Laidlaw Scholar Nikita Bhat has studied a new way to influence metabolic signaling with greater precision
"[Professor Kumar's] lab pushed me to ask better questions, think more creatively, and approach problems with both rigor and imagination," said Nikita Bhat (at left, with Krishna Kumar). "It has been central to my development as an independent scientist, and I am profoundly thankful for the experience." Photo: Jake Belcher
GLP-1 medications such as Ozempic and Zepbound have changed treatment for obesity and type 2 diabetes by acting on receptors that help regulate blood sugar and appetite—and have become household names in the process.
But for some patients, the benefits are accompanied with intense nausea and loss of muscle and bone mass. These side effects result in many patients stopping treatment or never reaching the prescribed recommended dose.
Krishna Kumar, Robinson Professor of Chemistry and a professor of biomedical engineering, notes, wryly, that for some patients, the benefits can come with “a digestive system making its objections abundantly clear.”
Current GLP-1 and GIP-based drugs typically act by binding receptors from outside the cell. Kumar’s lab is asking whether those same kinds of receptors can be modulated from within the cell membrane, with the long-term goal of understanding whether this strategy could produce more selective signaling, and fewer unwanted side effects.
A New Approach to the Problem
Tufts senior Nikita Bhat, a Laidlaw Scholar studying chemistry and biotechnology, has been exploring with Kumar the following question: Could metabolic receptors be influenced more precisely from the inside of the cell?
Their work focuses on GIPR, a key receptor that helps the body respond to food and regulate blood sugar. Like the GLP-1 receptor, GIPR belongs to a broader signaling family called G protein-coupled receptors, or GPCRs. These receptors help cells interpret signals from hormones, neurotransmitters, and other molecules, and they are the targets of more than a third of FDA-approved medicines.
At the center of Bhat and Kumar’s work are molecules known as pepducins. These lipid-linked peptides are designed to slip into the cell membrane and interact with receptors internally rather than only from the cell surface. It is a less conventional strategy, and it remains experimental.
Early laboratory results have been encouraging. In experiments, pepducins designed to target GIPR successfully activated the receptor. Some molecules, particularly those directed at a region called the second intracellular loop, or ICL2, appeared more potent than earlier designs, offering clues about how these molecules behave.
How pepducins activate GIPR is not fully understood and answering that question is a major next step. A robust mechanistic understanding could help scientists design more targeted molecules, predict their effects more reliably, and compare internal modulation with more conventional receptor activation.
The Broader Context
The GIPR project is not simply an effort to make another version of an existing diabetes or weight-loss drug. For Bhat, the larger question is how metabolic receptors can be controlled in more precise ways. Because GIPR helps coordinate how the body responds to food, blood sugar, and energy needs, learning how to control it from inside the cell could give researchers a new way to understand and potentially improve metabolic therapies.
Bhat has also considered how emerging therapeutic ideas move from the lab to the clinic. Through her Laidlaw Leadership in Action project at Ace Alzheimer Center in Barcelona, she created patient-facing science communication materials about Alzheimer’s disease treatments and observed clinical research related to GLP-1-based therapies being studied in Alzheimer’s disease. The experience underscored how biological pathways first associated with metabolism can raise questions across very different areas of medicine.
The Possibilities and Collaboration
The long-term potential of the work may extend beyond a single receptor. If researchers can learn how to control GPCRs from within the cell, the strategy could eventually be adapted to other receptors involved in metabolism, cancer, cardiovascular and neurological disease, addiction, and other indications.
“There’s going to be exponential growth in the number of such designed agents. It’s going to be used in a lot of fields. It’s almost as if you can control any receptor,” Kumar says.
Bhat sees the project as part of a broader effort to understand how molecular design can shape future therapies. “You can target any receptor that has any biological effect in your body, from the inside,” she says.
The pair now have several research papers in progress, and Kumar praises Bhat’s scientific drive and work ethic. “Nikita is awesome, and clearly poised for a career in research, having been admitted to nearly every grad program she applied to, as one does when being annoyingly brilliant,” Kumar says.
Bhat is more modest, but deeply grateful. She says her time in the Kumar lab was transformative, reshaping how she thinks about science and accelerating her growth as a researcher.
“The Kumar lab has been one of the most formative and inspiring experiences of my life,” Bhat says. “It is a rare environment that is both deeply nurturing and intellectually challenging, and that combination has shown me how ambitious science can really move forward. The lab pushed me to ask better questions, think more creatively, and approach problems with both rigor and imagination. It has been central to my development as an independent scientist, and I am profoundly thankful for the experience."
"As of now, I hope to continue exploring cool questions at the interface of chemistry, biology, and medicine," Bhat says.
