Leptin’s neural circuit identified
BOSTON (April 18, 2018)—Revealing surprising answers to a long-standing enigma about the brain target of the anti-obesity hormone leptin, neuroscientists at Tufts University School of Medicine have used CRISPR genome editing to identify a neural circuit in the hypothalamus as the primary mechanism in mediating leptin’s anti-obesity and anti-diabetes effects and have identified two distinct mechanisms underlying leptin’s inhibition of appetite. The research, which appears online in the journal Nature on April 18, advances efforts to find more effective therapies for obesity, type 1 and type 2 diabetes, and their complications.
Although its award-winning discovery transformed the study of obesity more than 20 years ago, leptin's mechanisms have remained a mystery. Secreted by white fat cells, leptin acts in the brains of humans and many other animals as a satiety signal to reduce appetite and maintain stable weight and blood sugar levels. Dysregulation of leptin or its receptors results in ravenous appetite and extreme overeating (hyperphagia), obesity, and type 2 diabetes (which accounts for approximately 91% of diabetes diagnosed in adults in the U.S., affecting about 21 million people). Leptin supplements are generally ineffective for these disorders because, for unknown reasons, most obese individuals are leptin-resistant, and leptin’s clinical applications remain limited despite extensive study.
“While it’s known that leptin receptors express in many neuronal types, extensive research has largely failed to uncover either a specific group of neurons that mediates leptin’s primary effects or the molecular mechanisms involved. Whether such a specific group of neurons even exists is also controversial. Without identifying the real target that leptin works on, it is difficult to study its pathway or even effectively test any hypotheses,” said Dong Kong, Ph.D., assistant professor of neuroscience at Tufts School of Medicine and senior author on the Nature paper. “Our mechanistic study provides important insight into the biggest issues – how leptin works and how leptin resistance develops – and making leptin a more clinically usable molecule to fight both obesity and diabetes. We also hope our research strategy and genetic tools will inspire researchers in other neurobiological and metabolic areas.”