Banting Medal winner investigating many roles of adiponectin, Philipp E. Scherer, PhD
Adipose tissue is emerging as one of the most potent regulatory tissues in the human body. There’s much more to it than fat and obesity.
“No other tissue has been so maligned for so long,” said Philipp E. Scherer, PhD, this year’s recipient of this the Banting Medal for Scientific Achievement.
Dr. Scherer called the adipocyte a “professional” secretory cell. It produces factors involved in inflammation, energy homeostasis, and extracellular matrix remodeling. Depending on the protein and the target tissues, factors produced in adipocytes can be anti-apoptotic, pro-angiogenic, anti-atherogenic, anti-inflammatory, and pro-adipogenic.
Type 2 diabetes and other metabolic disorders can be the result of pathologic expansion of adipose tissue, but adipose tissue expansion also plays a key role in the metabolic flexibility needed to accommodate changes in nutrition, external temperatures, physical activity, and other outside changes, he explained.
Too many adipocytes can lead to impaired angiogenesis, local hypoxia, fibrosis, increased unfolded protein response, and inflammation, he added. Adipocytes also unleash multiple anti-inflammatory compounds, as well as factors that can drive significant improvements in insulin sensitivity and improve wound healing. And depending on the levels of one of those factors, adiponectin, an obese individual can be metabolically healthy.
Individuals with high adiponectin levels are metabolically healthy while individuals with low adiponectin levels are metabolically unhealthy. High levels of adiponectin are associated with smaller adipocytes, improved hepatic insulin sensitivity, improved beta cell function, reduced chronic inflammation, and reduced fibrosis, Dr. Scherer said.
Increasing plasma adiponectin levels in individuals with type 2 diabetes can dramatically improve systemic insulin sensitivity. Higher levels of adiponectin are associated with decreased apoptosis in heart tissue and beta cells, increased beta cell mass, functional recovery in kidney disease, and other physiologic improvements.
Adiponectin also plays a key role in the beiging of white fat in response to cold temperatures or other triggers. The hormone is also important to the production of VEGF, a range of BMPs, metorin-like, irisin, and ErbB3. Adiponectin is also a key mediator for the maintenance of metabolic flexibility, which is the ability to switch fuel sources during fasting and feeding.
One of the most important of these metabolic intermediaries is uridine, which is important in thermoregulation, cell growth and proliferation, reproduction, insulin signaling, glycemia control, ischemia protection, and immune responses to cancer and infectious disease. In the fed state, uridine levels are high in the liver and suppressed in adipocytes. In the fasting state, uridine levels are high in adipose tissue and low in the liver. This entire process is regulated by Xbp1s, a critical factor in the feeding/fasting response in the liver, neurons, heart, and adipocytes.
Uridine biosynthesis in the liver is balanced against gluconeogenesis, Dr. Scherer explained. When uridine biosynthesis is high, while fed, gluconeogenesis is low. When uridine biosynthesis is low, while fasting, gluconeogenesis is high. Increasing uridine biosynthesis could divert calories into a biosynthetic pathway, allowing weight loss without a corresponding increase in heat production.
“We have only scratched the surface of adiponectin,” Dr. Scherer said. “We have to think beyond the metabolic function. Adiponectin plays an important role in many infectious diseases, cancers in obesity, and other diseases.”
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