WCM-Q research probes mechanisms of premature aging of fat cells in obesity

Researchers at Weill Cornell Medicine-Qatar (WCM-Q) have gained new insight into the molecular mechanisms by which obesity leads to premature aging of fat cells, and then to chronic inflammation, insulin resistance and – eventually - type-2 diabetes.

The researchers, led by WCM-Q’s Dr. Nayef Mazloum, developed a new in vitro laboratory test and used gene analysis and editing technologies to discover key molecules that regulate cellular senescence and aging in adipose (fat) cells and examined the function of two protein encoding genes - named STAT1 and STAT3 - in the regulation of inflammation that can lead to insulin resistance and type 2 diabetes. Cellular senescence is a process of deterioration akin to aging in which cells lose certain functions, particularly the ability to proliferate by cell division.  

Obesity and type-2 diabetes are two of the most pressing health issues facing Qatar. An estimated 41 percent of adult Qatari nationals are obese, compared to 13 percent worldwide. The global prevalence of type-2 diabetes among adults is around 10 percent, while in Qatar it is estimated that round 17 percent of adults have the condition, a figure that is projected to rise to 24 percent by 2050 if current trends continue.

While it is already well known that obesity causes premature aging of cells within the adipose tissue that can lead to inflammation and diabetes, the molecular mechanisms underlying this cellular dysfunction remain poorly understood. In order to examine these molecular mechanisms, the WCM-Q researchers devised a new laboratory test whereby they employed murine fat cell precursors (preadipocytes) and exposed them to repeated cycles of sublethal doses of hydrogen peroxide to induce premature aging, which triggered the release of inflammatory molecules. The researchers were then able to use WCM-Q’s advanced capabilities in transcriptome analysis to discover which genes were being expressed to produce the inflammation and identify disease-specific molecules involved in regulating the inflammatory pathways. Additionally, the team used CRISPR gene editing technology to delete the protein-encoding STAT1 and STAT3 genes in order to examine the effects of these genes on inflammation of the adipose cells.

Dr. Mazloum, Assistant Professor of Microbiology & Immunology and Assistant Dean for Student Research at WCM-Q said: “Obesity and type-2 diabetes are health challenges of critical importance to Qatar and the wider Gulf region. This research is very significant because the disease-specific molecules we have been able to identify could provide targets to guide the development of new drugs with which to treat obesity-related complications and diabetes. It is our belief that improving our understanding of the link between obesity and diabetes at the molecular level will be crucial for the creation of better therapies to tackle the condition.”

The research team validated their findings in adipose tissue retrieved from obese mice, and from human subjects in Qatar who were having bariatric surgery as treatment for obesity. The data the team collected provided clear evidence that STAT1 and STAT3 send molecular ‘signals’ that regulate inflammation, with STAT1 activity appearing to cause inflammation and STAT3 to curb it.

The groundbreaking research, titled ‘Signal Transducer and Activator of Transcription 3 (STAT3) Suppresses STAT1/Interferon Signaling Pathway and Inflammation in Senescent Preadipocytes’, has been published in antioxidants, a prestigious medical journal. 

The first author of the study is a recent Hamad Bin Khalifa University PhD graduate, Dr. Aisha Madani, who is supported by a Graduate Student Research Award (GSRA) grant (GSRA4-1-0330-17010) provided by the Qatar National Research Fund. Dr. Madani’s research in Dr. Mazloum’s lab at WCM-Q contributed to her PhD.

Dr. Madani said: “It is very exciting as a researcher to be studying obesity at the cellular and molecular level and to be able to mimic in the laboratory the type of cellular activity and damage that happens in the bodies of people with obesity. To have access to advanced technology to link the cellular activity to genetic factors at this early stage in my career is also extremely rewarding.”

Dr. Madani also noted the importance of the GSRA grant for supporting her studies in Qatar to gain the research skills and experience required to address scientific challenges related to the Qatar’s foremost health challenges, such as obesity and type 2 diabetes. The GSRA also plays a vital role in building the long-term research capacity of Qatar, she said.

Other researchers who contributed to the study were Dr. Yasser Majeed, Ms. Nour Al Sukhun, Dr. Najeeb Halabi, Ms. Shahina Hayat, Dr. Arash Rafii, Dr. Karsten Suhre, all of WCM-Q, plus Dr. Houari Abdesselem of the Qatar Biomedical Research Institute, Ms. Maha Agha of the Translational Research Institute (TRI) of Hamad Medical Corporation, Ms. Muneera Vakayil of the College of Health & Life Sciences of Hamad Bin Khalifa University (HBKU), Dr. Pankaj Kumar of PatsnapI Pte Ltd., Singapore and Dr. Mohamed Elrayess of the Biomedical Research Center of Qatar University.

The research was funded by the National Priorities Research Program (NPRP) grant (NPRP10-1-2051-60010) awarded to Dr. Mazloum and Biomedical Research Program (BMRP) funds from WCM-Q, a program funded by Qatar Foundation.

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