Goodman, Joel M., PhD
The cell biology of lipid storage
General Research Subject: Obesity
Focus: Adipocytes, Obesity
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Stored fat is good for you, up to a point: It provides energy in times of starvation. It sequesters free fatty acids that are harmful and can lead to diabetes, heart disease, and other tissue damage. Fat storage cells also secrete hormones that control appetite and provide metabolic balance. Too much fat, however, often leads to obesity, inflammation, osteoarthritis, high blood lipids, and diabetes. While fat storage, therefore, is central to all of this, little is known about the process. Fat is stored in organelles termed cytoplasmic lipid droplets. They are believed to bud off a cell compartment called the endoplasmic reticulum (ER). However, evidence is provided that droplets and the ER remain connected and that proteins and lipids may traffic freely between them, providing many opportunities for regulation. Seipin, a protein in the ER, may form the bridge, or the vent, between them and in fact, may play an important role in formation of droplets in the first place.
Experiments are proposed in yeast, a genetically manipulable organism, and human cells to test whether there is flow between ER and droplets, and whether seipin mediates droplet assembly and communication between ER and droplets. The packaging of fat into droplets is the basis of both obesity and protection from diabetes. Thus, identifying seipin and other molecules involved in this process as targets should provide the first step in designing drugs to better protect the body against diabetes and perhaps even against obesity.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Our project concerns the basic mechanism of fat storage within cells. A huge risk factor for diabetes is obesity, excess storage of fat. Another disease that, if untreated, leads to diabetes is generalized lipodystrophy, in which fat is not stored properly. Thus, both obesity and lipodystrophy have, as their root issues, fat storage. While we understand how excess energy is converted to fat, how cells package fat into lipid droplets is still relatively unknown. A better understanding of this process may reveal novel therapeutic targets to treat excess fat storage as well as the inability of cells to store fat properly in lipodystrophy. Treatment of both of these conditions should lower the incidence and severity of diabetes.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Response: Many people with diabetes suffer from the disease because their bodies have a limited capacity for efficient fat storage. The limited capacity can result in an increase in circulating fat that is involved in the generation of diabetes. Yet we do not know exactly how fat is stored in tissues, which is a very basic and general process in nearly all cells. We seek to understand this process at a molecular level. This understanding may lead to new drug targets to increase the efficiency of fat storage, which should lower circulating fat and ameliorate the incidence and severity of diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I am interested in basic mechanisms of organelle assembly. The lipid droplet is a fascinating organelle, the origins of which are obscure. Yet lipid droplets are at the center of the obesity epidemic and the resulting diabetes pandemic. Paradoxically, efficient fat storage is protective from diabetes, since inefficient fat sequestration in adipose lipid droplets results in increased levels of circulating lipid, leading to diabetes, heart disease, fatty liver, and other problems. Therefore, it is quite possible that understanding basic mechanisms of fat packaging in droplets will reveal targets that can be modulated with drugs to increase efficiency of storage and prevent these conditions. This award will permit us to study the function of seipin, a protein necessary for adipose development, and one in which we have evidence of a role in fat storage in all cells. Seipin protects individuals from diabetes, yet its molecular function remains obscure.
In what direction do you see the future of diabetes research going?
We are slowly unraveling the mechanisms by which the brain controls appetite and energy homeostasis. Much of this involves the ways in which adipokines, hormones secreted by fat tissue, affects the hypothalamus in the brain. As we get a more complete picture of the circuitry, we will identify novel targets for therapy to maintain energy homeostasis in populations susceptible to diabetes and prevent excess insulin secretion and the type II diabetes that often results. But these great strides that will be made must be matched by an effective campaign for healthy lifestyle choices.
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