The satiety mechanism described and restored in mice

Leptin is a hormone secreted by adipose cells, sending the satiety signal to the brain. Sometimes, certain overweight or obese individuals develop resistance to this hormone, which is no longer able to deliver its message. A team led by Vincent Prévot, Inserm Research Director at the Jean Pierre Aubert Research Centre in Lille, has used obese mice to show how the pathway transporting leptin to the brain can be reactivated.

Obesity acquired by a diet containing too much fat is associated with high and abnormal levels of circulating leptin. These circulating concentrations reflect the inability of leptin to reach the brain. So it remains ‘trapped’ in the bloodstream. In this study, published in Cell Metabolism, the researchers succeeded in finding the front door for this hormone to enter the brain and restored opening of this ‘cellular door’ in obese mice.


Leptin transport via the tanycytes © Inserm / Vincent Prévot

The research team was first able to describe the mechanism by which leptin passes through this cellular door: tanycytes (see diagram opposite: cells shown in yellow). These cells capture circulating leptin from blood vessels that, at this site, are specially-adapted to allow its passage (step 1). As it passes though the tanycyte, captured leptin activates an ‘ERK’ signalling pathway (step 2) that triggers its release into the cerebrospinal fluid (step 3). Leptin then activates brain regions that convey its anorexigenic action (step 4).

In cases of obesity. the researchers observed that the tanycyte is able to capture the hormone but can no longer release it into the brain. It develops what they call ‘leptin-resistance’ associated with the change in the activity of its receptor, ‘LepR’. The researchers then tested mice with a pharmacological treatment enabling leptin to reach the CSF.

Our study shows that transport of leptin through the tanycyte can be restored in obese mice using a pharmacological treatment by activating the ERK signalling pathway in this cell“, explains Vincent Prévot, Inserm Research Director.

This treatment allows leptin to activate neurones and finally restore the sensitivity of mice to this hormone by gradually restoring a balanced diet. 

 “Altered leptin transport by tanycytes could therefore constitute the first physiopathological event leading to central hormone resistance in overweight or obese individuals” he concludes.

Escaping the adverse effects of morphine

Despite its beneficial effects against pain, morphine use is accompanied by adverse effects such as constipation, nausea, vomiting, respiratory depression, and potential dependence on the drug.  A research team led by Alain Eschalier, Director of Inserm Unit 1107, Neuro-Dol, in Clermont Ferrand, has just shown that it is possible to separate these two types of effects, and retain the desired analgesic effect without the adverse effects. These results are published in the 17 December 2013 issue of Nature Communications.


3D visualization of morphine’s receptor when it is associated with its antagonist  © Kobilka Lab

The beneficial and adverse effects of morphine and other opiate drugs depend on the same receptor, the mu receptor. To separate them, the researchers worked on proteins located downstream of the receptor. They chose TREK-1, a channel that inhibits neuronal activity and is known from previous work to be involved in pain.

In the present study, the research team showed, using mice, that this channel is involved in the analgesic effect of morphine without any role in its adverse effects. Indeed, when the gene is deleted in mice, the analgesic effect of morphine tested in clinical pain models (post-operational type pain, for example) is reduced.

“The TREK-1 channels are essential for the analgesic effect of morphine, but are not involved in its adverse effects, since neither constipation, respiratory depression, nor physical dependence is changed in animals in which they have been deleted.

Direct activation of these channels may thus lead to a morphine-type analgesia without inducing the side-effects associated with this type of drug,” concludes Alain Eschalier, last author of the study.

The team is currently working on the synthesis of new TREK-1-activating drugs with members of the Analgesia Institute (a public-private partnership).

A disrupted biological clock: a risk factor for anxiety disorders

In mammals, light is essential in order for the body to function properly. This response to light is controlled in our bodies by a biological clock. Like well-oiled clockwork, the central clock located in a small structure of the brain known as the hypothalamus in turn synchronises numerous secondary clocks present in other areas of the brain, and in some peripheral organs. These clocks control the expression of many genes that allow the body to adapt to the environment on a daily basis.

