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Completed

NCT Number: NCT04687540

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

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.

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Key information

Conditions

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

Age range

18 year–40 year

Sex eligibility

Male

Study type

Interventional

Phase

Not applicable

Primary location

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

Copenhagen, 2100, Denmark

About this study

Lacking IL-6 signaling leads to an expansion of adipose tissue mass in rodents and humans. However, the underlying mechanisms have not been identified.This project aims to investigate the overall hypothesis that IL-6 receptor blockade changes substrate metabolism during postabsorptive and postprandial states to favor storage over mobilization of fat and to favor glucose over fat as a source for energy production. This hypothesis finds some support in the literature: Infusion of recombinant IL-6 into humans, leading to high concentrations of IL-6 in the circulation, stimulates lipolysis and free fatty acid oxidation.

Therefore, the investigators hypothesize that IL-6 receptor blockade impairs the mobilization of FFA from adipose tissue and impairs fat oxidation in skeletal muscle in the postabsorptive state. In the postprandial, state the investigators hypothesize that IL-6 receptor blockade reduces the insulin-induced uptake and deposition of fat by adipose tissue and skeletal muscle, therefore contributing to ectopic fat deposition in the liver.

In this study 12 lean and 12 obese male participants will be included. The participants will attend one screening visit and two study visits. The IL-6 receptor antibody tocilizumab will be infused on study visit 1.

Isotope dilution techniques, blood flow measurements, arterio-venous differences across adipose tissue and skeletal muscle, fat and skeletal muscle biopsies will be used to assess lipid, glucose and protein kinetics on a whole-body as well as fat and skeletal muscle level in the fasting state and after the ingestion of a liquid mixed-meal. Respiratory exchange ratio will be measured by indirect calorimetry.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

  • 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

Treatment and study plan

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.

Other names: RoActemra

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

Primary outcomes

  1. Whole-body, fat and skeletal muscle fat turnover

    Time frame: 0-21 days

    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

  2. Whole-body, fat and skeletal muscle glucose turnover

    Time frame: 0-21 days

    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

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

    Time frame: 0-21 days

    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

  4. Nutrient uptake

    Time frame: 0-21 days

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

Secondary outcomes

  1. Free fatty acids (FFA) (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial FFA levels in the presence of tocilizumab as compared to placebo

  2. Triglycerides (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial triglycerides levels in the presence of tocilizumab as compared to placebo

  3. Subjective feeling of hunger and fullness

    Time frame: 0-21 days

    Hunger and fullness will be assessed on a VAS scale.

  4. Insulin (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial insulin levels in the presence of tocilizumab as compared to placebo

  5. C-peptide (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial c-peptide levels in the presence of tocilizumab as compared to placebo

  6. Glucagon (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial glucagon levels in the presence of tocilizumab as compared to placebo

  7. Cortisol (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial cortisol levels in the presence of tocilizumab as compared to placebo

  8. Adrenaline (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial adrenaline levels in the presence of tocilizumab as compared to placebo

  9. Noradrenaline (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial noradrenaline levels in the presence of tocilizumab as compared to placebo

  10. Cytokines, incl. interleukin-6 (IL-6) (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial cytokine levels in the presence of tocilizumab as compared to placebo

  11. Total and active GLP-1 (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial total and active GLP-1 levels in the presence of tocilizumab as compared to placebo

  12. GIP (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial GIP levels in the presence of tocilizumab as compared to placebo

  13. PYY (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial PYY postabsorptive and postprandial in the presence of tocilizumab as compared to placebo

  14. Leptin (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial leptin levels in the presence of tocilizumab as compared to placebo

  15. Testosterone (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive testosterone levels in the presence of tocilizumab as compared to placebo

  16. TSH (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive TSH levels in the presence of tocilizumab as compared to placebo

  17. GH (plasma concentration)

    Time frame: 0-21 days

    Change in postabsorptive and postprandial GH levels in the presence of tocilizumab as compared to placebo

  18. Respiratory exchange ratio (RER)

    Time frame: 0-21 days

    Indirect calorimetry measured in post-absorptive and postprandial states

  19. Femoral artery blood flow

    Time frame: 0-21 days

    Change in femoral artery blood flow in the presence of tocilizumab as compared to placebo

  20. RNA sequencing

    Time frame: 0-21 days

    RNA sequencing on adipose tissue and skeletal muscle biopsies, monocytes with or without the influence of tocilizumab

  21. Mitochondrial respiration (Oroboros)

    Time frame: 0-21 days

    Mitochondrial respiration in skeletal muscle biopsies with or without the influence of tocilizumab

  22. Gastric emptying rate

    Time frame: 0-21 days

    Gastric emptying rate in the presence of tocilizumab as compared to placebo

  23. Plasma metabolome

    Time frame: 0-21 days

    Plasma metabolome with or without the influence of tocilizumab

  24. Plasma, lipidome

    Time frame: 0-21 days

    Plasma lipidome with or without the influence of tocilizumab

  25. Adipose tissue proteome

    Time frame: 0-21 days

    Adipose tissue proteome with or without the influence of tocilizumab

  26. Skeletal muscle proteome

    Time frame: 0-21 days

    Skeletal muscle proteome with or without the influence of tocilizumab

  27. Monocyte secretome

    Time frame: 0-21 days

    Change in the postabsorptive and postprandial secretory profile of monocytes in the presence of tocilizumab as compared to placebo

  28. IL-6 signaling activation in monocytes

    Time frame: 0 days

    IL-6 signaling pathway activation in monocytes from lean participants compared to from obese participants

Sponsors and collaborators

Lead sponsor

Rigshospitalet, Denmark

Other

Registry information

Important dates

Study start
2021
Primary completion
2021
Study completion
2021
First posted
Dec 29, 2020
Registry last updated
Apr 15, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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