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The NPY/AgRP neurones  
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Synaptic Plasticity in the ARC  
Anti-Obesity Therapies  

 

The Arcuate Nucleus

The arcuate nucleus (ARC) is one of the hypothalamic nuclei, situated next to the third ventricle and median eminence.  It contains many different groups of neurones but for the purposes of this website only the proopiomelanocortin (POMC) and the neuropeptide Y/ Agouti related protein (NPY/AgRP) neurones will be discussed.  These populations of neurones are involved in the control of appetite and they project centrally, to other areas of the hypothalamus and brain. 

The NPY/AgRP Neurones

The NPY/AgRP neurones release the peptides NPY and AgRP and the inhibitory neurotransmitter GABA.  They project to the lateral hypothalamus and upon activation, stimulate feeding, for this reason they are called orexigenic neurones.  During periods of fasting NPY concentration in the ARC is increased and central injection of NPY causes excessive eating which, if repeated, will lead to obesity.  These neurones carry out the appetite regulatory effects of leptin and ghrelin (see Figure 1) however if the NPY gene is knocked out, mice still respond normally to leptin, meaning that leptin has other target sites, the POMC neurones (Flier & Maratos-Flier, 1998).

POMC Neurones and the Melanocortins

The POMC neurones project to many brain areas, not just the hypothalamus, including a population that project to the brain stem.  When activated they inhibit food intake and so are called anorexigenic neurones.  The POMC neurones receive projections from the NPY neurones and are also responsible for the changes in food intake mediated by leptin and ghrelin (see Figure 1).  POMC neurones produce two different peptides, the β endorphins and the melanocortins.  An important peptide in appetite and obesity is the melanocortin alpha melanocyte stimulating hormone (alpha MSH), a powerful inhibitor of appetite, which acts on the melanocortin receptors MC3 and MC4.  For a more detailed description of the anatomy and regulatory mechanisms of the POMC neurones and the melanocortins, please refer to Cone, (2005) under key references.

 

Figure 1: Leptin and ghrelin act on neuronal populations in the arcuate nucleus which then transmit the information regarding current appetite status

Ghrelin and leptin interaction with neurones in the arcuate nucleus

 

The research into the role of POMC neurones in the control of appetite stemmed from the investigation into the lethal yellow mouse, an autosomal dominant obesity model, named because the mutation not only causes obesity but also affects the coat colour of the mouse.  This model results from the uncontrolled expression of the agouti protein which is normally involved in skin pigmentation and is an antagonist of the alpha MSH MC4 receptor.  The conclusion from these investigations was that blockage of the MC4 receptor in the brain, could be a factor in obesity.  This conclusion and the role of the POMC neurones and the melanocortins in appetite control has been supported by various studies; mice lacking the POMC gene, which produces the melanocortins, are obese and the same is true in people having a defect in the POMC gene.  At the end of feeding POMC neurones are activated and release their peptide alpha MSH, a potent inhibitor of appetite. Mice lacking the MC4 receptor do not respond to alpha MSH and so become obese and 5% of obesity cases happen because people only have one functional copy of the MC4 gene, making it the most common single gene mutation causing obesity.  Obesity can also arise through over expression of the MC4 antagonist AgRP (Cone, 2005).

These neuronal populations in the ARC project to the lateral hypothalamus which expresses MC4 receptors, from the lateral hypothalamus, many neuropeptides signal to higher brain areas (see Figure 1).

Synaptic Plasticity in the Arcuate Nucleus

During hunger, changes in excitability have been found to occur at the local level of the neurone.  Anorexigenic POMC neurones receive more inhibitory contacts and less excitatory contacts and the opposite is true for orexigenic NPY neurones.  This plasticity seems to involve leptin where it appears that leptin may act to rearrange neuronal networks in the arcuate nucleus. Using transgenic mice that express green fluorescent protein either in the POMC or NPY arcuate nucleus neurones, Pinto et al (2004) investigated the types of neuronal inputs to the arcuate nucleus in wild type and ob/ob mice. They found that ob/ob mice had more inhibitory projections into the POMC neurones and more excitatory projections to the NPY neurones (see Figure 2). Because of this the NPY neurones stimulated excessive eating and the POMC neurones were inhibited more. However after treatment with leptin, Pinto et al. (2004), found that the projections looked like that of the wildtype control mice, with fewer excitatory projections to the NPY neurones and more excitatory projections to the POMC neurones. This resulted in a decrease in appetite and weight loss.  They concluded that leptin had appeared to induce neuronal plasticity in the arcuate nucleus resulting in the inhibition of appetite. How it does this is as yet unknown. Clearly more research into this phenomenon of leptin induced neuronal plasticity in the arcuate nucleus is needed which will provide further important information into how leptin exerts its affects and so help our understanding of the pathogenesis of obesity.

 

Figure 2: Diagram shows that in mice with defective leptin signalling there are increased inhibitory projections to the POMC neurones and increased excitatory projections to the NPY/AgRP neurones. This can be reversed to the wild type phenotype after administration of leptin (adapted from Pinto et al. 2004).

Diagram showing increased inhibitory projections to POMC neurones and increased excitatory projections to NPY neurones in mice with defective leptin signalling.  This is reversed upon leptin administration

 

Therapeutic Manipulation of the melanocortin system

As described above alpha MSH has a clear role in inhibiting appetite and because of this there has been a lot of research into manipulating the system in order to provide a drug against obesity. This has proved difficult as the melanocortins are involved in many other physiological systems, not just appetite. Alpha MSH has also been found to be a potent stimulator of sexual behaviour in men and women for example where there is currently a drug called PT-141 that can be prescribed for sexual dysfunction in men and women (Hadley & Dorr, 2006). Alpha MSH is involved in heart rate, blood pressure and inflammation. Anti-obesity drugs that target the melanocortin system are obviously of great significance but until we fully understand its role in the various physiological systems this is a pipe dream due to the various side effects these may cause.

An effective anti-obesity drug has therefore proved very difficult to manufacture, with past drugs such as phentermine and fenfluramine being withdrawn from the market due to adverse side effects. However in 2006 the drug Acomplia was licensed which targets the endocannabinoid system and has been found to be very effective in clinical trials as an anti-obesity drug.

The next section will discuss the endocannabinoid system and the anti obesity drug Acomplia.

Key References

Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nature Neuroscience. 8 (5) pp571-578 - excellent and detailed overview of the POMC neurones and the melanocortin system

Morton et al. (2006) Central Nervous System Control of Food Intake. Nature Reviews. 443. pp289-295. - Excellent review giving detail on the molecular pathways activated in the brain and giving details about other brain nuclei involved in food intake

Pinto et al. (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science. 304. pp110-115 - Paper on the plasticity of the arcuate nucleus induced by leptin

 
   
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