Lipid to store? Send in the Seipin: Dissecting the Critical Roles for Seipin in Cellular and Organismal Lipid Storage.

Storing fat is a highly effective way to retain energy in times of excess so that it can be used later when nutrients are less freely available. Chemically, fat is stored inside living cells in droplets coated in specialised proteins. This is true in simple organisms such as yeast, which are made up of only one cell, as well as in humans. In humans and other animals, most lipid is stored in specialised fat cells. Animals evolved fat cells so that the stored fat could be kept away from other cells in the body. This is important because too much fat can be toxic to these other cells. For example, in obesity fat cells get overwhelmed and the fat overflows, building up in places like the liver and walls of the blood vessels. This causes obesity associated diseases like fatty liver, diabetes and heart disease.
We are interested in a protein called seipin which plays a critical role in the storage of fat in the body. A rare group of people who lack the seipin protein are not able to make fat cells. Because these people have nowhere to safely store fat they get fatty liver disease, severe diabetes and cardiovascular problems. Exactly what the seipin protein does remains unclear but it is needed to allow stem cells to turn into new fat cells. Seipin is also involved in making fat droplets form properly inside the cells.
In recent years we have discovered that seipin works like a docking station in the cells organising other proteins so that they can work together and perform important functions. By doing this seipin organises proteins to regulate fat storage in the cell but also organises proteins that work together to turn stem cells into new fat cells. We know some of the proteins that seipin binds, but we don't know which ones are actually needed for fat cell development or the storage of fat within the cells.
This project will specifically target different protein binding events to work out exactly how the seipin hub, and which associated proteins, control fat storage and new fat cell generation.
Overall, this project will work out exactly why we need seipin to make new fat cells but will also reveal new information about how cells make and store fat. This information can then be used to find new ways to improve fat storage in humans, something that goes wrong as we age or gain weight. If we find ways to can make fat cells work properly this could reveal new ways to prevent or treat major diseases linked to obesity and ageing like diabetes, heart disease and several forms of cancer.

Adipocytes are the defining cell type of adipose tissue and are uniquely specialised in lipid storage. They sequester lipid away from other cells and tissues in the body where lipid accumulation would otherwise impair their function. A lack of adipose tissue (as occurs in rare lipodystrophy syndromes) or adipose dysfunction (as occurs in obesity) leads to lipid accumulation in non-adipose tissues and disease.

This project examines a protein called seipin, which plays a fundamental, evolutionarily conserved role in regulating lipid droplet development within almost all cells, from yeast to man. However, seipin also plays a critical role in the development of new adipocytes from stem cells and the maintenance of adipose tissue. Indeed, seipin disruption causes a near complete lack of adipose tissue in humans leading to severe metabolic disease.

In this study we will specifically interrogate the interaction of seipin with acylglycerol-3-phosphate acyltransferase 2 (AGPAT2), whose disruption also causes severe adipose tissue loss in humans, and with the lipid droplet regulator LDAF1 (also known as promethin or TMEM-159). We will use cutting edge imaging methods, viral gene-therapy and pharmaco-genetics to define the importance of seipin-AGPAT2 and seipin-LDAF1 complexes in adipocyte development and lipid storage both in cells and in vivo. This will be coupled to state of the art metabolic phenotyping to define the consequences for metabolic health of manipulating these proteins and thereby adipocyte lipid storage.

These studies will provide new insights regarding adipose tissue development, adipocyte lipid handling and metabolic health. The findings will change our understanding of diseases associated with both rare syndromes of lipodystrophy and common obesity, suggesting novel therapeutic opportunities to improve lifelong health. This work will also reveal fundamental new insights regarding cellular lipid storage in almost all organisms, from yeast to man.