Dr Jon Long, an SDRC member and assistant professor of pathology at the Stanford School of Medicine is deeply interested in energy metabolism. He joined Stanford in January 2018 after completing his postdoctoral training at the Dana Farber Cancer Institute, Harvard Medical School. His lab focuses on mechanisms that control mammalian energy homeostasis with an emphasis on discovering new small molecules and pathways that regulate metabolism and physiology.
Dr Long recently presented research from his laboratory at the weekly SDRC member meeting uncovering a new metabolite implicated in energy homeostasis. His work identified a natural molecular pathway that drives cells to burn calories instead of storing them as fat, essentially inducing weight loss. It could have potential implications in treating obesity and other metabolic disorders.
Dr Long has ongoing collaborations and interactions with other SDRC members including Dr Joshua Knowles and Dr Carolyn Bertozzi. Here, he talks about how he became interested in energy metabolism, his work and his philosophy towards understanding and treating metabolic disorders.
You study pathways controlling mammalian energy homeostasis. What initially drove you to focus on this topic?
Every day, we each encounter a wide array of different energy states, depending on our last meal, our current activity levels, or the environmental temperature, just to name a few variables. How do we sense changes in our energy states, and what are the mechanisms that we use to respond and maintain energy balance? I’ve been attracted to this problem because energy metabolism is a universal process that we have all experienced.
How do you think about the problem of obesity and its related diseases like diabetes in the context of energy homeostasis?
The first law of thermodynamics says that energy cannot be made or destroyed, only converted. This law also applies to organismal energy metabolism. This means that counteracting obesity and its associated metabolic disorders like diabetes requires either a reduction of energy input or an increase in energy expenditure. So far, there is nothing available to increase energy expenditure in people. That seemed to me like an interesting arm that one could manipulate at a molecular level in specific ways to augment energy output and reduce obesity and metabolic disease.
Your group identified a new class of metabolites, N-acyl amino acids, which essentially promote energy expenditure and weight loss in mice. What led to this discovery?
The main discovery that I made during my postdoc and what my research at Stanford is based on is a family of circulating “anti-obesity” molecules in the body called N-acyl amino acids. We found that they directly stimulate mitochondria to increase mitochondrial respiration and increase energy expenditure. Our path to discovering these molecules started because we were studying an enzyme called PM20D1. Mice overexpressing PM20D1 exhibited a hypermetabolism through an unknown mechanism. We found that PM20D1 does this by catalyzing the formation of N-acyl amino acids from lipids and amino acids, and worked out from there the mechanism by which N-acyl amino acids stimulate respiration.
Obesity and diabetes are such complex diseases. Do you think that targeting metabolic homeostasis alone would be enough as a therapeutic strategy to solve the underlying problems in these diseases?
The increase in obesity and metabolic disorders is a very complex process with many underlying causes that range from socio-economic, environmental and genetic. Potential pharmacological intervention is just one of several strategies by which these diseases need to be addressed. I see our work as one small part of societal efforts to combat this constellation of disorders.
Does this mean we can finally eat whatever we want and still lose weight? How do you address all the science myths and fads around weight loss as a scientist?
Unfortunately for most of us, I don’t think there will ever be a day when we can eat whatever we want. I see it as my responsibility, through interviews like these, to explain as accurately as I can and from a scientific view, the pathways regulating energy metabolism and weight loss. As for the other myths and fads, all I can say is that I don’t pay attention but instead try to follow the standard medical advice- I try to eat a well-balanced diet and get some exercise.
How do you envision your research contributing towards therapy to combat diabetes and obesity?
One of the long-term goals of my research is to identify and understand new molecules and pathways that control energy expenditure. It would be my dream that we might be able to therapeutically exploit these energy expenditure pathways to develop new drugs that could reduce obesity in people. A better understanding about how N-acyl amino acids work might enable such a discovery.
How has the SDRC contributed to your research as a junior investigator?
The SDRC is a fantastic group of incredibly diverse scientists. Investigators come from endocrinology, or stem cells, or genetics, or engineering, or immunology, or developmental biology, just to name a few fields. This diversity of approaches has really served as a wonderful springboard for thinking about new ideas.
To learn more about Dr Long’s research, please visit https://longlabstanford.org/
Harini Chakravarthy is a science writer for the Stanford Diabetes Research Center.