Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6

NCT04687540 | Completed

• 1 other identifier: METO
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

The overall purpose of this explorative yet quantitative study project is to understand how blocking IL-6 signaling leads to the expansion of adipose tissue mass in humans in vivo. The aim is to gain in depth knowledge about how IL-6 receptor blockade affects human lipid, glucose and protein metabolism, specifically the uptake and storage of substrates from a meal vs. their utilization, hence the balance determining whether one gains or loses fat mass.

Conditions

Obesity; Healthy

Keywords

Interleukin-6; Tocilizumab; Postprandial; Postabsorptive; Substrate metabolism; Fat metabolism; Glucose metabolism; Protein metabolism; Isotope dilution technique

Outcome Measures

Primary Outcomes (4)

• Whole-body, fat and skeletal muscle fat turnover

  Rate of appearance and disappearance of glycerol and palmitate, fatty acid oxidation and re-esterification, arterio-venous differences of glycerol, palmitate, triglycerides across adipose tissue and skeletal muscle, triglycerides fractional synthesis rate in the postabsorptive and postprandial state in the presence of tocilizumab as compared to placebo

  0-21 days

• Whole-body, fat and skeletal muscle glucose turnover

  Rate of appearance and disappearance of glucose, arterio-venous differences of glucose across adipose tissue and skeletal muscle, glycogen fractional synthesis rate in the postabsorptive and postprandial state in the presence of tocilizumab as compared to placebo

  0-21 days

• Whole-body, fat and skeletal muscle amino acid and protein turnover

  Rate of appearance and disappearance of amino acids, arterio-venous differences of amino acids across adipose tissue and skeletal muscle, protein fractional synthesis rate in the postabsorptive and postprandial state, in the presence of tocilizumab as compared to placebo

  0-21 days

• Nutrient uptake

  Uptake of fatty acids, glucose and amino acids from a meal in the presence of tocilizumab as compared to placebo

  0-21 days

Secondary Outcomes (28)

• Free fatty acids (FFA) (plasma concentration)

  0-21 days

• Triglycerides (plasma concentration)

  0-21 days

• Subjective feeling of hunger and fullness

  0-21 days

• Insulin (plasma concentration)

  0-21 days

• C-peptide (plasma concentration)

  0-21 days

Study Arms (2)

Study day 1 (study visit 1)

PLACEBO COMPARATOR

Baseline measurements (pre-intervention) are obtained on study visit 1.

Drug: Tocilizumab

Study day 21 (study visit 2)

ACTIVE COMPARATOR

Post-intervention measurements: Participants will be under the influence of tocilizumab, which was injected at the end of study visit 1.

Drug: Saline 0.9%

Interventions

Tocilizumab DRUG

Baseline: Tocilizumab (infusion of 8 mg/kg bodyweight or a maximum of 800 mg) will be infused over 60 minutes at the end for the study day, therefore study visit 1 (study day 1) measurements are baseline.

Also known as: RoActemra

Study day 1 (study visit 1)

Saline 0.9% DRUG

Participants are under influence of tocilizumab since the effect of the drug will last for 4 weeks. Participants will be infused with saline at study visit 2 (study day 21). Placebo to tocilizumab will be saline (NaCl 0.9%) as tocilizumab is a colorless solution and has to be diluted with NaCl 0.9% prior to administration

Study day 21 (study visit 2)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy males:
• Age ≥ 18 years and ≤ 40 years
• BMI \< 18 and \> 25 kg/m2
• Healthy (based on screening)
• Stable body weight for 6 months
• Obese males:
• Age ≥ 18 years and ≤ 40 years
• BMI ≥ 30 and ≤ 40 kg/m2
• Healthy (based on screening)
• Stable body weight for 6 months

You may not qualify if:

• Smoking
• Evidence of severe thyroid or heart disease, inflammatory diseases, current infection, liver disease (transaminases \>2x upper normal range), kidney disease (creatinine \>1.5 mg/dl), known immunosuppressive disease, corticosteroid use, regular NSAID or paracetamol usage, aspirin use \>100 mg/d, history of carcinoma, history of tuberculosis, anemia (hematocrit \<33%), WBC \<2 x 10\^3/ul, platelets \<100 x 10\^3/ul, bleeding disorders, obstructive pulmonary disease
• Femoral hernia, vascular prosthesis, vascular thrombosis
• Previous nerve damage, many previous femoral catheter installations

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (1)

Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)

Copenhagen, 2100, Denmark

Location

Related Publications (7)

• Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med. 2002 Jan;8(1):75-9. doi: 10.1038/nm0102-75.

