New fat and new neurons: endocannabinoids control neurogenesis in obesity (Commentary on Rivera et al.)


  • Daniela Cota,

    1. Group ‘Energy Balance and Obesity’, INSERM U862, Bordeaux, France
    2. Université de Bordeaux 2, Neurocentre Magendie, Bordeaux, France
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  • Giovanni Marsicano

    1. Université de Bordeaux 2, Neurocentre Magendie, Bordeaux, France
    2. Group ‘Endocannabinoids and Neuroadaptation’, INSERM U862, Bordeaux, France
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Neurogenesis in the adult brain is a special form of structural plasticity whose function spans from protective responses to brain injury to modulation of memory and emotional processes (Abrous et al., 2005; Holtmaat & Svoboda, 2009). Adult neurogenesis is specific to discrete brain regions, such as the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus (SGZ) of the hippocampus, although recent evidence also suggests that it might be observed in the hypothalamus, and could causally participate in the regulation of energy balance (Kokoeva et al., 2005). Neurogenesis in the adult brain is affected by a plethora of factors, including nutrients derived from the diet and physical exercise (Abrous et al., 2005; Bouret, 2010). In particular, consumption of a high-fat diet and development of obesity might negatively affect neurogenesis, mostly in the hippocampus (Stranahan et al., 2008; Park et al., 2010), thus potentially impacting on mental health.

The endocannabinoid system (ECS) is known to regulate energy balance by engaging both central and peripheral mechanisms, and has been investigated as a potential target for the pharmacotherapy of obesity (Pagotto et al., 2006). Moreover, endocannabinoid signaling is known to modulate adult neurogenesis in both physiological and pathophysiological conditions (Aguado et al., 2005, 2007).

In the present issue of EJN, Rivera et al., (2011) merged these aspects of the ECS, and investigated, in rats, whether subchronic treatment with the cannabinoid type 1 inverse agonist AM251, which is known to cause a reduction in food intake and body weight, could also lead to changes in cell proliferation in structures such as the SVZ, SGZ, and hypothalamus. Interestingly, although the drug reliably decreased food intake and body weight in both low-fat-fed and high-fat-fed animals, the effects on brain cell proliferation were seen only during exposure to the high-fat diet. This suggests that the AM251-induced modulation of cell proliferation depends upon the types of nutrient (e.g. increased dietary fat) ingested, and not on caloric intake or adiposity changes. Neuroinflammation, which is known to impair neurogenesis (Monje et al., 2003), develops independently of increased adiposity when animals consume a high-fat diet (Posey et al., 2009). Although neuroinflammation was not investigated in the present study, its potential modulation through pharmacological blockade of CB1 could have participated in the described changes. Another possibility is that the treatment impacted differently on hypothalamic–pituitary–adrenal axis activity and consequently glucocorticoid levels, the latter having important effects on cell proliferation and neurogenesis (Stranahan et al., 2008).

Interestingly, the authors described a differential response to the treatment in the different areas studied. Whereas AM251 increased cell proliferation in the SGZ, it reduced the number of bromodeoxyuridine-positive cells in the SVZ and hypothalamus of high-fat-fed rats. This could be attributable to different neurogenic cellular pools being present in these areas. However, it could also be the result of an off-target effect of AM251 on vanilloid type 1 receptors, for instance, which has been implicated in the reduction in cell proliferation observed in the SVZ after AM251 administration (Goncalves et al., 2008).

Although precursor cell proliferation does not necessarily lead to functional neurogenesis, the findings by Rivera et al. (2011) point to the existence of a functional link between the ECS, high-fat diet exposure, and modulation of brain structural plasticity, adding a novel level of complexity to the role played by the ECS in the modulation of brain function.