The MVP: The ModernVivo Podcast

Season 1, Episode 3 Show Notes: Mukesh Kumar, PhD

An interview with Mukesh Kumar, PhD to discuss his findings on how neurons tap into fat reserves to keep synapses running when glucose runs low.

In this episode of The MVP, I sat down with Dr. Mukesh Kumar, a postdoctoral researcher at Weill Cornell Medicine, to discuss his research on triglyceride metabolism in neurons, published in Nature Metabolism in July of 2025. In this blog post you can read more about his findings and career journey. A PDF of his publication is available here to read and download. You can connect with Dr. Kumar on LinkedIn if you'd like to discuss his work further.

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Challenging the idea that neurons run on glucose alone.

For a long time, the prevailing view has been that neurons rely almost entirely on glucose to meet their energy needs. Dr. Kumar doesn't dispute that glucose is the dominant carbon source — but he and his team asked a question that had gone unanswered: what happens when glucose levels fluctuate? Neurons are extraordinarily energy-hungry, and if their demand isn't met, they die quickly. So is there a backup fuel?

Looking at transcriptomics data, the team found that neurons already carry all the enzymes needed for triglyceride metabolism and fatty acid oxidation. They also knew that disrupting a particular triglyceride lipase causes lipids to pile up inside neurons. That raised the central question of the paper: if these stored lipids aren't doing anything, why do they accumulate — and what happens to synaptic energy when you block the enzyme that mobilizes them?

Localizing the enzyme to the synapse.

The enzyme at the heart of this work is DDHD2, a neuron-specific triglyceride lipase that is mutated in a hereditary neurological disorder called hereditary spastic paraplegia (subtype 54, or HSP54). Patients and mouse models with non-functional DDHD2 show large accumulations of lipid in their neurons, but it wasn't known whether this disrupted the energy supply at synapses.

Dr. Kumar and his team showed clearly that DDHD2 is enriched at synaptic terminals — visible even in single, isolated neurons down to individual synaptic boutons. When they blocked the enzyme with an inhibitor (KLH45), lipid droplets accumulated at roughly 65–70% of synaptic terminals. As Dr. Kumar put it, this told them that the lipase isn't just present at the synapse — its function is localized there too. One of his takeaways from the work: metabolism isn't only biochemistry; it has to be understood in terms of where enzymes sit and act inside the cell.

Importantly, healthy neurons don't normally show these droplets. There's a constant, hidden flux of lipid being stored and mobilized — droplets only become visible when you block the breakdown step or flood the neurons with fatty acid. The work focused mainly on hippocampal neurons, with some experiments in cortical neurons; the underlying machinery looks similar in both, though whether it extends to other neuron types remains to be investigated.

From cells to a whole-animal result.

Some of the most dramatic findings came from the mouse work. When Dr. Kumar's collaborators injected mice with the DDHD2 inhibitor — or with a blocker of CPT1, the transporter that imports fatty acids into mitochondria — the animals shifted into a torpor-like, energy-conserving state within about one and a half to two hours, marked by a drop in core body temperature. Dr. Kumar was candid that the pharmacological approach isn't a perfectly clean experiment, and that a genetic knockout model (which the team didn't have access to) would strengthen the case. But because the lipase is so highly active in neurons, the result strongly suggests that this lipid pathway isn't a "nice to have" — it's a fundamental dependency for brain function and for an animal's broader physiological homeostasis.

Advice to those following in his footsteps.

I have kept the question always ahead of the technique. I learned techniques depending on what question I was going to ask… one should not be afraid of transitioning intellectually, and most of the good research happens at the interface of two different subjects.

In our discussion, Dr. Kumar reflected on a scientific path that has been anything but linear. He moved from biophysics and molecular motors in liver cells to lipid droplets in neurons — a transition he described as drastic on the surface, but grounded in the same underlying principles of how organelles and chemistry are reorganized inside a cell. That willingness to cross fields, he believes, is where the most interesting science tends to live, because those transition zones stay under-explored.

He also offered practical advice for scientists trying to pull on a thread of their own. When he joined a neurobiology lab as a biophysicist, he spent close to half a year simply learning the system and the basic techniques before jumping into experiments. His guidance: build a good harmony between three things — knowing your model system, knowing the techniques you'll primarily rely on, and knowing the question you're going to ask.

Dr. Kumar is currently supported by a Michael J. Fox Foundation fellowship focused on Parkinson's-related research. Over the next two years, he plans to investigate how lipid droplets interact — physically and functionally — with other organelles to maintain synaptic bioenergetics, and how that breaks down in neurodegeneration. He's especially interested in what happens when proteopathic aggregates like alpha-synuclein bind membranes and disrupt the exchange of metabolites between organelles.

He's keen to connect with researchers who work on relevant animal model systems, as well as those studying intracellular and intercellular communication — areas he'd like to strengthen and learn more about. Lipid metabolism in neurons is, in his words, a field that's been almost unexplored but is increasingly relevant to aging, cognitive decline, and neurodegeneration, and he hopes to help move it forward. Reach out to him on LinkedIn to connect.

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