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Fat cells release hormones that may play a part in the development of type 2 diabetes in obese people. A postdoc project will reveal the hitherto unknown mechanism behind the release of the hormones.

Fat cells, also known as adipocytes, store excess energy from food in the form of fat. This can later be mobilized and used by the body in the event of a low energy level. Adipocytes have other properties than storing energy, however. They play a crucial role in the development of metabolic diseases such as type 2 diabetes. One way this is thought to take place is through the release of signal substances – adipokines – from the adipocytes to the blood circulation. The adipokines are carried to the organs of the body such as the liver, muscles and brain, where they are involved in coordinating the energy balance.

Hitherto unknown mechanism may disturb whole body’s energy balance in obese people

One of the ways in which adipokines are secreted from the adipocytes is known as ectodomain shedding. In ectodomain shedding, small fragments of proteins bound to the membrane of the adipocytes are released. This process is facilitated by so-called proteases, collectively known as sheddases, that ‘cleave’ the bond between the adipokines and the cell membrane, thus releasing the active adipokines from the cell.

In her postdoctoral project, which is supported by a grant of DKK 1.8 million from the Danish Diabetes Academy, Hande Topel Batarlar will study a hitherto unknown mechanism in adipocytes whereby specific sheddases cleave the surface-bound protein AOC3, releasing a soluble form known as sAOC3 into the blood circulation.

The research group of which Hande Topel Batarlar is a member has obtained results indicating that obesity-associated sheddase activation, and hence the cleavage of AOC3, is associated with dysfunction in the energy balance of the whole body. In this project, Hande Topel Batarlar aims to reveal the molecular mechanisms underlying AOC3 cleavage and hence the release of the adipokine sAOC3.

Super-resolution microscopy to help reveal mechanism

‘In this project, I will investigate the molecular mechanisms in adipocytes that underlie proteolytic sheddase-induced cleavage of AOC3. This will be done using advanced super-resolution STED microscopy combined with genetically manipulated cell systems and mouse lines’, says Hande Topel Batarlar, who received her PhD from Dokuz Eylül University in Turkey in 2019.

Hande Topel Batarlar will use this method to study the effects of elevated AOC3/sAOC3 on the surrounding adipose tissue and on the rest of the body when AOC3 is spread via the blood circulation.

‘Ultimately, I want to study AOC3 signalling effects in human adipocytes and to analyse changes in sAOC3 products/activity in human adipose tissue biopsies from overweight people and type 2 diabetes patients as a possible new biomarker for diagnosis’, says Hande Topel Batarlar.

Collaboration with new centre at University of Southern Denmark and visit to Karolinska Institutet in Sweden

In the project, Hande Topel Batarlar will have the benefit of the research environment at the Center for Adipocyte Signaling (ADIPOSIGN) at the University of Southern Denmark, of which Jan Wilhelm-Kornfeld, the project’s PI, is a co-founder. The Center was founded in 2019 following a grant from the Novo Nordisk Foundation. The Center is led by Professor Susanne Mandrup and is a collaborative venture of the University of Southern Denmark, the University of Copenhagen and Cambridge University in the UK.

The project will also include several visits to Stockholm, where, in collaboration with Asst. Prof. Erdinç Sezgin of Karolinska Institutet, Hande will make use of advanced methods of super-resolution microscopy. The project will also involve collaboration with Dr Paul Meakin of the University of Leeds in the UK and Professor Matthias Blüher of Universitätsmedizin Leipzig.

By Nina Jensen, Project Manager, Danish Diabetes Academy

Facts

Name and title: Hande Topel Batarlar PhD, b. 1986

Awarded DKK 1.8 million by the Danish Diabetes Academy.

Project title: The Role of Proto-Adipokine AOC3 During Adipose Tissue Dysfunction in Metabolic Diseases.

Research centre: Department of Biochemistry and Molecular Biology, University of Southern Denmark

Email: handetb@bmb.sdu.dk

Tel: +45 50 35 02 56

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Contact Danish Diabetes Academy

Tore Christiansen, Managing Director

Email: tore.christiansen@rsyd.dk

Tel: +45 2964 6764