Mechanism linking serotonin to food intake revealed

Cathleen Genova

Genetic mouse models have provided surprising insight into mechanisms linking serotoninergic compounds with the regulation of feeding behavior and body weight. The research, published in the November 26th issue of the journal Neuron, pinpoints a specific group of brain cells that mediate energy balance and may lead to the development of anti obesity drugs with fewer side effects.

The serotonin (5-hydroxytryptamine [5-HT]) system, which includes the 5-HT_2C receptor (5-HT_2CR) subtype, has been shown to play an important role in the regulation of energy homeostasis. Previous work demonstrated that excessive food intake and obesity are linked with 5-HT_2CR deficiency and that the atypical antipsychotic drugs, which appear to block 5-HT_2CRs, are associated with serious weight gain. Further, 5-HT_2CRs are known to contribute to the appetite suppressant effects of d-fenfluramine, a drug widely prescribed to combat obesity in the 1990s that was later banned because of a negative impact on heart valves.

"We have known for some time that drugs activating 5-HT_2CRs potently suppress appetite, but the underlying mechanisms for these effects are not fully understood," says senior study author Dr Joel K. Elmquist from the University of Texas Southwestern Medical Center at Dallas. "We also know that pro-opiomelanocortin (POMC) neurons in the hypothalamus of the brain release neuropeptides that activate the central melanocortin receptors which is required to maintain food intake, body weight and glucose homeostasis. The melanocortin pathway has been hypothesized to be a downstream mediator of the effects of 5-HT_2CRs on feeding behavior."

To investigate whether serotonin action on POMC neurons is sufficient to mediate the inhibitory effects of serotonin compounds on appetite, Dr Elmquist and colleagues generated mice in which 5-HT_2CR was globally disrupted (called 2C null), but 5-HT_2CR expression could be reactivated in any cells that were engineered to express Cre-recombinase. Crossing ₂C null mice with mice that express Cre-recombinase in POMC neurons resulted in mice with 5-HT_2CRs expressed only in POMC neurons (called ₂C/POMC). The researchers observed that ₂C null mice, as expected, exhibited excessive eating, hyperactivity, and obesity and showed reduced responses to serotonin drugs known to suppress appetite. However, unexpectedly, all the metabolic deficiencies observed in the ₂C null mice were completely restored in the ₂C/POMC mice.

These findings suggest that expression of 5-HT_2CRs solely on POMC neurons is sufficient to mediate the effects of serotoninergic compounds on food intake. "Our unique genetic mouse models have revealed that POMC neurons are physiologically important targets of potent anorexigenic serotonin compounds such as d-fenfluramine to suppress appetite. In addition, our results highlight the importance of the central 5-HT_2CRs expressed by POMC neurons in maintaining normal feeding behavior and body weight homeostasis," concludes Dr Elmquist.

Interestingly, another characteristic phenotype of ₂C null mice, epileptic seizures, was not rescued by re-expression of 5-HT_2CRs on POMC neurons. These findings indicate that 5-HT_2CRs regulate neuronal excitability through actions in other central nervous system sites, and the re-activatable ₂C null mouse model would serve as an excellent tool to tackle this issue as well as to reveal other physiological functions of 5-HT_2CRs.

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Xu Y, Jones JE, Kohno D, et al. 5-HT_2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis. Neuron 2008 Nov;60(4):582-589   [Summary]