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Séminaire impromptu - Sébastien BouretEarly life origins of obesity: role of hypothalamic development

Abstract :

The incidence of obesity is increasing at an alarming rate and this worldwide epidemic represents an ominous predictor of increases in diseases such as type 2 diabetes and metabolic syndrome. Epidemiological and animals studies suggest that alteration of the metabolic and hormonal environment during critical periods of development is associated with increased risks for obesity, hypertension, and type 2 diabetes in later life. There is general recognition that the developing brain is more susceptible to environmental insults than the adult brain. In particular, there is growing appreciation that developmental programming of neuroendocrine systems by the perinatal environment represents a possible cause for these diseases. This seminar will discuss potential periods of vulnerability for the development of hypothalamic neurons involved in feeding regulation. It will also provide an overview of recent evidence concerning the action of perinatal hormones (including leptin and ghrelin) in programming the development and organization of hypothalamic circuits. Finally, this presentation will present recent findings on the role of autophagy in the development of hypothalamic feeding pathways. 

Selected publications

1.Coupe B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. Loss of autophagy in proopiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metabolism, 15(2):247-255, 2012 

2.Caron E, Ciofi P, Prevot V, Bouret SG. Alteration in neonatal nutrition causes perturbations in hypothalamic neural circuits controlling reproductive function. The Journal of Neuroscience, 32(33): 1186-11494, 2012 (also This week in The Journal p. 

3. Ishii Y, Bouret SG. Embryonic birthdate of hypothalamic leptin-activated neurons in mice. Endocrinology, 153(8): 3657-3667, 2012

4. Bouret SG, Bates SH, Chen S, Myers MG Jr., Simerly RB. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. The Journal of Neuroscience, 32(4):1244-1252, 2012

5. Langlet F, Levin BE, Luquet S, Dunn-Meynell AA, Balland E, Lacombe E, Mazur D, Bouret SG, Prevot V, Dehouck B. Glucose and VEGF signaling promote blood-hypothalamus barrier plasticity and increase access of blood-borne molecules to the arcuate nucleus in response to fasting. Cell Metabolism, in press, 2013.

6. Laloux C., Mairesse J., Van Camp G., Giovine A, Branchi I., Bouret S.G., Morley-Fletcher S., Bergonzelli G.E., Malagodi M, Gradini R, Nicoletti F, Darnaudéry M., Maccari S. Increased trait anxiety in infancy caused by maternal stress. Psychoneuroendocrinology, 37:1646-1658, 2012 7. Steculorum MS, Bouret SG. Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring. Endocrinology, 152(11): 4171-4179, 2011 (also News & Views p. 4007-4009)

Scientific focus :

Neural networks necessary for many instinctive behaviors and physiological functions are formed primarily during the perinatal period under the influence of what appear to be activity independent developmental mechanisms. When an individual is confronted with environmental conditions that differ markedly from those present during perinatal development, however, disorders can ensue. This seems to be particularly true for prevalence of obesity. Epidemiological evidence indicates that alterations in perinatal nutrition (e.g. caloric restriction and overfeeding) can predispose an individual toward obesity and associated diseases such as type 2 diabetes, especially in an environment with wide availability of calorie dense foods. Despite these observations, little is known about the underlying mechanisms mediating this metabolic imprinting. Our general research interest is to understand how neural networks controlling energy balance develop as well as to investigate the long-term consequences of their abnormal development on metabolism.

Daniela Cota (daniela.cota @

Sébastien Bouret

Chargé de recherche CNRS dans une équipe Inserm à Lille, Sébastien Bouret, 36 ans, dirige aujourd’hui le Laboratoire international associé « Neurobese » basé à Los Angeles. Il partage donc son temps entre la France et les Etats-Unis. Voir son interview


Dr. Bouret has a broad background in the field of metabolic programming and the neurobiology of obesity (key papers: Bouret et al., Trophic action of leptin on hypothalamic neurons that regulate feeding, Science 304:108-110, 2004; Bouret et al., Hypothalamic neural projections are permanently disrupted in diet-induced obese rats, Cell Metabolism, 7:179-185, 2008; Coupe et al., Loss of autophagy in proopiomelanocortin perturbs axon growth and causes metabolic dysregulation Cell Metabolism, 15:247-255, 2012), with specific training and expertise in key research areas for this application. Dr. Bouret’s research has directly led to several breakthroughs in the understanding of the complex hormonal signals and neurodevelopmental substrates responsible for appetite regulation (key review: Organizational actions of metabolic hormones. Frontiers in Neuroendocrinology, in press, 2013). Most notably, he discovered that the fat-derived hormone leptin plays a crucial role in brain development by acting as a growth factor in the hypothalamus. More recently, Dr. Bouret’s lab has discovered a role for neonatal ghrelin in hypothalamic development and lifelong metabolic regulation.