Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Thousands of genes are involved in the regulation of our day-to-day metabolism and relatively little is understood about their function. One key protein, an ABC Transporter called ABCC5, has recently been predicted to be a susceptibility gene for Type 2 diabetes. In a new study selected as Editor's Choice in Obesity, Associate Professor Heidi de Wet has confirmed ABCC5's role in energy metabolism and identified the mechanism behind its metabolic impact for the first time.

Rare gut endocrine cells visualised using green fluorescence (left) and electron microscopy (right)

A multitude of physiological signals regulates our appetite and metabolism. An empty stomach triggers the “hunger hormone”, Ghrelin, which acts on the brain to stimulate feelings of hunger. When the stomach becomes full, those hunger signals are muted. The arrival of digested food in the small intestine from the stomach engages with hormone-secreting cells known as enteroendocrine cells. These cells are the first point of contact between you and your food: the digested food triggers receptors on these endocrine cells causing them to release hormones into the circulatory system. These hormones have very important downstream effects: they regulate the release of insulin from the pancreas, prompt capillaries to move blood towards the stomach to absorb the food, trigger feelings of satiety in the brain, and interacts with the liver, muscle and fat to enable it to absorb glucose. In essence, “these hormones are spectacularly important because they drive human metabolism in response to food.” (Prof de Wet).

ATP-binding cassette transporters (ABC transporters) are proteins found in cell membranes that transport various substances in and out of the cell. This family of transporters is very well known in the context of certain diseases. Loss of function mutations in the CFTR gene (ABCC7) can cause the respiratory disease Cystic Fibrosis, while gain of function mutations in the multidrug resistance-associated protein 1 (ABCC1) can cause a tumour to become resistant to chemotherapy. However, the function of one of these transporters, an orphan transporter called ABCC5, was unknown for some time, until a recent study found compelling evidence for its key role in energy metabolism.

A Genome-Wide Association Study used subcutaneous adipose tissue from patients and control subjects stored as part of a diabetes biobank. The study demonstrated that overexpression of ABCC5 in human adipose tissue would cause their subjects to have a three-fold increased risk of developing type 2 diabetes with age. The individuals with increased levels of ABCC5 had increased visceral fat accumulation and were more insulin resistant. Consequently, the study predicted that ABCC5 may be the new susceptibility gene for Type 2 diabetes. However, the mechanism behind this susceptibility was unknown.

In order to confirm the role of ABCC5 in energy metabolism and understand the mechanism behind ABCC5’s metabolic impact, a team led by Associate Professor Heidi de Wet knocked the gene out in mice using a CRISPR technique and examined their metabolic profile. Distinctly opposite to the human overexpression phenotype, mice with no ABCC5 were lean, had less fat and were more active. They also demonstrated increased insulin sensitivity and increased amounts of gut hormone being released in response to an oral glucose dose. “These mice were probably metabolically more healthy because they were able to respond better to the amount of food arriving in their small intestine. But, still we were unsure of the mechanism; how does ABCC5 manage to get more gut hormone released into the blood stream of these mice?” (Prof de Wet).

Upon further investigation, the team were able to show that ABCC5 is most likely a neuropeptide transporter, meaning its function is to load neuropeptides into vesicles inside cells. The vesicle content is then released by a process called exocytosis, which refers to the series of events triggered when the receptors in enteroendocrine cells detect digested food, culminating in the secretion of hormones from these cells. “Neuropeptides are information molecules, and these information molecules can be dumped into the circulation to tell your body how to respond to the arrival of digested food in the stomach.” (Prof de Wet). Once the vesicle content is released, the hormones are then free to act on downstream targets. 

For the first time, the role of ABCC5 in glucose metabolism and in the regulation of metabolism in humans has been established. The de Wet Group has been able to find a direct link between ABCC5, its metabolic impact as predicted in the Genome-Wide Association Study, and the specific function this ABC transporter has in the gut.

 

The full paper "Abcc5 Knockout Mice Have Lower Fat Mass and Increased Levels of Circulating GLP‐1" is available to read in Obesity. The paper is Editor's Choice in the August issue.

This story is featured on the Oxford Science Blog.

Similar stories

Key cause of type 2 diabetes uncovered

Research led by Dr Elizabeth Haythorne and Professor Frances Ashcroft reveals high blood glucose reprograms the metabolism of pancreatic beta-cells in diabetes. They have discovered that glucose metabolites, rather than glucose itself, are key to the progression of type 2 diabetes. Glucose metabolites damage pancreatic beta-cell function, so they are unable to release enough of the hormone insulin. Reducing the rate at which glucose is metabolised, and these glucose metabolites build up, can prevent the effects of hyperglycaemia.

New study shows clinical symptoms for Alzheimer’s can be predicted in preclinical models

Establishing preclinical models of Alzheimer’s that reflect in-life clinical symptoms of each individual is a critically important goal, yet so far it has not been fully realised. A new collaborative study from the University of Oxford has demonstrated that clinical vulnerability to an abnormally abundant protein in Alzheimer’s brain is in fact reflected in individual patient induced pluripotent stem cell-derived cortical neurons.

Updating the circuit maps of the sympathetic neural network

A new review from Professor Ana Domingos’ lab and colleagues offers a fresh modern viewpoint on sympathetic neurons and their relation to immune cells and obesity.

New Pfizer grant paves the way to a better understanding of how body fat is controlled

Professor Ana Domingos has been awarded a highly competitive independent research grant from Pfizer to discover ‘the role of Sympathetic-associated Perineurial barrier Cells in obesity’.

Collaborative MRC grant paves the way to new therapeutic targets for stress and anxiety disorders

Dr Armin Lak, Associate Professor Ed Mann and Professor Zoltán Molnár have been awarded a £733K Project Grant from the Medical Research Council on “Orexinergic projections to neocortex: potential role in arousal, stress and anxiety-related disorders”.