A disruption in the molecular components of the biological clock is often associated with psychiatric disorders, but the question of causality has remained unanswered until now.

To tackle this question, a team of Inserm researchers led by Emmanuel Valjent (ATIP/Avenir Team, Inserm Unit 661, Institute for Functional Genomics, Montpellier), evaluated a range of behaviours associated with psychiatric illnesses, using mice in which two essential genes for the circadian clock (cryptochrome 1 and cryptochrome 2) had been inactivated.

Their work demonstrated causal relationships between the disruption of genes encoding the cryptochrome 1 and 2 proteins (Cry1 and 2) and anxiety-related behaviours.

Indeed, mice deficient in Cry1 and 2 proteins, in which the clock is disrupted, showed characteristic behavioural changes that included an abnormally high level of anxiety.

This is reflected in rodents by an increased aversion to open spaces. Interestingly, mice deficient in either of the Cry1 or Cry2 proteins, in which the biological clock is only slightly altered, showed the same behavioural changes.

These results clearly indicate that, apart from their critical roles in the regulation of the molecular clock, these proteins are directly involved in controlling the emotional state. This study, published in the journal Frontiers in Behavioural Neuroscience, enables a better understanding of the complex relationship between the biological clock and behaviours associated with psychiatric illnesses such as anxiety.

Collaboration ou concurrence : que se passe-t-il dans notre cerveau ?

Prevention of risk of sudden death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is one of the most frequent causes of sudden non-accidental death in young adults. The origin of SUDEP remains unknown, since it generally occurs at night, unwitnessed. SUDEP sometimes occurs in hospital, while the vital functions are being monitored and recorded. These are the data that Prof. Philippe Ryvlin, who leads the Inserm team TIGER (Translational and Integrative Group in Epilepsy Research), at the Lyon Neuroscience Research Center, has analysed in order to better understand this problem.

The international study MORTEMUS, the results of which are published in the 4 September issue of The Lancet Neurology journal, has enabled the identification and evaluation of those rare cases of cardiorespiratory arrest that have occurred in hospital units specialising in epilepsy. In total, 16 SUDEP cases were analysed, with the help of data collected from 147 units located in Europe, Israel, Australia and New Zealand, between January 2008 and December 2009. The majority of SUDEP cases studied happened at night (14 out of 16).

Results show that patients who died from SUDEP showed the same series of events leading to cardiovascular arrest. Breathing became more rapid (18-50 breaths per minute), following a severe seizure, and this accelerated breathing was followed within 3 minutes by sudden transient or terminal cardiorespiratory collapse. Where the dysfunction was transitory, the researchers observed that it recurred after several minutes, leading to terminal apnoea and subsequent cardiac arrest.

This study also highlights the suboptimal monitoring of patients admitted to specialist epilepsy units, and indicates the need for improved safety measures in these units.

“Our data help to lift the veil on the cause of these deaths, and contribute elements to help prevent these sudden deaths, for example by improving the monitoring of patients in specialist hospital units, especially at night-time,” 

explains Prof. Philippe Ryvlin, leader of the Inserm team.

Multiple sclerosis: a composite treatment to repair damaged nerve fibres

A team of researchers led by Brahim Nait Oumesmar, Inserm Research Director at the PITIE-SALPETRIERE NEUROSCIENCES RESEARCH CENTER (CRICM) in collaboration with the University of Luxembourg, has just discovered a new molecule capable of stimulating the repair of the myelin destroyed in experimental models of multiple sclerosis. This advance will be published in The Journal of Neuroscience.

Multiple Sclerosis (MS) is the most frequent cause of disability in young adults [1]. The condition is characterised by inflammatory lesions in the brain, spinal cord and optic nerve. It is considered to be an auto-immune disease. In MS sufferers, the defence system becomes disordered. Instead of fighting external pathogens, the immune system attacks its own cells.

