Clinical trial NCT04687540: Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6
Official title: Meal-regulated Substrate Metabolism, Influence of Obesity and IL-6
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity
Healthy
Keywords: Interleukin-6
Tocilizumab
Postprandial
Postabsorptive
Substrate metabolism
Fat metabolism
Glucose metabolism
Protein metabolism
Isotope dilution technique
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2020-12-29
Enrollment: 25
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

Primary outcomes:
measure: Whole-body, fat and skeletal muscle fat turnover
timeFrame: 0-21 days
measure: Whole-body, fat and skeletal muscle glucose turnover
timeFrame: 0-21 days
measure: Whole-body, fat and skeletal muscle amino acid and protein turnover
timeFrame: 0-21 days
measure: Nutrient uptake
timeFrame: 0-21 days
Secondary outcomes:
measure: Free fatty acids (FFA) (plasma concentration)
timeFrame: 0-21 days
measure: Triglycerides (plasma concentration)
timeFrame: 0-21 days
measure: Subjective feeling of hunger and fullness
timeFrame: 0-21 days
measure: Insulin (plasma concentration)
timeFrame: 0-21 days
measure: C-peptide (plasma concentration)
timeFrame: 0-21 days
measure: Glucagon (plasma concentration)
timeFrame: 0-21 days
measure: Cortisol (plasma concentration)
timeFrame: 0-21 days
measure: Adrenaline (plasma concentration)
timeFrame: 0-21 days
measure: Noradrenaline (plasma concentration)
timeFrame: 0-21 days
measure: Cytokines, incl. interleukin-6 (IL-6) (plasma concentration)
timeFrame: 0-21 days
measure: Total and active GLP-1 (plasma concentration)
timeFrame: 0-21 days
measure: GIP (plasma concentration)
timeFrame: 0-21 days
measure: PYY (plasma concentration)
timeFrame: 0-21 days
measure: Leptin (plasma concentration)
timeFrame: 0-21 days
measure: Testosterone (plasma concentration)
timeFrame: 0-21 days
measure: TSH (plasma concentration)
timeFrame: 0-21 days
measure: GH (plasma concentration)
timeFrame: 0-21 days
measure: Respiratory exchange ratio (RER)
timeFrame: 0-21 days
measure: Femoral artery blood flow
timeFrame: 0-21 days
measure: RNA sequencing
timeFrame: 0-21 days
measure: Mitochondrial respiration (Oroboros)
timeFrame: 0-21 days
measure: Gastric emptying rate
timeFrame: 0-21 days
measure: Plasma metabolome
timeFrame: 0-21 days
measure: Plasma, lipidome
timeFrame: 0-21 days
measure: Adipose tissue proteome
timeFrame: 0-21 days
measure: Skeletal muscle proteome
timeFrame: 0-21 days
measure: Monocyte secretome
timeFrame: 0-21 days
measure: IL-6 signaling activation in monocytes
timeFrame: 0 days
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)
Study officials:
affiliation: CFAS, Rigshospitalet
name: Helga Ellingsgaard, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.