Bouret Laboratory

Research Topics

  • Early life determinants of obesity and diabetes
  • Hormonal control of brain development
  • Nutritional influences on the development and plasticity of neuronal systems that control appetite and glucose regulation
  • Neuroendocrine substrates of Prader-Willi Syndrome

Research Overview

The general research interest of Dr. Bouret’s lab is to understand how early life events program lifelong obesity and metabolism. His research has directly led to several breakthroughs in the understanding of the complex hormonal signals and neurodevelopmental substrates responsible for appetite and glucose regulation. Most notably, he discovered that metabolic hormones such as leptin and ghrelin play a crucial role in hypothalamic development and lifelong body weight regulation. More recently, his lab has discovered an unanticipated inhibitory role for prenatal leptin in the development of the autonomic innervation of pancreatic islets. Dr. Bouret’s lab is also interested in studying how perinatal nutrition (such as maternal obesity) and genetic predispositions to obesity (such as Prader-Willi Syndrome) influence the development of brain metabolic circuits.

Key Findings

  • Development of hypothalamic circuits that regulate food intake and body weight

Despite the importance of hypothalamic circuits in controlling food intake and body weight in adults, surprisingly little was known about the development of these important pathways. Dr. Bouret published the first systematic study that applied a tract tracing method to examine the ontogeny of projection pathways from the arcuate nucleus. These studies also provided the first demonstration that leptin exerts a profound neurotrophic effect on hypothalamic feeding circuits during a restricted postnatal critical period.

1. Bouret SG, Draper SJ, Simerly RB. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science, 304(5667):108-110, 2004 (also News & Views, p. 63-64; Science Editor’s Choice). PMID: 15064420

2. Bouret SG, Draper SJ, Simerly RB. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. Journal of Neuroscience, 24(11):2797-2805, 2004. PMID: 15028773

3. 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. PMID: 22279209

4. Caron E, Sachot C, Prevot V, Bouret SG. Distribution of leptin-sensitive cells in the postnatal and adult mouse brain. Journal of Comparative Neurology, 518(4):459-476, 2010. PMID: 20017211

5. Bouret SG. Organizational actions of metabolic hormones. Frontiers in Neuroendocrinology, 2013; 34(1):18-26 (cover article). PMID: 23357643

  • Development of hypothalamic feeding circuits in obesity-prone rats

In collaboration with Dr. Barry E. Levin, Dr. Bouret’s lab studied the development of hypothalamic feeding circuits in an outbred line of rats that are prone to diet-induced obesity. Diet-induced obesity (DIO) in rats is a useful model to study the pathogenesis of human obesity because DIO rats, like humans, have a polygenic mode of inheritance and rats and humans develop the metabolic syndrome when a moderate amount of fat is added to the diet. We discovered that DIO rats display an abnormal organization of hypothalamic neural pathways involved in energy homeostasis that may be the result of altered responsiveness of arcuate neurons to the trophic actions of leptin during early postnatal life. Thus, the studies described in this paper provide an unanticipated link between decades of work on strains of rodents that are prone to diet-induced obesity and our previous work showing a neurotrophic role for leptin in development of hypothalamic circuits that control feeding.

1. Bouret SG, Gorski JN, Kirigiti MA, Levin BE, Simerly RB. Neural Projections from the arcuate nucleus of  the hypothalamus are permanently disrupted in diet-induced obese rats. Cell Metabolism, 7(2):179-185, 2008 (cover article). PMID: 18249177

2. Patterson CM, Bouret SG, Dunn-Meynell A.A., Levin B.E. Three-weeks of post-weaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling. Am J Physiol Reg Integr Comp Physiol, 296(3):R537-548, 2009. PMID: 19158409

3. Patterson C, Bouret SG, Park S, Dunn-Meynell, Levin BE. Large litter rearing enhances leptin sensitivity and protects selectively bred diet-induced obese rats from becoming obese. Endocrinology, 151(9), 4270-4279, 2010. PMID: 20668022

4. Johnson MD, Bouret SG, Dunn-Meynell AA, Boyle CN, Lutz TA, Levin BE. Early postnatal amylin treatment enhances hypothalamic leptin signaling and neural development in the selectively bred diet-induced obese rat. Am J Physiol Regul Integr Comp Physiol., 311:R1032-R1044, 2016. PMID: 27629888

5. Bouret S, Levin BE, Ozanne SE. Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity. Physiological Reviews, 95(1):47-82, 2015. PMID: 25540138

  • Involvement of gut-derived signals in hypothalamic development

The gut-brain axis is an important component of vertebrate physiology but little is known about the development of this axis. Dr. Bouret’s lab has recently discovered an unexpected role for the stomach-derived hormone ghrelin in brain development. We found that ghrelin can influence the development of the same hypothalamic circuits that it subsequently utilizes to regulate food intake and energy balance. Moreover, we showed that this developmental action of ghrelin has important functional consequences for long-term metabolic regulation. We further showed that postnatal overnutrition results in early changes in the gut-brain axis. These papers represent the first examination of the programming action of any gut peptide and have profound implications for ghrelin as a possible contributor to early-onset obesity through a direct inhibitory effect on hypothalamic development.

1. Steculorum SM, Collden G, Coupe B, Croizier S, Andrews Z, Jarosch F, Klussmann S, Bouret SG. Ghrelin programs development of hypothalamic feeding circuits. The Journal of Clinical Investigation, 125(2): 846-858, 2015 (also J Clin Invest (commentary), 490-492, 2015). PMID: 25607843

2. Collden G, Balland E, Parkash J, Caron E, Langlet F, Prevot V, Bouret SG. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Molecular Metabolism, 4(1):15-24, 2015. PMID: 25685686

3. Zigman JM, Bouret SG, Andrews ZB. Obesity impairs the action of the neuroendocrine ghrelin system. Trends in Endocrinology and Metabolism, 27(1):53-63. PMID: 26542050

Current Funding

  • R01 National Institute of Health (NIDDK), Leptin and the nutritional programming of obesity and diabetes, $1,803,339 TDC. This project is designed to study the role of the fat-derived hormone leptin in the wiring of the pancreas in a context of maternal obesity.
     
  • R01 National Institute of Health (NIDDK), Hypothalamic miRNAs in the pathogenesis of obesity, $750,000 TDC. The goal of this project is to study the role of small non-coding RNAs in the development and function of neurons known to be involved in the regulation of food intake, body weight, and glucose homeostasis.
     
  • Foundation for Prader-Willi Research, Development of appetite-related neural circuits in a mouse model for Prader-Willi Syndrome, $100,000 TDC. The long-term of this project is to investigate the development of hypothalamic appetite-related circuits in a pre-clinical model for Prader-Willi Syndrome.