Insulin-sensitive fat leads to obesity

SORLA is a protein that influences metabolism in adipose tissue. If there is too much of the molecule, fat cells become overly sensitive to insulin and break down less fat. This new link between SORLA and increases in body weight was discovered by Dr. Vanessa Schmidt, a postdoc in Prof. Thomas Willnow’s lab at the MDC, who then worked with an international team to gain a detailed understanding of how the protein has its effects. The work appears in The Journal of Clinical Investigation. SORLA was previously known for its role in defending the brain against Alzheimer’s disease.

Cells are true masters of garbage separation. Some proteins are marked for destruction while others are recycled, sorted into different cellular compartments, and then sent on their way to the cell’s equivalents of incinerators and chaff cutters.

One protein involved in this sorting system is SORLA, which is a member of the sortilin family of proteins. Willnow and Schmidt discovered that SORLA is involved in Alzheimer’s and have spent more than a decade researching its role in the neurodegenerative disease. They found out that by resorting proteins involved in the development of Alzheimer's, SORLA reduces their ability to form harmful deposits. The Alzheimer-related protein beta-amyloid is a fragment of a longer protein and only occurs when the molecule is broken down in cellular compartments called lysosomes, which serve as a sort of garbage disposal system. SORLA stops this from happening by sorting the longer form of the molecule into compartments where they are recycled rather than broken down.

SORLA is genetically linked to obesity

Alzheimer’s is not the only condition in which SORLA is involved. Analyses of genes in large groups of people found that those who had inherited specific forms of the SORLA gene were likely to have a larger waist circumference and increased levels of body fat. “These kinds of genetic studies can only detect statistical links; they do not identify the underlying mechanism that causes them,” says Willnow. “Nonetheless, we have known for many years that obesity is a risk factor for Alzheimer’s. That’s why we were interested in seeing if there was a functional explanation for this.”

SORLA's functions suggested that it might play a role in metabolic disorders related to body fat. Cellular sorting mechanisms not only remove damaged or unnecessary molecules from cells – they are also used to fine-tune signaling and pathways within cells that are related to metabolism.

SORLA correlates with obesity in study participants and in animal experiments

Weight increase of mice fed with a high-calorie diet. TG, mice with elevated SORLA in fat tissue; WT, normal mice; KO, mice without SORLA. Image: Vanessa Schmidt/MDC.

In order to understand SORLA’s role in metabolism, Schmidt investigated people participating in a clinical study and carried out experiments in cell cultures and animal models.

Investigating the adipose tissue of 362 overweight people was a central part of the work. “Overcoming the organizational hurdles to obtain human samples was not easy, but they are what makes the publication so convincing,” says Schmidt. What she found confirms the link found in the genetic studies: the more SORLA found in a person's fat, the more overweight they were.

But are elevated levels of SORLA the reason for the excess weight, or just a consequence of it? The researchers answered this question by conducting experiments on mice in which they caused the SORLA gene to be produced in excessive amounts only in adipose tissue. When the animals were given a diet of high-calorie food, they quickly became obese. By contrast, mice that in which the SORLA gene had been deactivated were markedly thinner than mice with normal SORLA levels, even though they were eating the same food.

Too much SORLA leads to excessive insulin sensitivity

Fat tissue with normal SORLA levels. The cells appear normal-sized. Image: Vanessa Schmidt.

So the researchers had found that SORLA does indeed modulate body fat in animals and humans – but they still did not know exactly why this happened. Tests on adipose tissue isolated from the mice helped Schmidt and Willnow’s team draw closer to the answer.

First they discovered that metabolism was out of balance in the mice’s fat cells. Those with an overactive SORLA gene were deriving more energy from carbohydrates and lowering the amount of fat they burned. The situation was exactly the opposite in the mice with deactivated SORLA genes.

The key element in these changes seemed to be the metabolic hormone insulin. The body releases insulin when levels of sugar compounds in the blood rise – after a carbohydrate-rich meal, for instance. The body then reduces the amount of fat it burns and instead uses the now-abundant sugar molecules to produce energy. To make this happen, insulin binds to a receptor on the surface of the fat cells that tells the cell to stop breaking down fat. To deactivate this "stop" signal, the cell absorbs the insulin receptor and breaks it down.

Cells with an excess of SORLA clearly reacted more strongly to insulin. Studies on cell cultures allowed the researchers to follow SORLA and the absorbed insulin receptors on their way through the cell’s sorting stations. They found that SORLA marked the insulin receptors for recycling and prevented them from being broken down in lysosomes. Higher SORLA levels thus meant that more insulin receptors were being recycled to the surface of the cell, where they could bind more insulin molecules. This makes the cell oversensitive to the hormone, and it sends the signal to stop breaking down fat too often.

Higher insulin sensitivity leads to obesity

“Insulin resistance is also a feature of type 2 diabetes, but it is not the only way fat metabolism can get disrupted," Willnow says. “Another way is for adipose tissue to become overly sensitive to insulin." On a normal diet, however, it didn't matter much whether mice had levels of SORLA that were too high, too low, or normal. Mice with too much of the protein only gained extreme amounts of weight when they ate "fast food" that was high in fat and carbohydrates. “Adipose tissue that is overly sensitive to insulin only becomes a problem if you have an unhealthy diet,” says Willnow.

With their findings, Schmidt and Willnow present an entirely new, previously unknown signaling pathway within cells. This will likely be relevant in treating people with metabolic conditions, because the adipose tissue of overweight people has high levels of SORLA.

SORLA’s role in Alzheimer’s and obesity is based on the same underlying mechanism: to maintain health, proteins within cells need to be sorted in the proper way. Any imbalance in this process can affect a wide variety of functions in the body.

Vanessa Schmidt1, Nadja Schulz2, 3, Xin Yan1, Annette Schürmann2, 3, Stefan Kempa1, Matthias Kern4, Matthias Blüher4, Matthew N. Poy1, Gunilla Olivecrona5, and Thomas E. Willnow1 (2016): „SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity.“ Journal of Clinical Investigation. doi: 10.1172/JCI84708

1Max Delbrück Center for Molecular Medicine, Berlin; 2German Institute of Human Nutrition, Potsdam-Rehbrücke; 3Deutsches Zentrum für Diabetesforschung, München-Neuherberg; 4University Medical Center, University of Leipzig; 5Department of Medical Biosciences and Physiological Chemistry, Umeå University, Sweden.

Featured image: Fat cells with insulin receptor marked red, early endosomes green, nuclei blue and lipid droplets white.