  PMID: 11786910 BACKGROUND

• Wueest S, Item F, Boyle CN, Jirkof P, Cesarovic N, Ellingsgaard H, Boni-Schnetzler M, Timper K, Arras M, Donath MY, Lutz TA, Schoenle EJ, Konrad D. Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice. Am J Physiol Regul Integr Comp Physiol. 2014 Jun 1;306(11):R861-7. doi: 10.1152/ajpregu.00533.2013. Epub 2014 Apr 2.

  PMID: 24694381 BACKGROUND

• Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N, Fagerlind SR, Seide SK, Nymand S, Ball M, Vinum N, Dahl CN, Henneberg M, Ried-Larsen M, Nybing JD, Christensen R, Rosenmeier JB, Karstoft K, Pedersen BK, Ellingsgaard H, Krogh-Madsen R. Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial. Cell Metab. 2019 Apr 2;29(4):844-855.e3. doi: 10.1016/j.cmet.2018.12.007. Epub 2018 Dec 27.

  PMID: 30595477 BACKGROUND

• Christensen RH, Lehrskov LL, Wedell-Neergaard AS, Legaard GE, Ried-Larsen M, Karstoft K, Krogh-Madsen R, Pedersen BK, Ellingsgaard H, Rosenmeier JB. Aerobic Exercise Induces Cardiac Fat Loss and Alters Cardiac Muscle Mass Through an Interleukin-6 Receptor-Dependent Mechanism: Cardiac Analysis of a Double-Blind Randomized Controlled Clinical Trial in Abdominally Obese Humans. Circulation. 2019 Nov 12;140(20):1684-1686. doi: 10.1161/CIRCULATIONAHA.119.042287. Epub 2019 Nov 11. No abstract available.

  PMID: 31710522 BACKGROUND

• Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA, Pedersen BK. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab. 2005 Jan;288(1):E155-62. doi: 10.1152/ajpendo.00257.2004. Epub 2004 Sep 21.

  PMID: 15383370 BACKGROUND

• van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab. 2003 Jul;88(7):3005-10. doi: 10.1210/jc.2002-021687.

  PMID: 12843134 BACKGROUND

• Trinh B, Rasmussen SJ, Brogger-Jensen ME, Engelhard CA, Lund A, Tavanez AR, Vassilieva A, Janum S, Iepsen UW, Kiens B, Moller K, Pedersen BK, Van Hall G, Ellingsgaard H. Inhibition of basal IL-6 activity promotes subcutaneous fat retention in humans during fasting and postprandial states. Cell Rep Med. 2025 Apr 15;6(4):102042. doi: 10.1016/j.xcrm.2025.102042. Epub 2025 Mar 26.

  PMID: 40147447 DERIVED

MeSH Terms

Conditions

Obesity

Interventions

tocilizumab; Sodium Chloride

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Helga Ellingsgaard, PhD

  CFAS, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Only subjects will be masked regarding order of saline and tocilizumab infusion
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Group leader

Model Details: The study is designed in a placebo-controlled crossover manner, consisting of a screening visit and two study visits. Due to the 4-week wash out period of the IL-6 receptor antibody tocilizumab, the order of study visits will be identical in all subjects; hence, study visits will not be randomized. Subjects will be infused with tocilizumab at the end of study visit 1. This will allow us to study the effect of tocilizumab on study visit 2.

Study Record Dates

• First Submitted: December 17, 2020
• First Posted: December 29, 2020
• Study Start: April 9, 2021
• Primary Completion: August 1, 2021
• Study Completion: August 1, 2021
• Last Updated: April 15, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)