Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6
- Registration Number
- NCT04687540
- Lead Sponsor
- Rigshospitalet, Denmark
- 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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 25
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Study day 21 (study visit 2) Saline 0.9% Post-intervention measurements: Participants will be under the influence of tocilizumab, which was injected at the end of study visit 1. Study day 1 (study visit 1) Tocilizumab Baseline measurements (pre-intervention) are obtained on study visit 1.
- Primary Outcome Measures
Name Time Method Whole-body, fat and skeletal muscle fat turnover 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
Whole-body, fat and skeletal muscle glucose turnover 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
Whole-body, fat and skeletal muscle amino acid and protein turnover 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
Nutrient uptake 0-21 days Uptake of fatty acids, glucose and amino acids from a meal in the presence of tocilizumab as compared to placebo
- Secondary Outcome Measures
Name Time Method Subjective feeling of hunger and fullness 0-21 days Hunger and fullness will be assessed on a VAS scale.
Triglycerides (plasma concentration) 0-21 days Change in postabsorptive and postprandial triglycerides levels in the presence of tocilizumab as compared to placebo
Free fatty acids (FFA) (plasma concentration) 0-21 days Change in postabsorptive and postprandial FFA levels in the presence of tocilizumab as compared to placebo
Insulin (plasma concentration) 0-21 days Change in postabsorptive and postprandial insulin levels in the presence of tocilizumab as compared to placebo
C-peptide (plasma concentration) 0-21 days Change in postabsorptive and postprandial c-peptide levels in the presence of tocilizumab as compared to placebo
Glucagon (plasma concentration) 0-21 days Change in postabsorptive and postprandial glucagon levels in the presence of tocilizumab as compared to placebo
Cortisol (plasma concentration) 0-21 days Change in postabsorptive and postprandial cortisol levels in the presence of tocilizumab as compared to placebo
Adrenaline (plasma concentration) 0-21 days Change in postabsorptive and postprandial adrenaline levels in the presence of tocilizumab as compared to placebo
Noradrenaline (plasma concentration) 0-21 days Change in postabsorptive and postprandial noradrenaline levels in the presence of tocilizumab as compared to placebo
Cytokines, incl. interleukin-6 (IL-6) (plasma concentration) 0-21 days Change in postabsorptive and postprandial cytokine levels in the presence of tocilizumab as compared to placebo
Total and active GLP-1 (plasma concentration) 0-21 days Change in postabsorptive and postprandial total and active GLP-1 levels in the presence of tocilizumab as compared to placebo
GIP (plasma concentration) 0-21 days Change in postabsorptive and postprandial GIP levels in the presence of tocilizumab as compared to placebo
PYY (plasma concentration) 0-21 days Change in postabsorptive and postprandial PYY postabsorptive and postprandial in the presence of tocilizumab as compared to placebo
Leptin (plasma concentration) 0-21 days Change in postabsorptive and postprandial leptin levels in the presence of tocilizumab as compared to placebo
Testosterone (plasma concentration) 0-21 days Change in postabsorptive testosterone levels in the presence of tocilizumab as compared to placebo
TSH (plasma concentration) 0-21 days Change in postabsorptive TSH levels in the presence of tocilizumab as compared to placebo
GH (plasma concentration) 0-21 days Change in postabsorptive and postprandial GH levels in the presence of tocilizumab as compared to placebo
Respiratory exchange ratio (RER) 0-21 days Indirect calorimetry measured in post-absorptive and postprandial states
Femoral artery blood flow 0-21 days Change in femoral artery blood flow in the presence of tocilizumab as compared to placebo
RNA sequencing 0-21 days RNA sequencing on adipose tissue and skeletal muscle biopsies, monocytes with or without the influence of tocilizumab
Mitochondrial respiration (Oroboros) 0-21 days Mitochondrial respiration in skeletal muscle biopsies with or without the influence of tocilizumab
Gastric emptying rate 0-21 days Gastric emptying rate in the presence of tocilizumab as compared to placebo
Plasma metabolome 0-21 days Plasma metabolome with or without the influence of tocilizumab
Plasma, lipidome 0-21 days Plasma lipidome with or without the influence of tocilizumab
Adipose tissue proteome 0-21 days Adipose tissue proteome with or without the influence of tocilizumab
Skeletal muscle proteome 0-21 days Skeletal muscle proteome with or without the influence of tocilizumab
Monocyte secretome 0-21 days Change in the postabsorptive and postprandial secretory profile of monocytes in the presence of tocilizumab as compared to placebo
IL-6 signaling activation in monocytes 0 days IL-6 signaling pathway activation in monocytes from lean participants compared to from obese participants
Trial Locations
- Locations (1)
Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)
🇩🇰Copenhagen, Denmark