Genetically Increasing Fat Burning to Improve Metabolic Function as a Potential Therapy for Type 2 Diabetes
Researcher Spotlight: Sarah Nicoloro
Sarah Nicoloro is a senior research scientist in the laboratory of Michael Czech, PhD, who is helping to advance an approach to treating type 2 diabetes by reprogramming fat cells to improve how the body handles glucose.
Her path to research began with a desire in high school to help people as a physician. While her career ultimately took a different direction, the mission stayed the same. “The research we’re doing has the potential to help a lot of people with diabetes and obesity,” she said. “It’s just a different way of doing it—and it’s very exciting.”
Her work focuses on adipocytes—fat cells that play a central role in metabolism. In people with obesity and type 2 diabetes, these cells often store excess energy and contribute to insulin resistance. The Czech lab, in a collaborative project with the laboratory of Silvia Corvera, MD, are editing genes of adipocytes to increase fat burning and improve their metabolic function, exploring ways to convert these “white” fat cells into more metabolically active “brown-like” cells, which burn energy and improve glucose control.
In the following Nature Communications study, the team demonstrated that this approach can work in human cells. They reprogrammed fat cells in the lab, expanded them, and tested their function in our preclinical “humanized” mice models. The results showed improved glucose metabolism, highlighting the potential of this strategy as a future cell-based therapy.
CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease
Tsagkaraki E, Nicoloro SM, DeSouza T, Solivan-Rivera J, Desai A, Lifshitz LM, Shen Y, Kelly M, Guilherme A, Henriques F, Amrani N, Ibraheim R, Rodriguez TC, Luk K, Maitland S, Friedline RH, Tauer L, Hu X, Kim JK, Wolfe SA, Sontheimer EJ, Corvera S, Czech MP. Nat Commun. 2021 Nov 26;12(1):6931. doi: 10.1038/s41467-021-27190-y. PMID: 34836963
This work builds on years of research in the Czech Lab, where scientists are uncovering how fat tissue can be re-engineered to support metabolic health. By enhancing the body’s ability to burn energy and regulate blood sugar, these approaches could lead to new treatments that go beyond managing symptoms to addressing underlying disease mechanisms.
For Nicoloro, the impact is what matters most. “Even though I’m not seeing patients directly, this research could help many more people in the long run,” she said.
“Sarah is an amazing lab colleague and leader in our group. Her efforts have been critical to our success,” said Dr. Czech, the Isadore and Fannie Foxman Chair in Medical Research and Professor of Molecular Medicine. “She brings outstanding intellectual input into her projects, superb management skills and terrific collegiality in enriching our learning environment.”
The Road from College to the Research Lab
Sarah spent the summer between her junior and senior years at UMass Lowell, where she earned her bachelor's degree, interning at a Boston-based biotechnology company focused on cell xenotransplantation technology, called Diacrin. That’s where she met Dr. Czech, who was on their scientific advisory board. He was advising on general scientific principals and specifically the diabetes program.
It was during that internship that Sarah’s plans changed from medical school, to a research career. The internship led to a full-time position after graduation.
After a few years working at Diacrin, she was hired at UMass Chan Medical School as a research assistant with pediatric endocrinologist Rosalind Brown, investigating thyroid diseases by using rat fetal thyroid cells. Grant funding expired after one year, but there was an opening in the Czech Lab.
Joining the Czech Lab in 1998
"The Human Genome Project was not yet complete,” said Sarah. “There was still a lot of unknowns about genes and proteins compared to today.”
The lab’s focus during the early 2000’s was to learn about the interactions taking place within adipocytes. They were particularly interested in insulin signaling and GLUT4 trafficking. GLUT4 is the principal glucose transporter protein responsible for insulin-regulated glucose uptake in fat and muscle cells. Some of that work employed a Nobel Prize winning technology called RNAi, discovered by Craig Mello and Andrew Fire. RNAi was a novel and specific way to knock-down genes. She considers it "a complete game-changer.”
Glucan-Encapsulated siRNA Particles (GeRPs)
The Czech lab recognized the potential of RNA interference (RNAi) as a therapeutic tool for inflammation and metabolic disease including obesity and diabetes. They developed siRNA screens and identified the protein coding genes Map4k4 and RIP140 as metabolic regulators. In a successful collaboration with Gary Ostroff, Sarah was part of a team of scientists who developed a novel small interfering RNA (siRNA) delivery system. GeRPs are made from baker’s yeast that have been treated to remove all proteins except the glucan shell. The Glucan shell was then used to encapsulate siRNA to deliver to cells in vivo
“That was a very exciting time,” said Sarah. “Not only was it successful, interesting and fun, but the GeRPs technology taught us about the difficulty of targeting specific cells for delivery. Since there is no known target specific to fat cells, it led to our current project of genetically altering adipocytes outside of the body, then putting them back in.”
People Matter Most
For nearly 30 years Sarah has worked on many different projects, but her fondest memories include the people she’s worked with. “Our lab has attracted and produced world-class scientists,” she said. “Some joined the lab as students and left with their PhD. It’s been rewarding to teach them and learn from them. It’s a collaborative atmosphere.”
She credits Dr. Czech as a mentor, manager and teacher.
About Sarah
Sarah was born in Montreal. Her parents are British and moved from Scotland to Montreal in the late 1960’s. They eventually settled in Mississauga in the Canadian province of Ontario. Her father worked in the cargo shipping business and the family relocated to Beverly, MA during her senior year of high school.
Favorites
- Book: The Secret Life of Bees
- Movie(s): All the Star Wars films
- Restaurant: Joey’s Bar & Grill in Worcester
- Sports Team: New England Patriots
- Hobbies: Cycling, photography and spending time with her three children and wonderful friends & family