By Carmen K. Chan

Graphic design by Qingyue Guo

In 2021, an estimated 2.11 billion (45.1%) adults globally were considered overweight or living with obesity, a figure estimated to grow to 3.8 billion by 2050, representing over half of the world’s adult population.¹ Obesity is a major risk factor for type 2 diabetes (T2D), heart disease, stroke, and the buildup of fat in the liver.² These diseases are strongly associated with illness and early death, with heart disease remaining a leading cause of death in Canada.^3,4 The growing prevalence of obesity places substantial burden on healthcare systems and the economy,⁵ underscoring the need to better understand the biology driving metabolic disease to identify new treatment strategies.

Despite the global scale of obesity, the cultural narrative stubbornly remains: “eat less and move more.” For Dr. Cynthia Luk, an endocrinologist and Clinician-Scientist at St. Michael’s Hospital, this fails to capture the complexities she sees in her patients. She explains that “as a clinician, it’s difficult to work around these cultural stigmas. We must remember that these are complex diseases. Some components are controllable, while others are determined by genetics and biology.” Framing obesity as a matter of individual willpower overlooks biological factors (such as genetics, sex, and co-existing medical conditions) and systemic barriers (including cost of living and access to healthcare) that can make sustained weight loss far more complex than “eat less and move more.”

One key biological factor lies in fat tissue itself. When fat tissue becomes dysfunctional, it can disrupt how the body stores fat and regulates fat in the blood (lipids), increasing risk for other metabolic diseases. Yet not everyone with obesity develops the same complications. Some remain metabolically healthy, while others develop complications like T2D and heart disease. Could biological differences in fat tissue explain why obesity-driven metabolic disease develops in some people but not others? These types of questions frequently arise in Dr. Luk’s clinical work.

Dr. Luk is the Director of the Lipid Clinic at St. Michael’s Hospital, one of the largest of its kind in Canada. The clinic acts as a resource for the community, seeing patients referred by both family doctors and other specialists for complex diabetes and lipid disorders. Patient experiences directly inform research in her lab. “Working day-to-day with people that are struggling to manage metabolic disease—being hungry all the time, trying to fit in exercise—is there a better way to manage this?” she asks. Addressing these questions could reveal key biological drivers of obesity and point toward new therapies.

For Dr. Luk, research offers a way to answer these questions and create long-term change beyond the brief window of clinic visits. “Patient interactions are ten-to-fifteen minutes. With research, you can ask bigger, long-term questions and change the way we do things,” she says. Following her medical training, Dr. Luk completed a PhD and postdoctoral fellowship with Dr. Minna Woo, where her interest in the biological drivers of metabolic disease began to take shape. Dr. Luk now leads her own lab investigating signalling pathways like cell death and fibrosis (thickening or scarring of tissue) that are well established in other diseases, and explores their role in metabolic tissues, including fat, liver, and the cardiovascular system. 

One of her favourite projects, started in Dr. Minna Woo’s lab, examined the role of caspase-8, a key player of cell death, in fat cells. Obesity places prolonged metabolic stress on fat tissue that can cause fat cells to die. Fat cell death is accompanied by the release of inflammatory factors that interfere with the body’s ability to respond to insulin, contributing to insulin resistance and T2D.^6,7 In her 2023 work published as “Paper of the Month” in Diabetes, Dr. Luk and her team found that caspase-8 levels were increased in fat from individuals with T2D and in mice with metabolic disease. Removing caspase-8 from fat cells in obese mice reduced weight gain, inflammation, and insulin resistance.⁸ These findings identify caspase-8 as a key biological factor driving fat tissue dysfunction during obesity, and suggest blocking caspase-8 in fat tissue could be a therapeutic strategy for obesity-driven metabolic diseases. 

Another major focus of her lab is fibrosis in fat tissue. Fibrosis causes tissues to become stiff and scarred, which impairs their normal function. Dr. Luk’s team has been studying the Hippo signalling pathway which has been linked to fibrosis across multiple organs. A key component of this pathway is a protein called yes-associated protein (YAP), which controls genes that promote cell growth. When YAP becomes overactive, it can lead to excessive cell growth and fibrosis. Dr. Luk’s team found that YAP activity was increased in humans with T2D and in mice with obesity and insulin resistance. Removing YAP from fat cells of obese mice reduced fat fibrosis and decreased fat mass, which was accompanied by improved blood sugar.⁹ These findings suggest that targeting YAP in fat could prevent fat fibrosis and slow the progression of metabolic disease.

Together, Dr. Luk’s work highlights how obesity and metabolic disease are driven by complex biological mechanisms that extend far beyond willpower or lifestyle. While these discoveries may appear straightforward, each finding is built on years of uncertainty, setbacks, and persistence.

When asked what makes an impactful Clinician-Scientist, Dr. Luk emphasizes perseverance. She explained, “when you apply for a grant, there’s a small chance of acceptance, but you try anyway. You keep responding to feedback and refining what you do with the hope that one day the work is meaningful to patients.” Even when progress feels incremental, the field is moving quickly, which brings hope to patients who have already begun benefiting from novel interventions. She added that, “I think endocrinology and metabolism is the most exciting field right now. When I started training, there were a few insulins and people often got amputations for T2D complications. Now there are multiple insulins, a whole menu of medications, and advances in lifestyle care.” Perseverance in research enables breakthroughs that transform care for people living with metabolic disease.

For Dr. Luk, the intersection of research and care is where change happens. In the clinic, she sees the daily challenges her patients face. In the lab, she works to understand the biology behind those challenges. Ultimately, her goal is to move beyond the stigma and towards a better understanding, treatment, and prevention strategies for metabolic disease.

References

1. Ng M, Gakidou E, Lo J, et al. Global, regional, and national prevalence of adult overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. The Lancet. 2025;405:813–38. doi:10.1016/S0140-6736(25)00355-1.
2. Abdelaal M, le Roux CW, Docherty NG. Morbidity and mortality associated with obesity. Ann. Transl. Med. 2017;5:161. doi:10.21037/atm.2017.03.107.
3. Heart Disease in Canada 2017. https://www.canada.ca/en/public-health/services/publications/diseases-conditions/heart-disease-canada.html.
4. Leading causes of death. World Health Organization; n.d.
5. Janssen I. The public health burden of obesity in Canada. Can. J. Diabetes. 2013;37:90–6. doi:10.1016/j.jcjd.2013.02.059.
6. Hotamisligil GS, Murray DL, Choy LN, et al. Tumor necrosis factor a inhibits signaling from the insulin receptor (cy e/lnu non-Iul-dependent diabetes mdstus/glucose ranport/tyrine e receptor). vol. 91. 1994. doi:10.1073/pnas.91.11.4854.
7. Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 2005;46:2347–55. doi:10.1194/jlr.M500294-JLR200.
8. Luk CT, Chan CK, Chiu F, et al. Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation. Diabetes. 2023;72:1751–65. doi:10.2337/db22-1033.
9. Han DJ, Aslam R, Misra PS, et al. Disruption of adipocyte YAP improves glucose homeostasis in mice and decreases adipose tissue fibrosis. Mol. Metab. 2022;66. doi:10.1016/j.molmet.2022.101594.