic rate, rate of appearance and disappearance of free fatty acids, fatty acid oxidation, glucose rate of appearance and disappearance and protein synthesis and degradation during rest and exercise with and without IL-6 receptor blockade. We will assess the acute effects of blocking IL-6 as well as the long-term consequences of IL-6 receptor blockade on all the above parameters.

Overall, we hypothesize that blocking IL-6 changes substrate kinetics. More specifically we hypothesize that blocking IL-6 reduces the appearance of free fatty acids, reduces the lipolytic rate and lipid oxidation. We hypothesize that the consequences of blocking IL-6 will be observed during resting and exercising conditions and both immediately and longterm after IL-6 receptor blockade. We hypothesize that IL-6 receptor blockade results in an increased respiratory exchange ratio (RER) and thus increased reliance on glucose as substrate.

In this study 10 healthy males and 10 obese males will be included. Subjects will be infused with saline on 2 of the study days and tocilizumab on 1 of the study days.

Isotope dilution techniques with [6,6-2H2]Glucose, [1,1,2,3,3-D5]glycerol, K-[U-13C16]palmitate, L-[ring-D5]phenylalanine, L-[D2]tyrosine will be applied to assess lipid, glucose and protein kinetics. Respiratory exchange ratio will be measured by indirect calorimetry. The BORG scale will be used to assess the perceived exertion during exercise.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• BMI < 18 and > 25 kg/m2 or ≥ 30 and ≤ 40 kg/m2
• Healthy (based on screening)

Exclusion Criteria:

• Smoking
• Severe thyroid or heart disease
• inflammatory diseases
• current infection
• liver disease
• kidney disease
• immunosuppressive disease
• corticosteroid use
• regular NSAID usage
• aspirin use >100 mg/d
• history of carcinoma
• history of tuberculosis
• anemia
• neutropenia
• low platelets
• bleeding disorders
• obstructive pulmonary disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Saline infusion; Subjects will be infused with saline (placebo) on study day 1	Drug: Saline 0.9%; 100 ml NaCl 0.9% will be infused over 1 hour; Other Names: Saline
Active Comparator: Tocilizumab infusion; Subjects will be infused with tocilizumab on study day 2	Drug: Tocilizumab infusion; Tocilizumab (8mg/kg body weight diluted to 100 ml NaCl 0.9%) will be infused over 1 hour; Other Names: RoActemra
Other: Saline infusion under tocilizumab influence; Subjects will be infused withsaline (but still under the influence of tocilizumab) on study day 3	Drug: Saline 0.9%; 100 ml NaCl 0.9% will be infused over 1 hour; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipolytic rate	Rate of appearance and disappearance of glycerol and palmitate, fatty acid oxidation during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glucose kinetics	Rate of appearance and disappearance of glucose during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Protein metabolism	Rate of appearance and disappearance of phenylalanine and tyrosine during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Respiratory exchange ratio (RER)	RER during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Perceived exhaustion during exercise	Borg scale (rate of perceived exertion during exercise; score range from minimum 6 to maximum 20; 6 = "no feeling of exertion", 20 = "very, very hard") in the presence of tocilizumab as compared to placebo	0-28 days
Glucose	Change in glucose during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Insulin	Changes in insulin during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
C-peptide	Change in c-peptide during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Glucagon	Change in glucagon during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Cortisol	Change in cortisol during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Adrenaline	Change in adrenaline during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Noradrenaline	Changes in noradrenaline during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Interleukin 6	Change in IL-6 during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Free fatty acids	Change in free fatty acids during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days
Triglycerides	Changes in triglycerides during rest and exercise in the presence of tocilizumab as compared to placebo	0-28 days

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Helga Ellingsgaard, Ph.D., CFAS, Rigshospitalet

Publications and helpful links

General Publications

• Trinh B, Peletier M, Simonsen C, Plomgaard P, Karstoft K, Pedersen BK, van Hall G, Ellingsgaard H. Amino Acid Metabolism and Protein Turnover in Lean and Obese Humans During Exercise-Effect of IL-6 Receptor Blockade. J Clin Endocrinol Metab. 2022 Jun 16;107(7):1854-1864. doi: 10.1210/clinem/dgac239.
• Trinh B, Peletier M, Simonsen C, Plomgaard P, Karstoft K, Klarlund Pedersen B, van Hall G, Ellingsgaard H. Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men. Cell Rep Med. 2021 Sep 9;2(9):100396. doi: 10.1016/j.xcrm.2021.100396. eCollection 2021 Sep 21.

Study record dates

Study Major Dates

• Study Start (Actual): June 12, 2019
• Primary Completion (Actual): April 3, 2020
• Study Completion (Actual): April 3, 2020

Study Registration Dates

• First Submitted: May 22, 2019
• First Submitted That Met QC Criteria: May 27, 2019
• First Posted (Actual): May 30, 2019

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Exercise; Tocilizumab; Lipolysis; Interleukin-6; Substrate Metabolism
• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity
• Other Study ID Numbers: TOSS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No