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Rethinking the Drivers Behind Weight Gain—YMSM Welcomes Guest Lecturer John Speakman

September 27, 2021
by Isabella Backman

The Yale Center for Molecular and Systems Metabolism (YMSM) virtually welcomed John Speakman, PhD, DSc, professor and chair of zoology at the University of Aberdeen, on Tuesday, September 7, as a part of the center’s monthly lecture series. His lecture, “Macronutrient effects on food intake and body weight regulation,” detailed his research seeking to uncover the underlying factors driving the ongoing obesity epidemic, including his surprising findings. His recently published, groundbreaking study on human metabolism and age has been in the headlines, making his seminar to the Yale community especially timely.

The word “pandemic” may draw to mind images of masking and social distancing. However, according to Speakman, the world is also facing an ongoing obesity pandemic. Obesity is a result of prolonged energy imbalance—in other words, overconsumption of food or a lack of physical activity creates an imbalance between incoming and outgoing energy. Because obesity is linked with increased risk of such chronic diseases as diabetes and cancer, Speakman and his team hoped to find the drivers of this growing problem.

“A big question in the field is, ‘Is the major cause on the incoming side of the equation, or the outgoing side?’” said Speakman.

First, the team explored whether a decrease in energy expenditure was the culprit behind obesity. To measure energy expenditure in humans, scientists use a technique called the doubly labeled water method in which subjects drink a glass of water containing uncommon isotopes of hydrogen and oxygen. This allows scientists to track carbon dioxide production and, in turn, energy expenditure. The team conducted a literature review of energy expenditure studies using this technique encompassing roughly 7,000 measurements. The data revealed that energy expenditure has not declined in correlation with increasing rates of obesity.

“It was thought anecdotally that we had become less active, and as a result, had increased susceptibility to weight gain,” says Anton Bennett, PhD, Dorys McConnell Duberg Professor of Pharmacology, professor of comparative medicine, and director of YMSM. “That is not the case. Energy expenditure is not part of the obesity story.”

Next, the team turned its attention to food intake. Over the years, experts have debated whether fat, sugar, or carbohydrates were the problem foods causing obesity. Instead, Speakman’s team revealed a surprising finding—after mice were placed on very low protein diets, they lost almost all of their body fat. “Their body weight just fell off a cliff,” said Speakman.

Furthermore, when mice are placed on restricted diets, they often experience post-restriction hyperphagia, or intense hunger, in which they drastically increase their food intake for several days after being taken off their diet. However, the protein-restricted mice did not show this behavior. This finding opened the door to allowing the team to study how low protein diets target pathways in the brain involving regulating food intake and hunger signals, and how inhibiting these pathways could potentially be a way for helping patients control their food intake.

“If we can inhibit mTOR [a signaling pathway] in the brain with drugs, we can potentially block hunger that results from reduced food intake,” Speakman said. “We can stop them from getting hungry when they’re on a diet, and that may be an adjunct therapy to dieting.”

Speakman’s widely publicized paper in Science showed—contrary to popular belief—that our metabolisms don’t decline as we transition from young to middle adulthood. In fact, between the ages of 20 and 60, our metabolism remains steady as we age. According to Bennett, the finding will likely “re-write textbooks on human metabolism.” The publication of this high-profile study made Speakman’s virtual visit to Yale even more exciting. “This data is generally consistent with the main themes of his seminar at Yale,” says Bennett. “Energy expenditure itself is not a driver of obesity.”

Investigators at the YMSM are also seeking to better understand the brain signaling pathways that Speakman discussed in his seminar. The center currently has 11 members with a range of interests in metabolism from the molecular to the systems level. Their projects include studying the control of hunger in the brain through the hypothalamus, and how fat tissue responds to different macronutrients.

“The investigators at the Molecular and Systems Metabolism Center have varied interests, all of which feed into the broad understanding of how these metabolic pathways—either in the brain or the muscle or the liver—all come together as a more integrated system to control whole body metabolism,” says Bennett. “Dr. Speakman’s work ties that all together by bringing these studies at the human level in these larger population-based types of experiments.”

The dysfunction of metabolism occurs in many diseases. Through bringing together scientists interested in understanding the molecular underpinnings of metabolism from cells to the entire body, the center’s goal is to better understand the basis of human disease.

“We’re looking to provide a nucleus for metabolism research at Yale by reaching out to other centers at the Yale community to grow new collaborations and new scientific opportunities for metabolic research that impacts human disease,” Bennett says.

Submitted by Robert Forman on September 27, 2021