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Genetic Identification of A Neural Circuit Preventing Obesity and Diabetes

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Dong Kong and Chris Bartolome and their research on leptin signaling and diabetes

Obesity affects more than one third of the US population and has become a worldwide epidemic. It represents a major risk factor for many modern disorders, including cardiovascular disease, diabetes, stroke, and neurodegenerative disease. Leptin, a satiety hormone produced in proportion to accumulated fat tissue, acts exclusively in the brain to suppress appetite and stimulate energy expenditure. Dysfunctions in leptin or leptin signaling result in severe obesity and diabetes in both animals and human. Therefore, leptin is an important regulator of both body weight and blood glucose. Although leptin has been extensively studied since its pivotal discovery in 1994, the neural circuitry underlying its anti-obese and anti-diabetic actions is still unclear. Reported on April 18 in the journal Nature, a group of neuroscientists led by Dr. Dong Kong, assistant professor of neuroscience at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences, have employed cutting-edge genome editing methods and identified the primary neural circuit mediating leptin’s action on both body weight and blood glucose.

Christopher Bartolome, a senior Sackler PhD student in the Neuroscience Program, focused on leptin signaling in insulin-deficient diabetes and performed a systematic, unbiased survey of leptin’s neural targets. By working together with post-doctoral researcher in the Kong Lab, Dr. Jie Xu, co-first author of the Nature paper, Christopher demonstrated that a hypothalamic group of neurons expressing agouti-related peptide (AgRP) are mediating the primary action of leptin on feeding, energy expenditure, and blood glucose. They found that AgRP neurons are overactivated in insulin-deficient diabetic mice and acute inhibition of these neurons remarkably attenuated both diabetic hyperphagia and hyperglycemia. Importantly, when they exploited CRISPR gene-editing technology and specifically deleted leptin receptors (LepR) in AgRP neurons in young adult mice, they observed dramatically increased feeding, body weight, and elevated blood glucose, largely recapitulating the severe obesity and diabetes in LepR-null db/db mice. Furthermore, the authors have also reported a complex molecular mechanism in AgRP neurons that mediates leptin signaling, via enhancing GABAergic neurotransmission and opening of potassium channels. Taken together, these findings solved a long-existing enigma of leptin by identifying AgRP neurons as the primary target of leptin in the brain to regulate both body weight and blood glucose. These studies will also have broad meanings in both basic and translational research and likely provide novel insights in the development of treatment of obesity and diabetes.

 

Xu J*, Bartolome CL*, Low CS, Yi X, Chien CH, Wang P, Kong D. 2018. Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature Epub ahead of print. *equal contribution Abstract