MS destroys the myelin sheaths surrounding the neurons that carry information. Chronic lesions appear characterised by a loss of the nerve fibres. Although the causes of MS are still unknown, current treatments are mainly directed at modulating the immune response and have very little impact on the repair of the myelin sheaths (or remyelinisation). Finding treatments designed to stimulate remyelinisation is thus a major new research direction for MS. Remyelinisation might make it possible to re-establish nerve conduction and prevent the condition of MS sufferers from deteriorating further.

The research team headed by Brahim Nait Oumesmar, Inserm research director at the PITIE-SALPETRIERE NEUROSCIENCES RESEARCH CENTER (CRICM) in collaboration with the University of Luxembourg, has identified a new synthesising molecule capable of stimulating the repair of myelin lesions in experimental models of MS.

This synthesis molecule, known as TFA-12, is part of a derivative of vitamin E.

Their work has shown that TFA-12 both reduces the formation of inflammatory lesions but, above all, favours the repair of myelin lesions.

Research has also shown that this molecule stimulates the regeneration of the oligodendrocytes, the cells that are the origin of myelin synthesis in the central nervous system.  This work will thus enable the development of new pharmacological strategies, promoting the remyelinisation of the neurons in cases of MS.

Schéma fonctionnement sclérose en plaques

[1] The average age at which the symptoms first appear is thirty, and the condition affects more women than men. There are 80,000 MS sufferers in France.

Migraine to the Tip of the Genes

An international consortium has just revealed five new genetic regions associated with migraine in a study published on 23 June 2013 in the journal Nature Genetics, bringing the total number identified in recent years to 12. Researchers from Inserm Unit 708 “Neuroepidemiology” in Bordeaux participated in the vast research by comparing nearly 118,000 items of data from patients suffering or not suffering from migraine, produced from 29 different genomic studies.

Migraine is a type of repetitive headache characterised by very intense pain and other symptoms such as nausea, sensitivity to light and noise. It affects almost one adult in five. A study of the origins remains difficult due to the episodic nature of the complaint but, very recently, several genetic markers have been associated with migraine.

In this new study, researchers listed 12 genetic regions associated with migraine. Seven of them had already been reported and five new ones were identified.

The study shows that some of them can be found near the genes controlling the brain circuits and the genes responsible for maintaining brain tissue in good health.

“The results obtained from this very large database will make it possible to determine the biological mechanisms for the origin of migraines” explains Tobias Kurth, Inserm Research Director at Inserm Unit 708 “Neuroepidemiology”. We believe that most of these genes are interconnected and could deregulate brain tissue thus producing the symptoms of migraine,” he adds.

Researchers also identified 134 additional genetic regions that are potentially associated with an individual’s susceptibility to developing migraine.

Genetic involvement in epilepsy?

A gene involved in so-called “focal” epilepsy, the most frequent form of the condition, has been discovered by the research team directed by Eric Leguern and Stéphanie Baulac of  Inserm unit 975 “Genetics and physiopathology of family epilepsy” at the Institut du Cerveau et de la Moelle (ICM) of the Pitié-Salpêtrière Hospital. The researchers studied families in which the affected members presented with various focal epilepsy syndromes. In 37% of families, mutations were found in a shared gene. This discovery makes it possible to envisage new mechanisms that should help to produce a better understanding of the condition. The results of the study were published in a letter in the journal Nature Genetics dated 31 March 2013.

Focal epilepsy represents nearly 70% of all epilepsies. Of these, several family syndromes were identified and characterised by the epileptogenic focus of the attacks, namely dominant autosomic nocturnal frontal epilepsy, temporal lobe family epilepsy and variable-focus family epilepsy.

Thanks to the clinical characterisation of 16 families, in collaboration with clinicians at the Strasbourg University Hospitals, researchers have just discovered an important gene involved in several forms of family focal epilepsy. The high-speed DNA sequencing technique makes it possible to identify a mutation that introduces a mismatch with the reading of the DEPDC5 gene (DEP domain containing protein 5) which codes for a protein whose function is still unknown. The subsequent high-speed sequencing of the gene revealed the presence of mutations in six families of the cohort out of 16, i.e. more than one third. The high frequency of mutations in the DEPDC5 gene would seem to presage favourable outcomes for patients and families in terms of molecular and clinical diagnosis.

