Circadian Rhythm

Project 1:

Day-night Rhythm in Human Skeletal Muscle Metabolism

Many processes in the body are synchronized to a day-night rhythm, mastered centrally in de hypothalamus. However, in our 24/7 culture, we often do not obey to the daynight cycle imposed upon us by nature. Recent evidence from both observational and experimental studies indicates that this behavior negatively influences our metabolic and cardiovascular health, possibly leading to obesity and type 2 diabetes mellitus (T2DM). An important hallmark of obesity and T2DM is a decreased skeletal muscle mitochondrial function, which can be restored by activating the AMPK-SIRT1 pathway. Interestingly, recent research indicates that also AMPK and SIRT1 are under the influence of a day-night rhythm, suggesting that this rhythm would also be present in skeletal muscle mitochondrial function.

However, to date, no information is available on a day-night rhythm of mitochondrial function in human skeletal muscle. Yet, this information is important: if mitochondrial metabolism is indeed regulated in a day-night rhythm it may open opportunities for optimization of the timing of (drug) treatment to improve mitochondrial metabolism, thereby opening new leads for therapeutic interventions in T2DM.

In this project we aim to investigate the presence of a day-night rhythm in skeletal muscle mitochondria of healthy young participants. Secondary objectives include linking this rhythm to variations in whole body energy consumption and exploring day-night differences in liver triglyceride content.

PhD students: Dirk van Moorsel, Jan Hansen
Collaborators: Prof. Dr. Bart Staels, Institut Pasteur de Lille, France

Project 2:

Please treat again later! Fine-tuning treatment-timing in type 2 diabetes mellitus

The increase in metabolic diseases like type 2 diabetes mellitus (T2DM) is in part the result of modern lifestyle changes like decreased physical activity and consumption of energy-dense foods. Recently, a novel risk factor for metabolic diseases was discovered: late-night and shift work. Changing sleep-wake cycles and consumption of food at arbitrary times can lead to circadian disturbances in energy metabolism. Indeed, animal studies clearly demonstrate that important tissues, which function in maintaining cellular homeostasis, are regulated by clockworks.

Sirtuin 1 (SIRT1), a cellular energy sensor, is thought to play a key role in proper regulation of this cellular clock system. So, disturbances in cellular energy homeostasis can easily affect SIRT1 expression, with major consequences on the internal clock system of a metabolic tissue. As SIRT1 is also implicated in regulating mitochondrial oxidative capacity and insulin sensitivity, two important hallmarks of type 2 diabetes, it is clear that SIRT1 is an important target for treatment of metabolic-oriented diseases. Hence, we here hypothesize that low SIRT1 expression levels, mediated by metabolic imbalances, induce circadian disruption in skeletal muscle.

In this project, we will investigate whether human primary myotubes of obese and type 2 diabetic patients demonstrate altered SIRT1 expression and whether a circadian rhythm disruption is present. Furthermore, we will test if SIRT1 agonists can reverse circadian disturbances in skeletal muscle, resulting in improved skeletal muscle insulin sensitivity and mitochondrial oxidative capacity. Due to putative variations in circadian expression of SIRT1, timing of agonist supplementation may be crucial for eventual treatment efficacy.

This project is financed by a grant from NUTRIM, school for Nutrition and Metabolism
Phd student: Jan Hansen
Collaborators: Prof. Dr. Bart Staels, Institut Pasteur de Lille, France


Project 3:

Circadian Rhythm of Muscle Mitochondrial Metabolism

Many processes in the human body are synchronized to the environmental day-night cycle by the biological clock system, with the central pacemaker located in the brain. Research from the last decade’s shows the central core of the molecular clock mechanism is composed of a negative feedback loop mediated via the proteins PER and CRY that represses CLOCK/ BMAL1-mediated gene transactivation. More recently it has become clear that most peripheral tissues, including metabolic tissues such as liver, pancreas and skeletal muscle, contain the same molecular clock mechanism. The aim of the current project is to examine the role of circadian rhythm in the regulation of muscle mitochondrial function, and its relationship to insulin sensitivity. Studies will be performed in humans; we will examine the effect of circadian misallignment on skeletal muscle mitochondrial function and insulin sensitivity.

This project is financed by a grant from ZonMW TOPgrant
Phd student: Jacob Wefers
Collaborators: Prof. Dr. Bart Staels, Institut Pasteur de Lille, France, Prof. Dr. Dries Kalsbeek, AMC, Netherlands, Dr. Frank Scheer, Harvard, Boston, USA.