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A molecular switch for feeding and fasting could hold clue to obesity and aging

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Mumbai
15 Jul 2020
A molecular switch for feeding and fasting could hold clue to obesity and aging

Between the night's dinner and the next morning's breakfast, our body is in the fasting state. However, to keep our cells alive and functioning, many genes inside the cells stay working. These nightshift-working genes have a manager, a protein called SIRT1, which oversees their work through the night. When we wake up in the morning to our favorite breakfast, and the glucose starts cruising in our veins again, these genes are no longer needed and have to be shut down.

Switching off SIRT1, as though it were a molecular switch, shuts down the genes that worked through the night. Now, a study by researchers at the Tata Institute of Fundamental Research (TIFR), Mumbai, and the Indian Institute of Science Education and Research, Pune, finds that the switching off is done by adding a small sugar molecule to SIRT1. The study also suggests that malfunctioning of this switch could lead to obesity and aging. The study was published in the Proceedings of the National Academy of Sciences (PNAS) and was funded by the Department of Atomic Energy, Government of India.

The workings of the fasting genes happen in our liver, which hosts the necessary biochemical reactions, with SIRT1 leading it like a choirmaster. Any gene in the cell is 'switched on' when proteins, called transcription factors, bind to the gene. They allow the information in the genes to be read by enzymes and later produce the proteins needed to run the cell. SIRT1 interacts with a specific set of transcription factors, which initiate a particular set of genes, whose job is to tide us over when the body is fasting. But this script will change after the intake of food.

When we eat, modified sugar molecules (glycosyl moieties) get added to SIRT1, finds the current study.

"We have discovered that glucose controls the functions of SIRT1, whereby its derivative binds and modifies ('glycosylation') SIRT1 and reduces its levels," says Prof Ullas Kolthur from Department of Biological Sciences, TIFR, Mumbai, and the corresponding author of the paper.

When the levels of SIRT1 fall, the downstream activities of the managed genes fall too, like a set of Dominos.

The study also shows that modified SIRT1 interacts much less with the transcription factors. After the glycosylation, SIRT1 wasn't allowed to stay in the nucleus of the cell, where it usually binds to the transcription factors. Instead, it was shunted out into the cytoplasm and then unceremoniously degraded by another set of enzymes, since it was no longer required until the body starts fasting again. When fasting begins, SIRT1 would again be produced, and the cycle continues.

However, if the glycosyl molecules stick to SIRT1 longer than what was needed, it led to obesity and aging, the study found. Besides, if glycosylation was hampered in any way, it led to SIRT1 being active all the time, causing a rise in blood sugar levels—a condition known as the pre-diabetic state.

"The loss of SIRT1 is associated with obesity and aging, while its over-activation resulted in perturbed liver functions and a pre-diabetic like state," says Dr. Chattopadhyay, first author of the paper.

Since SIRT1 is a master regulator and problems associated with glycosylation cause aging and obesity, it could be a target for developing drugs against them.

The study highlights how a small change at the molecular level can bring about massive changes in our body's metabolism. "It is interesting to note that both excessive modification by glucose, as in the case of obesity and aging, and no modification, are both detrimental to our physiology," says Prof Ullas. "Therefore, glucose-derived modification of SIRT1 keeps a check on its activity and functions, specifies downstream molecular signaling, and fine-tunes gene expression in the liver," he explains.

The study found that SIRT1 influenced other metabolic processes too.

"Our study shows that this glucose-dependent modification also modulates insulin signaling, mitochondrial functions, and fat metabolism," Dr. Chattopadhyay says. Insulin is a hormone that controls glucose levels in the blood, and the lack of it causes diabetes. "Hence ways to regulate this modification might be beneficial in tackling lifestyle disorders and aging-related diseases" she concludes.


This article has been run past the researchers, whose work is covered, to ensure accuracy.