Not just weight loss: the “biochemical secret” linking intermittent fasting to brain health revealed
A study identifies the key role of succinate in linking the benefits of intermittent fasting to metabolism, brain function and behaviour in obesity
A team of scientists has discovered that succinate, a key compound in energy metabolism, can mediate the beneficial effects of intermittent fasting on metabolism, and especially on behaviour and brain inflammation in obese people. The study was published in the journal Acta Physiologica and is the result of an international collaboration coordinated by Paola Tognini, a researcher at the Scuola Superiore Sant'Anna in Pisa, and Amalia Gastaldelli of the Institute of Clinical Physiology of the CNR in Pisa. Other institutions involved in the study are the University of Pisa, the Scuola Normale Superiore and the University of California Irvine.
‘Thanks to this study, we could develop nutritional or pharmacological approaches aimed at modulating succinate to prevent not only diabetes and other cardiometabolic diseases, but also mood disorders and cognitive decline associated with obesity, offering neurobiological protection superior to that of simple calorie restriction,’ says Paola Tognini, researcher at the Health Science Centre of the Sant'Anna School and coordinator of the study.
Risk factors of obesity on cognitive disorders and neurodegenerative diseases
Obesity is a known risk factor for cardiometabolic diseases, including type 2 diabetes and hypertension. However, obesity does not only weigh on the scales: it affects the brain, increasing the risk of cognitive disorders, neurodegenerative and neuropsychiatric diseases. Intermittent fasting has shown positive effects, but the mechanisms by which diet influences brain health have long remained unclear.
The beneficial effects of intermittent fasting
The research team used an experimental model of obesity induced by a high-fat diet, comparing it with a balanced daily diet and the effects of intermittent fasting, a particular dietary regime that alternates between a balanced diet and 24-hour fasting periods.
The main results showed that switching from a high-fat diet to a balanced diet or intermittent fasting reduces body weight and fat mass and improves glucose tolerance. However, only intermittent fasting significantly improves exploratory behaviour and decreases anxiety levels, effects associated with reduced inflammation in the brain.
‘Thanks to advanced metabolomics techniques, we were able to identify succinate as a key molecule that connects the body's metabolism with the brain,’ explains Amalia Gastaldelli, research director at the CNR Institute of Clinical Physiology in Pisa, head of the research group on Metabolic Diseases and Multi-Omic Analysis, who designed the study together with Paola Tognini.
The analysis of metabolites in different tissues and in the bloodstream revealed a specific metabolic signature of intermittent fasting characterised by a reduction in the metabolite succinate in plasma and an increase in the liver and brown adipose tissue.
"Surprisingly, administering succinate alone reproduces most of the effects of intermittent fasting, especially in terms of behavioural change and anxiety reduction; as if the molecule were the “secret” of intermittent fasting," explains Andrea Tognozzi, a PhD student in Clinical and Translational Sciences at the University of Pisa, collaborator at the Biology Laboratory (Bio@SNS) of the Scuola Normale Superiore, and first author of the study.
These results suggest that succinate modulation, particularly its increase in the liver and brown adipose tissue and its reduction in the bloodstream, represents a new biochemical correlate of the benefits of intermittent fasting on metabolism, behaviour and brain inflammation.
Study reference
Tognozzi A. et al., Succinate Modulation as a Biochemical Correlate of Metabolic and Neurobehavioral Changes Associated With Intermittent Fasting in Obesity, Acta Physiologica, 2026. DOI: 10.1111/apha.70143
