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

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04687540
• Other study ID #: METO
• Status: Completed
• Phase: N/A
• Start date: April 9, 2021
• Est. completion date: August 1, 2021

Study information

• Verified date: April 2022
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: August 1, 2021
• Est. primary completion date: August 1, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy
• Obesity

Intervention

Drug:
• Tocilizumab
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.
• Saline 0.9%
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

Locations

Country	Name	City	State
Denmark	Rigshospitalet, Centre of Inflammation and Metabolism (CIM) Centre for Physical Activity Research (CFAS)	Copenhagen

Sponsors (1)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark

Country where clinical trial is conducted

Denmark, 

References & Publications (6)

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. — View 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. Epub 2004 Sep 21. — View Citation

van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, Hiscock N, Møller 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. — View Citation

Wallenius V, Wallenius K, Ahrén 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. — View 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. — View Citation

Wueest S, Item F, Boyle CN, Jirkof P, Cesarovic N, Ellingsgaard H, Böni-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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	Free fatty acids (FFA) (plasma concentration)	Change in postabsorptive and postprandial FFA levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Triglycerides (plasma concentration)	Change in postabsorptive and postprandial triglycerides levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Subjective feeling of hunger and fullness	Hunger and fullness will be assessed on a VAS scale.	0-21 days
Secondary	Insulin (plasma concentration)	Change in postabsorptive and postprandial insulin levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	C-peptide (plasma concentration)	Change in postabsorptive and postprandial c-peptide levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Glucagon (plasma concentration)	Change in postabsorptive and postprandial glucagon levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Cortisol (plasma concentration)	Change in postabsorptive and postprandial cortisol levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Adrenaline (plasma concentration)	Change in postabsorptive and postprandial adrenaline levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Noradrenaline (plasma concentration)	Change in postabsorptive and postprandial noradrenaline levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Cytokines, incl. interleukin-6 (IL-6) (plasma concentration)	Change in postabsorptive and postprandial cytokine levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Total and active GLP-1 (plasma concentration)	Change in postabsorptive and postprandial total and active GLP-1 levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	GIP (plasma concentration)	Change in postabsorptive and postprandial GIP levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	PYY (plasma concentration)	Change in postabsorptive and postprandial PYY postabsorptive and postprandial in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Leptin (plasma concentration)	Change in postabsorptive and postprandial leptin levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Testosterone (plasma concentration)	Change in postabsorptive testosterone levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	TSH (plasma concentration)	Change in postabsorptive TSH levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	GH (plasma concentration)	Change in postabsorptive and postprandial GH levels in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Respiratory exchange ratio (RER)	Indirect calorimetry measured in post-absorptive and postprandial states	0-21 days
Secondary	Femoral artery blood flow	Change in femoral artery blood flow in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	RNA sequencing	RNA sequencing on adipose tissue and skeletal muscle biopsies, monocytes with or without the influence of tocilizumab	0-21 days
Secondary	Mitochondrial respiration (Oroboros)	Mitochondrial respiration in skeletal muscle biopsies with or without the influence of tocilizumab	0-21 days
Secondary	Gastric emptying rate	Gastric emptying rate in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	Plasma metabolome	Plasma metabolome with or without the influence of tocilizumab	0-21 days
Secondary	Plasma, lipidome	Plasma lipidome with or without the influence of tocilizumab	0-21 days
Secondary	Adipose tissue proteome	Adipose tissue proteome with or without the influence of tocilizumab	0-21 days
Secondary	Skeletal muscle proteome	Skeletal muscle proteome with or without the influence of tocilizumab	0-21 days
Secondary	Monocyte secretome	Change in the postabsorptive and postprandial secretory profile of monocytes in the presence of tocilizumab as compared to placebo	0-21 days
Secondary	IL-6 signaling activation in monocytes	IL-6 signaling pathway activation in monocytes from lean participants compared to from obese participants	0 days