“The identification of mutations in families whose members suffer from frontal, temporal  or variable focal epilepsy shows that this gene is a common denominator in epileptic syndromes long considered to be unrelated, due to the fact that the focus was found to be in different parts of the brain and the electro-clinical expression observed during attacks also being different”

, explains Stéphanie Baulac, Inserm head of research. “ These results suggest for the first time that the site that initiates the attacks is dissociated from the molecular cause”.

This discovery will make it possible to embark on new pathways to a better understanding of the pathological mechanisms of epilepsy for the development of new therapeutic targets, focal epilepsy being one of the most pharmaco-resistant conditions.

These research projects benefited from finance from the Institut Hospitalo-Universitaire IHU-A-ICM  in its “Investments for the future” initiative.

Photo: ©Inserm / L.Peris

Food quality and recurrent episodes of depression

Depression is a common multifactorial condition in which the appearance of symptoms is often linked to patients’ lifestyle. Of these factors, nutrition appears to play a significant role. Studies performed in a collaborative project between INSERM researchers in Montpellier and at University College London suggest than an improvement in the quality of nutrition is associated with a reduction in the recurrence of episodes of depression, particularly in women. These results have been published in the American Journal of Clinical Nutrition.

For the research, researchers at Unit 1061 “Neuropsychiatrie : recherche epidemiologie et clinique” (INSERM/University of Montpellier) and University College London analysed ten years’ worth of data (1993-2003), in 4215 civil servants in the Whitehall II cohort working in London. The quality of their food intake was scored against the Alternative Healthy Eating Index (AHEI)[1].

The quality of nutrition for female participants in the study (and whether they complied with the food recommendations of the AHEI) over 10 years was associated with the recurrence of symptoms of depression measured five years later. This correlation was not found in men. The originality of the study lies in the analysis of data repeated over time, making it possible to study the direction of movement of the nutritional relationship and symptoms of depression.

“We observed that an improvement or maintenance by the participants of their AHEI score over a ten-year period of monitoring reduced the risk of their developing recurrent symptoms of depression by 65% in comparison with women having a low score”, explains Tasnime Akbaraly, head of research at INSERM and co-author of the study. “The results suggest that following the nutritional recommendations of the AHEI throughout an adult’s lifetime would make it possible to reduce the recurrence of episodes of depression,” concludes the researcher.

[1]The AHEI score is based on a diet rich in fruit, vegetables, nuts, soya, fibre, trans fatty acids, the proportion of white meat to red meat, the ratio of polyunsaturated fatty acids to saturated fatty acids, alcohol consumption and the long-term consumption of multivitamins.

How does the brain decide when one needs to take a break

Before we start to exert ourselves, our brain decides to assess the situation, evaluating the cost involved and the benefits that can be derived from it. One question has not been properly explored, namely, how does the brain decide when it is time to take a break, during a period when it is involved in strenuous activity? Florent Meyniel & Mathias Pessiglione, of the INSERM 975 unit “Centre de recherche en neurosciences de la Pitié Salpetrière”, have suggested that the accumulation and dispersal of a brain signal indicating fatigue respectively trigger the decision to stop or resume the work in progress. 

To test this hypothesis, the researchers developed a test in which 39 participants were invited to squeeze their fists tightly in exchange for a payment proportional to the length of time during which they were able to perform this feat.

The researchers used two brain imaging techniques to record the participants’ brain activity during the test, one to precisely pinpoint the signal and the other to show how it changed over time.

Their results show that the brain signal they were seeking corresponds to activity in a particular region of the brain, the insula posterior, which incidentally is also involved in the perception of pain. This signal accumulated when an effort was being made, and did so as fast as the strength used increased, dispersing during rest periods, and operating at a speed proportional to the monetary stakes involved. Furthermore, the prospect of making money from the activity enabled the subjects to exert themselves to the limit of their strength, i.e. to raise the fatigue threshold at which the brain triggers a rest break.

The researchers’ discovery suggests that the brain uses a mechanism to maximise the benefits linked to effort, while preventing the body from exhausting itself.