Brain Star Award winner Lisa Fang

Lisa Fang

Dr. Lisa Fang, Memorial University of Newfoundland

Lisa Z Fang, Victoria Linehan, Maria Licursi, Christian O Alberto, Jacob L Power, Matthew P Parsons, & Michiru Hirasawa. (2023). Prostaglandin E2 activates melanin-concentrating hormone neurons to drive obesity. Proceedings of the National Academy of Science of the United States of America. 120, e2302809120 (2023). doi:

Study first to establish a direct link between an inflammatory molecule and activity in appetite-promoting neurons linked to obesity

High-fat diets (HFD) have contributed to the epidemic rise of obesity in many modern societies. This is thought to be due, at least in part, to HFD-induced inflammation in the hypothalamus, a brain region critical in energy balance. New research by Lisa Fang and colleagues and Memorial University provides insight on the mechanism through which inflammation, usually associated with sickness, can cause excess weight gain. They show that an inflammatory molecule called prostaglandin E2 is induced in the hypothalamus by HFD and directly activates a group of appetite-promoting neurons. Blocking this activation protects mice from obesity and fatty liver. This identifies a direct link between hypothalamic inflammation and weight gain, which may serve as a possible therapeutic target for obesity and metabolic syndrome.

Decades of research has established the critical role of hypothalamic inflammation in sickness, and specifically with fever, anorexia and weight loss. Surprisingly, hypothalamic inflammation is also induced by high-fat diet (HFD) and plays a causal role in diet-induced obesity. Prior to this study, there were no satisfactory explanation for how hypothalamic inflammation could produce opposite energy balance outcomes during sickness syndrome and obesity. Furthermore, despite neurons being the ultimate effectors of the central control of energy balance, the neuronal mechanism linking hypothalamic inflammation to obesity remained elusive. Lisa Fang and colleagues have identified a mechanism that directly bridges these gaps.

The study demonstrates that prostaglandin E2, a well-known inflammatory mediator of sickness syndrome, also mediates positive energy balance under HFD conditions by directly activating appetite-promoting melanin-concentrating hormone (MCH) neurons. Interestingly, MCH neurons can bidirectionally respond to varying levels of PGE2, with low levels (such as those seen during obesity) activating, while high levels (such as those seen during sickness syndrome) inhibit MCH neurons. This explains the contradictory observation of hypothalamic inflammation resulting in sickness syndrome as well as obesity.

The researchers further went on to identify a prostaglandin E2 receptor called EP2R as the mediator of MCH neuron activation during HFD conditions. Importantly, genetic removal of these receptors in MCH neurons in both male and female mice prevented diet-induced obesity. Therefore, they established that HFD induces activation of MCH neurons, which is mediated by PGE2 EP2R to promote excess weight gain in the development and maintenance of obesity.

This study is the first to establish a direct link between an inflammatory molecule and the activity of an appetite-promoting neuron.

This is critical for the advancement of the field of obesity and may aid in the development of novel therapeutics for those with obesity in the future.

About Lisa Fang

Dr. Lisa Fang performed this work during her PhD training under the supervision of Dr. Michiru Hirasawa at Memorial University. Lisa was the primary driver in the experiments described in this study, providing the functional evidence for the role of EP2R signalling on MCH neurons in obesity, which was imperative to the paper. Lisa also performed data analysis, and together with Dr. Hirasawa, wrote the manuscript with input from co-authors. Dr. Fang received her PhD in 2023 and is now a postdoctoral research associate at Washington University in St Louis.

Sources of funding

This study was funded by a Canadian Institutes of Health Research project grant to M.H. L.Z.F. was a recipient of the CIHR Doctoral Research Award and the Heart and Stroke Foundation Graduate Scholarship. V.L. was a recipient of a CIHR/RDC Doctoral Research Award.