Overnight metabolic changes linked to liver fat build-up, Oxford study finds
Researchers identify how overnight metabolic changes could drive liver fat build-up
The University of Oxford has identified that the most common liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), follows strong day-night metabolic patterns. Their research reveals that the metabolic changes driving the disease are most pronounced overnight when the body is least equipped to process sugar and fat.
MASLD, previously known as non-alcoholic fatty liver disease, affects an estimated 40% of adults globally. Severe cases can lead to cirrhosis, liver failure, liver cancer, and cardiovascular disease. It is strongly associated with obesity and insulin resistance, which drives fat buildup in the liver.
Night-time metabolic issues
The study found that night-time metabolic dysfunction persists even after weight loss and liver fat reduction, suggesting it might be a critical, early driver of MASLD. Using 24-hour metabolic investigations including biopsies and insulin sensitivity tests, researchers observed worsened insulin resistance not only in the liver but also in muscle and abdominal fat tissue overnight. Liver fat production was increased during this period, while blood insulin levels dropped, further amplifying fat buildup in the liver.
Impact of evening meals
Further investigations revealed that many MASLD patients consume over 40% of their daily calorie intake at dinner, leading to a problematic combination. Eating heavy evening meals could accelerate the disease as the largest energy load is introduced when metabolism is least efficient.
Dr Thomas Marjot, NIHR Academic Clinical Lecturer at the University of Oxford and lead author, said:
"Some diseases are already known to fluctuate across the day – for example, symptoms of asthma can worsen overnight, and rheumatoid arthritis is often worse in the morning. However, because MASLD is frequently asymptomatic or causes non-specific symptoms, it has always been unclear whether it follows a daily rhythm.
To work this out, we had to perform very detailed metabolic investigations during both the day and the night. Our findings were really striking — all the key pathways known to cause fat build-up in the liver worsened at night: the body was far less responsive to insulin, the liver produced more fat, and muscle and abdominal fat tissue couldn't perform their metabolic functions effectively.
We then wanted to understand whether unhealthy night-time metabolism was a cause or an effect of MASLD — which came first? Importantly, we saw that metabolic dysfunction at night persisted even after patients lost weight and reduced the fat in their liver. This suggests that altered metabolism at night may occur early and could be a primary driver of MASLD.
This work offers exciting opportunities to use the body's natural rhythms to help treat MASLD, including optimising the timing of exercise and helping to inform the best time of day to take medications. Our study also clearly shows that for patients with MASLD, having a large evening meal is a bad idea. Consuming lots of calories just before bed, when the body is less able to process food efficiently, means that sugar and fat are more likely to end up being stored in the liver."
The patient perspective
Rowan Waller, a 43-year-old participant from Oxford, said his involvement in the study had inspired him to make lasting changes to his lifestyle after being diagnosed with MASLD during routine tests.
He explained:
"I first met the study researchers in a hospital clinic after being told I had MASLD. At this point I was keen to try and lose some weight and improve my overall health. Although the study involved quite a lot of investigations, I had a vague fear of missing out if I didn't do it. I knew I was going to get some health benefit and I was interested to understand how my liver was working both day and night.
I managed to lose two stone (14 kg) and it was great to see my metabolism improve in real-time across the course of the study. Having been involved in research, I am now much more conscious of my lifestyle including eating and drinking habits. I often don't drink - even when going to watch football – and I am also trying to avoid fatty foods, particularly in the evening."
Research implications
Professor Rachel Upthegrove, NIHR Oxford Health BRC Director, said:
"It is fantastic to see such ambitious experimental medicine studies performed in humans. This study gives a powerful insight into how altered diurnal rhythms can lead to liver damage, which has implications for how we understand and treat not only MASLD but other metabolic diseases including obesity, insulin resistance, and diabetes."
The research was supported by the NIHR, as well as the Wellcome Trust and Rosetrees Trust.