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Leptin – A complex adiposity signal that kick started the surge of obesity research

Probably the biggest breakthrough for the study of appetite regulation came in 1994 when the molecular geneticist Jeffrey Friedman discovered the adiposity signal leptin.  Using the ob/ob mice which were thought to lack a satiety signal, Friedman and colleagues found 'ob' to code for a gene which they called leptin, after the Greek word ‘leptos’ meaning thin (Zhang et al, 1994). Mice deficient in this gene are morbidly obese and this obesity can be reversed by giving the mice leptin.   The leptin receptor was subsequently found in 1995 and is a member of the cytokine receptor family (Tartaglia et al, 1995).

Leptin is a signalling molecule released from adipocyte cells to signal regarding adiposity levels. It is secreted into the blood, secretion proportional to body fat, where it travels to the brain causing a decrease in appetite (see Figure 1) through acting on specific neurones in the brain.

Figure 1: Showing secretion of leptin proportional to adipocyte lipid volume

figure 1 showing leptin proportional to lipid content of adipocyte

 

Pharmacological use of leptin

Unsurprisingly there was huge media interest in leptin as it was thought of as the miracle cure for obesity and the biotechnology company Amgen paid $20 million to license leptin.  However the results of the clinical trials on obese people were disappointing with very few of the participants losing weight.  It appeared that the majority of people were not obese due to a deficiency in leptin but were just unable to respond to it; they had more fat cells and so more circulating leptin and as a result reduced sensitivity of the leptin receptor.  The failure of the trial, however, overshadowed the fact that around 30% of the people did actually lose weight and so may actually have low circulating levels of leptin.  Potentially these people would then indeed benefit from leptin therapy.  The task now though is to determine those people that have a lower circulating level of leptin, a mammoth task.

The use of leptin as a drug has proved invaluable in the disease lipodystrophy and in people who have a defective leptin gene and so are constantly hungry.  Administration of leptin has provided a cure for these diseases.

Where does leptin act?

Leptin inhibits food intake by acting in the appetite control centres of the brain as administering leptin into the brain causes a significant reduction in food intake which does not occur after peripheral injection. Leptin receptor mRNA is found primarily in the hypothalamic arcuate nucleus, ventromedial nuclei and dorsomedial hypothalamic nuclei, regions that are known to be involved in appetite control (Schwartz et al, 1999). 

Figure 2: Showing leptin receptor mRNA in the ventromedial hypothalamic nuclei (VMN), arcuate nucleus (ARC) and in the dorsomedial hypothalamic nuclei (DMN) (adapted from Schwartz et al, 1996)

Autoradiogram of leptin receptor mRNA hybridisation in the hypothalamus

How does leptin work?

The weight loss caused by leptin seems to arise because of 2 effects;

1. Inhibiting appetite through its actions on the appetite-stimulating neuropeptide Y (NPY) neurones and the appetite-inhibiting proopiomelanocortin (POMC) neurones, located in the hypothalamic arcuate nucleus (see Figure 3) (Cheung et al 1997, Schwatz et al, 1999). Leptin inhibits the NPY/AgRP neurones by acting on its receptors and causing a decrease in the release of the inhibitory neurotransmitter GABA.  This causes the POMC neurones to become free of inhibition and so they can increase their firing rate leading to the production of alpha MSH – an inhibitor of appetite.  Leptin also acts directly on the POMC neurones (Cowley et al, 2001) (The role of the arcuate nucleus and the NPY and POMC neurones will be explained later in the website but for access now please click here).

Figure 3: Leptin activation of neurones in the arcuate nucleus

Leptin inhibiting appetite through inhibiting NPY neurones causing activation of POMC neurones

 

2. Leptin also increases energy expenditure by increasing body temperature and oxygen consumption (see Figure 4)

Figure 4: Showing the effects of leptin on body temperature and oxygen consumption (adapted from Pellymounter et al, 1995)

Graphs showing that leptin increases body temperature and oxygen consumption

As yet it is still unknown as to how exactly leptin exerts its inhibitory effects on feeding behaviour, clearly if this were known then the potential to harness its effects for the treatment of eating disorders would be an enticing prospect.  It has been found to act on the JAK STAT pathway, effecting gene transcription and other cellular signalling pathways but a definitive mode of action has not been found (for more information of these pathways please refer to Schwartz et al (2000)).  Leptin's mode of action is probably very complex with it affecting many different signalling pathways.  Understanding these pathways and the genes that leptin targets will undoubtedly help scientists to understand how this molecule works and ultimately how we can manipulate particular steps in the leptin pathway to be of therapeutic potential in the treatment of obesity and its related disorders.

Leptin is synthesised in many other tissues including the stomach, ovary, placenta and liver and its receptors are also located in a diverse range of tissues (Margetic et al, 2002).  It has been found to play a role in many other physiological functions such as reproduction, where levels of leptin appear to dictate the commencement of menstruation and in foetal development where there is a surge in leptin levels in the first week of life, which does not correspond to a decrease in food intake but is thought to be a developmental signal.  During development, mice deficient in leptin have disruptions in the arcuate nucleus neural projections, but not other hypothalamic projections.  These effects can be reversed upon leptin treatment (Bouret et al, 2004).  Its role in development may factor in the onset of leptin dependent childhood obesity which imply that leptin’s role extends way beyond that of being just an adiposity signal.

Leptin’s primary function is still under consideration as it clearly plays a role in many other physiological processes. Leptin appears to have evolved very efficiently, having many roles.  For example it can be thought of as a signal informing the body when it has sufficient fat to accommodate an ‘expensive’ physiological function like reproduction.  Leptin therefore appears to protect the body against starvation by only allowing energy dense processes to occur when the body is sufficiently ready.  Its primary role is complex, is it a satiety signal to prevent overeating or an evolutionarily efficient signal protecting against starvation?

Leptin is a signal which acts centrally, telling the brain to stop eating, there is another peripheral signal originating in the stomach which instructs the brain to promote eating.

This signal is called ghrelin.

Key References

Zhang et al (1994) Positional Cloning of the mouse obese gene and its human homologue. Nature 372 pp425-432 - these authors first identified leptin

Schwartz et al (2000) Central Nervous System Control of Food Intake. Nature 404 pp661-671 - Excellent paper detailing the effects of leptin on molecular pathways in the brain.

 
 
   
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