Blanc SVSE 4 - Sciences de la vie, de la santé et des écosystèmes : Neurosciences

The role of the mTORC1 pathway in the modulation of hypothalamic adult neurogenesis and neuroinflammation in diet-induced obesity. – Neurobese

The mTORC1 pathway and the regulation of neurogenesis and neuroinflammation in obesity

Modulation of the activity of the mTORC1 pathway in the brain hypothalamus has been recently linked to the control of energy balance. Similarly, hypothalamic neurogenesis and neuroinflammation seem to participate to the control of food intake and body weight. All these processes might have a role in the pathophysiology of diet-induced obesity.

Determine the impact of mTORC1, neurogenesis and neuroinflammation in obesity

Obesity is a major health problem in developed countries and a growing one in the developing world. However, despite this, efficient anti-obesity treatments are currently lacking. Thus, because of the social and medical burden represented by obesity, intense research in recent years has focused on understanding the physiology of energy balance regulation, in order to identify possible therapeutic targets that will help halt obesity and its disastrous consequences. Such efforts have led to discover the role of intracellular pathways also known as “fuel sensing” mechanisms that, within the hypothalamus, modulate feeding behavior and body weight, and whose activity can go awry in obesity. One of such pathways is the mTORC1 (mammalian Target of Rapamycin complex 1) cascade that we have demonstrated to have a role in the hypothalamic regulation of energy balance and that it is also known to control cell growth. Processes like neurogenesis and neuroinflammation in the adult hypothalamus have also been implicated in the regulation of energy balance. Because of these recent findings in the present project we aim at determining the link among the mTORC1 pathway, the reciprocal modulation of hypothalamic neurogenesis and neuroinflammation and the consequent impact on energy balance. In particular, we will determine whether the modulation of the mTORC1 pathway affects hypothalamic neurogenesis and neuroinflammation and whether such modulation participates to the development of diet-induced obesity. We expect that our studies will lead to a better understanding of the physiopathological mechanisms leading to obesity, thus helping find new therapeutic approaches to tackle and eventually prevent obesity and its associated consequences.

To reach our goals we will combine genetic, pharmacological, behavioral, metabolic, neuroanatomical and molecular approaches. In particular, we will use mice with a defective mTORC1 pathway and will assess changes in adult neurogenesis and neuroinflammation within the hypothalamus using several cellular and molecular markers. While, modifications of energy balance in vivo and in response to high-fat diets and to treatment known to affect energy balance by modulating adult neurogenesis will be evaluated by assessing changes in feeding behavior, adiposity (via a quantitative body MRI analysis) and energy expenditure (via indirect calorimetry studies).

The project is currently ongoing. Of note, it has received financial support from the Pôle PROD'INNOV of the Aquitaine region.

The use of the approaches proposed in the project will therefore allow us obtaining a very detailed characterization of the molecular and neuronal mechanisms that might underline the actual link among caloric intake, relative changes in brain neuroanatomy and molecular function, and actual behavior. Taking into account the epidemic of obesity and the health threat that it represents, we expect that our studies will lead to a better understanding of the physiopathological mechanisms leading to this disease, thus helping find new therapeutic approaches to tackle and eventually prevent obesity and its associated consequences.

André C, Cota D. Coupling nutrient sensing to metabolic homoeostasis: the role of the mammalian target of rapamycin complex 1 pathway. Proc Nutr Soc. 2012 Aug 9:1-9.
In this recently published review we highlight the link between different types of nutrients and modulation of the mTORC1 pathway and the impact of such a modulation on the regulation of energy balance.

Obesity is a major health problem in developed countries and a growing one in the developing world. Obesity-related diseases account for up to 8% of health costs in Europe. However, despite this, efficient anti-obesity treatments are currently lacking. Thus, because of the social and medical burden represented by obesity, intense research in recent years has been focusing on understanding the physiology of energy balance regulation, in order to identify possible therapeutic targets that will help halt obesity and its disastrous consequences. Such efforts have lately led to discover the role of several molecular pathways also known as “fuel sensing” mechanisms that, particularly within the hypothalamus, modulate feeding behavior and body weight, and whose activity can go awry in obesity. One of such cellular pathways is the mammalian Target of Rapamycin complex 1(mTORC1) signaling cascade. We have recently demonstrated that mTORC1 signaling, which is known to control protein synthesis and cell growth, integrates cellular fuel status with hormonal-related signaling in specific populations of hypothalamic neurons that use this information to regulate energy balance. Processes like neurogenesis and neuroinflammation in the adult hypothalamus have also been lately implicated in the regulation of energy balance. Recent evidence has shown that induction of neurogenesis in the adult hypothalamus is the mechanism underlying the ability of neurotrophic factors, like ciliary neurotrophic factor (CNTF), to maintain the body weight loss induced by the drug in diet-induced obese animals even beyond treatment cessation. Conversely, hypothalamic neuroinflammation has a causal role in the development of hyperphagia and obesity. Interestingly, neuroinflammation is known to modulate adult neurogenesis. Furthermore, we have shown that hypothalamic mTORC1 signaling critically mediates CNTF actions on food intake and body weight. Thus, in the present project we aim at determining the link among the mTORC1 pathway, the reciprocal modulation of hypothalamic adult neurogenesis and neuroinflammation and the consequent regulation of energy balance. In particular, we will study whether mTORC1 signaling has a critical role in mediating the long-term effects of CNTF treatment on body weight loss; we will establish whether such involvement is due to the modulation of either hypothalamic adult neurogenesis or neuroinflammation and we will finally clarify whether decreased hypothalamic neuroinflammation critically regulates energy balance by favoring neurogenesis through an mTORC1-dependent mechanism.
To reach our goals we will combine genetic, pharmacological, behavioral, metabolic, neuroanatomical and molecular approaches. The use of these approaches will therefore allow us obtaining a very detailed characterization of the molecular and neuronal mechanisms that might underline the actual link among caloric intake, relative changes in brain neuroanatomy and molecular function and actual behavior.
Taking into account the epidemic of obesity and the health threat that it represents, we expect that our studies will lead to a better understanding of the physiopathological mechanisms leading to this disease, thus helping find new therapeutic approaches to tackle and eventually prevent obesity and its associated consequences.

Project coordinator

Madame Daniela COTA (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE BORDEAUX) – daniela.cota@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE BORDEAUX
INRA INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE - CENTRE DE RECHERCHE DE BORDEAUX
INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION DE BORDEAUX

Help of the ANR 548,774 euros
Beginning and duration of the scientific project: - 48 Months

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