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Written by:
Paul Holland
31 May 2023

Researchers at the University of Cambridge and the University of East Anglia (UEA) have made an important discovery in the race to find treatments for obesity and related diseases, such as diabetes.

A new study published today is the first to reveal the molecular structure of a protein called ‘Uncoupling protein 1’ (UCP1).

This protein allows brown fat tissue, or ‘good fat’, to burn off calories as heat – in contrast to conventional white fat that stores calories.

The breakthrough was made by an international collaboration between the University of Cambridge, UEA, the University of Pennsylvania and the Free University of Brussels.

The team say that their findings provide crucial molecular details that will help develop therapeutics that activate UCP1 artificially to burn off excess calories from fat and sugar.

And that this could one day combat obesity and related diseases, such as diabetes.

Lead researcher Professor Edmund Kunji, Trinity Hall Fellow in Natural Sciences, said: “Our paper reveals, for the first time, the structure of UCP1 in atomic detail, and how its activity in brown fat cells is inhibited by a key regulatory molecule.”

Using the Krios G3i, a cryogenic electron microscope at the Penn Singh Center for Nanotechnology, the team were able to view UCP1 in atomic detail.

“This is an exciting development that follows more than four decades of research into what UCP1 looks like and how it works,” said Vera Moiseenkova-Bell, an associate professor of Pharmacology and faculty director of the Beckman Center for Cryo-Electron Microscopy.

Professor Kunji said: “Our work shows how a regulator binds to prevent UCP1 activity,    but more importantly the structure will allow scientists to rationalise how activating       molecules bind to switch the protein on, leading to the burning of fat.

“The activated tissue can also remove glucose from the blood, which can help control diabetes.

“This is a significant breakthrough in this field,” he added.

Dr Paul Crichton, from UEA’s Norwich Medical School, said: “As well as the conventional white fat that we are all familiar with, we can also develop brown fat.

“Brown fat is the good fat – it breaks down blood sugar and fat molecules to create heat and help maintain body temperature.

“Most of our fat, however, is white fat, which stores energy – and too much white fat leads to obesity.

“UCP1 is the key protein that allows the specialised brown fat to burn off calories as heat.

“We know that mammals switch on UCP1 activity in brown fat tissue to protect against the cold and to maintain body temperature – especially in new-borns, that cannot yet shiver to keep warm.

“Brown fat varies in humans, where it correlates with leanness in the population – and there has been a lot of interest in how to increase brown fat and activate UCP1 therapeutically, as a potential way to treat obesity.

“A lot of research has been focusing on finding ways to encourage brown fat and how to turn white fat into brown fat – in order to burn more calories and fight metabolic disease.

“But even with more brown fat – UCP1 must still be ‘switched on’ to gain full benefit. And research has been hampered by a lack of details on the molecular make up of UCP1. Despite more than 40 years of research, we did not know what UCP1 looks like to understand how it works – until now.”

This research was supported by the Medical Research Council, the Biological and Biotechnological Sciences Research Council, and by the National Institutes of Health/National Institute of General Medical Sciences. Nanobody discovery was funded by the Instruct-ERIC part of the European Strategy Forum on Research infrastructures, and the Research Foundation – Flanders, and the Strategic Research Program of the Vrije Universiteit Brussel.

‘Structural basis of purine nucleotide inhibition of human uncoupling protein 1’ is published in the journal Science Advances.

Top image: Mitochondria are compartments in each human cell, where food components are broken down to generate a cellular fuel called ATP. As part of this process the mitochondria charge up by pumping out protons (H+), but the human uncoupling protein (UCP1), when activated, short-circuits them by leaking the protons back, converting the energy to heat. Shown are UCP1 in its inactive form (inset, left), inhibited by a nucleotide, as shown in the paper, and in its activated form (inset, right), generating heat, which is still unresolved structurally.