The Scientific Sessions symposium Interorgan Cross Talk—Metabolites, Proteins, and Extracellular Vesicles featured a panel of investigators who discussed emerging research that provides insight into the ways organ systems communicate with each other to regulate and maintain energy homeostasis.

The session, which was originally presented Monday, June 28, can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Jonathan Z. Long, PhD, Assistant Professor of Pathology, Stanford University, discussed research into molecular transducers and the anti-obesity effects of physical activity.

“In recent years, there has been growing interest in an endocrine hypothesis for exercise,” Dr. Long said. “This endocrine hypothesis states that exercise induces the production of circulating blood-borne factors, and these exercise-inducible factors then mediate tissue crosstalk to control glucose and lipids and also to regulate energy balance.”

Historically, most studies of exercise-inducible secreted factors have focused on muscles as a source of myokines, he said, but recent research has identified numerous other molecules that are secreted from muscle in exercise.

“But the story gets a little bit more complex than that because muscle is, in fact, not the only tissue to secrete molecules in response to physical activity. Work over the past few years has now demonstrated that many tissues participate in tissue crosstalk and produce circulating blood-borne factors upon physical activity,” Dr. Long said.

These factors include the secretion of adipokines and lipokines from adipose tissue, and the secretion of hepatokines from the liver, all of which regulate metabolic crosstalk and glucose and lipid homeostasis, he explained.

Dr. Long and his colleagues identified the circulating metabolite N-lactoyl-phenylalanine (N-Lac-Phe), a lactate-derived molecule that’s produced in macrophages and epithelial cells and represents a peripheral brain signal that regulates food intake. Their studies have shown that N-Lac-Phe is dramatically accumulated in exercise when lactate levels are high, in comparison to other peripherally produced hormones that regulate food intake.

“Lac-Phe is unusual because its selective production in exercise appears to be unique and is not something observed with any of the other molecules,” Dr. Long said. “What this would suggest is that there might be other lactate-derived molecules that can mediate tissue crosstalk in exercise, and we’re actively exploring that.”

Yu-Hua Tseng, PhD, Professor of Medicine, Harvard Medical School, and Senior Investigator, Joslin Diabetes Center, discussed the physiological role of brown adipose tissue, or brown fat, in energy metabolism.

“In addition to its function in dissipating energy and producing heat—the so-called thermogenic function—brown fat also exerts a number of non-thermogenic functions, including producing different molecules that regulate systemic metabolism,” Dr. Tseng explained.

Exposure to cold has been shown to be an effective way to activate brown adipose tissue and causes dynamic changes in lipid metabolism, she continued.

“Cold exposure can turn on brown fat to increase its ability to take up glucose. It can also increase energy expenditure and reduce fat mass,” Dr. Tseng said. “More importantly, cold exposure can also help to improve insulin sensitivity, even in type 2 diabetic individuals.”

Additionally, she said cold-activated brown adipose tissue has been shown to produce different lipid mediators, including the anti-inflammatory and pro-resolving lipid mediator maresin 2.

“Maresin can either resolve inflammation locally in brown adipose tissue or systemically in the liver, and this can improve obesity-induced glucose intolerance and insulin resistance,” Dr. Tseng said.

Kristin I. Stanford, PhD, Associate Professor of Physiology and Cell Biology, Ohio State University, discussed research looking at exercise-induced hormones in systemic metabolism, including the effects of exercise on brown adipose tissue.

“Part of why we’ve been interested in brown adipose tissue is because of its role in obesity,” she said. “We know that brown adipose tissue is a highly energetic organ that plays an essential role in energy balance and thermogenesis, and the amount of brown adipose tissue is inversely correlated with fat mass, or BMI (body mass index), in humans.”

Dr. Stanford’s lab is studying whether exercise training causes adaptations to brown adipose tissue that contribute to improved metabolism. While the effects of exercise on brown adipose tissue have resulted in conflicting reports, Dr. Stanford said a recent study in humans demonstrated that athletes had a decrease in cold-stimulated brown adipose tissue activity compared to lean non-athlete controls. Further studies have indicated that increasing brown adipose tissue in exercise increases in vivo cardiac hemodynamics.

Anthony W. Ferrante, MD, PhD, the Dorothy and Daniel Silberberg Associate Professor of Medicine, Columbia University, discussed work in his lab looking at the interaction of adipose tissue macrophages (ATMs) in metabolic and immune homeostasis, including the hypothesis that macrophages contribute to normal lipid homeostasis in adipose tissue.

“They have the general functions of all macrophages in tissues, functioning to clear dead cells and debris, playing important roles in angiogenesis, and as sentinels for surveillance of pathogens,” Dr. Ferrante said. “But each tissue macrophage has its own tissue-specific function, and we think, in adipose tissue, that lipid homeostasis is critical.”

Dr. Ferrante and his colleagues have shown that ATMs catabolize lipids that they take up in a lysosomal-dependent fashion, and that autophagy is not required to deliver lipids to the lysosomes.

“This suggested that the lipid was not in lipid droplets,” Dr. Ferrante said. “We’ve shown that adipocytes secrete lipid-laden exosomes at quite high rates, and that this lipid is captured by macrophages, and we think is necessary for healthy fat.”