Ongoing research into the mechanisms of inter-organ crosstalk, including the key signaling pathways involved in obesity and diabetes, may provide targets for new therapies to treat, and potentially even prevent, these and other metabolic disorders, according to Jiandie Lin, PhD, Professor in the Department of Cell and Developmental Biology and the Life Sciences Institute at the University of Michigan.
For his contributions to the understanding of inter-organ crosstalk of emerging endocrine hormones, and for his pioneering work in chromatin control of metabolic gene programs, Dr. Lin is the recipient of the 2020 ADA Outstanding Scientific Achievement Award.
Dr. Lin discussed the role of metabolic signaling in the pathophysiology of metabolic disease during his Outstanding Scientific Achievement Award Lecture, Emerging Endocrine and Paracrine Hormones in Health and Metabolic Disease, which he presented Monday morning during the Scientific Sessions. His lecture can be viewed by registered meeting attendees at ADA2020.org through early September.
“Inter-organ crosstalk refers to hormonal signaling from one organ or tissue to another, and it’s a way our body sends its nutrient and energy status to communicate and respond to physiological needs to maintain homeostasis,” Dr. Lin said.
Metabolic homeostasis in the body, he said, is regulated by three major compartments—peripheral metabolic tissues, which process nutrients in the body and generate energy in response to physiological demands; the central nervous system, which works as a command center to regulate feeding and systemic energy balance; and the gut microbiome, which Dr. Lin said has emerged as an important contributor to systemic metabolic homeostasis.
“These three compartments communicate with each other through a large number of metabolic, hormonal, and neural signals,” Dr. Lin explained. “For example, nutrients that metabolize could have powerful effects on cellular signaling and metabolism, as in endocrine hormones sending the metabolic status of the body and relaying signals to both peripheral tissues and the central nervous system. Then, neural signals, such as epinephrine and norepinephrine, released by the sympathetic nerves could induce adipose tissue lipolysis and stimulate thermogenesis.”
Dr. Lin’s recent research has focused on energy metabolism in peripheral tissues—particularly skeletal, liver, and adipose tissue—and questions related to chromatin signaling and metabolic gene programs, inter-tissue crosstalk via endocrine hormones, and metabolic tissue microenvironment.
“A common feature of metabolic regulation in these tissues is that myofibers, hepatocytes, and adipocytes are highly responsive to physiological signals and have a great deal of plasticity,” he said. “We’ve been exploring how chromatin signaling regulates metabolic gene programs in response to physiological stimuli, including a major focus on the discovery of new signaling molecules that mediate inter-tissue metabolic crosstalk.”
Two endocrine hormones that appear to be novel messengers between adipose tissue and the liver, for example, are a fat-derived hormone, Neuregulin 4 (NRG4), and a liver-derived hormone, Tsukushi (TSK), Dr. Lin said.
“In studying these two hormones, we see that NRG4 is released by adipose tissue and acts on the liver to regulate hepatic metabolism and preserve hepatocyte health under stress conditions, while TSK is responsive to activation of energy expenditure and functions as a negative feedback signal to restore energy balance,” he said. “These studies support the idea that endocrine function of peripheral metabolic tissues may be more pervasive than we currently appreciate. I’m sure more endocrine hormones will be discovered in the years to come.”
Dr. Lin said that a greater understanding of the signaling pathways that control inter-organ crosstalk and the continued discovery of new hormones, many of which are potential drug targets, may provide new biomarkers for metabolic disease and novel therapeutic targets.
“We are at the early stage of precisely mapping the molecular and cellular nature of tissue microenvironments and understanding their contribution to physiology and disease—we hope to see continued expansion of research in this area,” he said.