Circadian Rhythmicity in Cold-induced Thermogenesis

Leiden University Medical Center24 enrolled

Overview

This study aims to investigate whether maximum cold-induced non-shivering thermogenesis (e.g. thermogenesis as a consequence of BAT activity) differs between morning and evening.

Brown adipose tissue (BAT) recently emerged as a novel player in energy expenditure (EE) in humans as it combusts fatty acids and glucose towards heat. Human BAT can be activated by sympathetic stimulation resulting from cold exposure or treatment with sympathomimetic drugs. Short-term acclimation to mild cold was shown to reduce fat mass in obese subjects and decrease peripheral insulin resistance of patients with T2DM. Recently, in preclinical studies the investigators showed that BAT has a circadian rhythm. It is currently unknown whether this is also the case in humans. The investigators postulate that BAT activity should display a circadian rhythm that adapts to changes in circadian behavior, and may determine glucose/lipid levels throughout the day.

Study Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Healthy Obese Glucose Intolerance

Interventions

Personalized cooling protocolPROCEDURE

As an intervention, a personalized cooling protocol will be used in order to activate BAT and induce non-shivering thermogenesis. During the cooling procedure, subjects will be exposed to mild cold (approx. 14°C) for 150 min. Since the onset temperature of shivering shows a high interindividual variation, we will use a personal cooling protocol to ensure maximum non-shivering EE (and thus an equal maximum activation of BAT). The right temperature will be determined via a subjective method, e.g. to ask the subject if he or she experiences shivering. The time needed to achieve the right temperature is approximately 30-60 minutes. Then, the stable cooling period of 90 min is started. During this time the subject will be asked every 15 minutes whether he is experiencing shivering. If so, temperature will be increased with 2-3°C so that shivering just stops.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Dutch white Caucasian males or females * Age: 18-35 years * Lean group: BMI ≥ 18 and ≤ 25 kg/m2 * Obese glucose tolerant group: BMI ≥ 30 and ≤ 42 kg/m2 and fasted plasma glucose levels \< 5.5 and/or 2 h after OGTT ≤ 7.8 mM * Obese impaired glucose tolerant group: BMI ≥ 30 and ≤ 42 kg/m2 and fasted plasma glucose levels ≥ 5.5 and/or 2 h after OGTT between 7.8 and 11.1 mM Exclusion Criteria: * Diabetes mellitus (determined on basis of fasting or OGTT defined by ADA criteria (30) * Any other active endocrine disease (thyroid disease, any signs of Cushing's syndrome, adrenal disease and lipid-associated disorders such as familial hypercholesterolemia) * Any chronic renal or hepatic disease * Use of medication known to influence glucose and/or lipid metabolism or brown fat activity (e.g. beta blockers, antidepressants) * Smoking * Abuse of alcohol or other substances * Pregnancy * Participation in an intensive weight-loss program or vigorous exercise program during the last year before the start of the study * Current participation in another research projects that may influence the current research project * Clinically relevant abnormalities in clinical chemistry at screening (to be judged by the study physician)

Locations (1)

Leiden University Medical Center

Leiden, Netherlands

Outcomes

Primary Outcomes

Change in cold-induced non-shivering thermogenesis between morning and evening

Thermogenesis is estimated by the change in energy expenditure after cold exposure, measured by indirect calorimetry. This will be measured in the morning and in the evening.

Time frame: Change in cold-induced non-shivering thermogenesis between morning (total duration of measurement 120 minutes) and evening (total duration of measurement 120 minutes). The time frame comprising both the morning and evening measurement will be 72 hours.

Secondary Outcomes

Change in glucose metabolism (mmol/L)

Serum glucose (mmol/L) before and during cold exposure in the morning versus the evening.

Time frame: Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.

Change in insulin (pmol/l)

Serum insulin (pmol/l) before and during cold exposure in the morning versus in the evening.

Time frame: Change between morning and evening: measured at several timepoints during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.

Change in lipid metabolism (cholesterol) (mmol/L)

Cholesterol (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) in serum (mmol/L). Before and during cold exposure in the morning and in the evening.

Time frame: Change between morning and evening: measured at severaltime points during 3.5 hours. The time frame comprising both the morning and evening measurement will be 72 hours.

Change in lipid metabolism (triglycerides) (mmol/L)

Triglycerides, glycerol and free fatty acids in serum (mmol/L). Before and during cold exposure in the morning and in the evening.

Data from ClinicalTrials.gov

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