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.
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 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.
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.”
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 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 grant 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 added, “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.”