The main focus of this laboratory is to understand, at the molecular level, how the hypothalamus achieves its diverse physiological functions. The neuroendocrine hypothalamus consists of a complex array of distinct neuronal phenotypes, each expressing a specific complement of neuropeptides, neurotransmitters and receptors. Many of our vital needs, such as those for growth, reproduction, nutrition, sleep, and stress responses, depend on hormonal balance or homeostasis, which is controlled by both external and internal stimuli or signals at the hypothalamic level.
A) Regulation of GnRH Neurons and Afferent Control Mechanisms: In order to begin to dissect the molecular signals responsible for the release of specific peptides from individual hypothalamic neurons, my laboratory has focussed on the peptide that controls reproduction, gonadotropin-releasing hormone or GnRH. A large number of neuromodulators have been implicated in the control of reproductive function, as they have been found to regulate GnRH synthesis and secretion. My research program studies many aspects of GnRH function, and how afferent neurons affect the GnRH neurons. We also study the direct regulation of these afferent neurons, such as kisspeptin, neuropeptide Y, and gonadotropin inhibitory hormone, by steroids and other peripheral signals.
B) Generation and Characterization of Hypothalamic Cell Models: We therefore analyze the direct actions of neuromodulators on individual GnRH neurons; the transcriptional mechanisms dictating the neurogenesis of individual hypothalamic neurons; and the development of specific immortalized hypothalamic neuronal cell models in order to understand the molecular mechanisms involved in interneuron communication and signaling. To address this last point, my laboratory has recently generated a number of cell models representing other specific cell types from the hypothalamus. These models have been used by many labs worldwide to understand how hypothalamic neurons function. These models include embryonic- and adult-derived cell models from the mouse and rat, and represent the many cell types found in the hypothalamus and hippocampus.
C) Analysis of the Neuropeptides involved in Energy Homeostasis: We have a strong track record of neuroendocrine research, and have also expanded our research program to include the study of neuropeptides involved in both reproduction and energy homeostasis. Currently half of my research efforts are directed towards studies related to the function of the GnRH and afferent neurons, such as kisspeptin, neuropeptide Y and gonadotropin inhibitory hormone, and the other half has extended our research program to include studies of many of the neuropeptide-expressing neurons involved in energy homeostasis. These include neuropeptide Y, neurotensin, brain ghrelin, corticotropin-releasing hormone, and proopiomelanocortin. We are currently analyzing the changes in gene expression and signal transduction events after exposure to key peripheral signals such as insulin, ghrelin, glucose, leptin, and estrogen. We also study the mechanisms involved in neuroinflammatory signal transduction induced by exposure of neurons to excess nutrients, such as saturated fatty acids and high glucose. Importantly, there is also a direct relationship between nutritional status and reproduction, therefore my research program is poised to utilize all the information gained to provide insight into the complex nature of integrated neuroendocrine control of basic physiology.
Banting and Best Diabetes Centre, University of Toronto Centre for Research in Women’s Health, University of Toronto Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto The Endocrine Society The Society for Neuroscience Canadian Society for Endocrinology and Metabolism American Association for the Advancement of Science Women in Endocrinology Association for Women in Science (AWIS) International Federation for Neuroendocrinology (Canadian Representative on Council).
1. Palmitate induces neuroinflammation, ER stress, and Pomc mRNA expression in hypothalamic mHypoA-POMC/GFP neurons through novel mechanisms that are prevented by oleate.
Tse EK, Belsham DD.
Mol Cell Endocrinol. 2017 Nov 24. pii: S0303-7207(17)30603-2. doi: 10.1016/j.mce.2017.11.017. [Epub ahead of print]
2. Beneficial Effects of Metformin and/or Salicylate on Palmitate- or TNFα-Induced Neuroinflammatory Marker and Neuropeptide Gene Regulation in Immortalized NPY/AgRP Neurons.
Ye W, Ramos EH, Wong BC, Belsham DD.
PLoS One. 2016 Nov 28;11(11):e0166973. doi: 10.1371/journal.pone.0166973. eCollection 2016.
3.Signaling in the hypothalamus: New concepts.
Mol Cell Endocrinol. 2016 Dec 15;438:1-2. doi: 10.1016/j.mce.2016.11.001. No abstract available.
4. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons.
Dalvi PS, Chalmers JA, Luo V, Han DY, Wellhauser L, Liu Y, Tran DQ, Castel J, Luquet S, Wheeler MB, Belsham DD.
Int J Obes (Lond). 2017 Jan;41(1):149-158. doi: 10.1038/ijo.2016.183. Epub 2016 Oct 24.
5. Nutrient-sensing mechanisms in hypothalamic cell models: neuropeptide regulation and neuroinflammation in male- and female-derived cell lines.
Loganathan N, Belsham DD.
Am J Physiol Regul Integr Comp Physiol. 2016 Aug 1;311(2):R217-21. doi: 10.1152/ajpregu.00168.2016. Epub 2016 Jun 15. Review.
PMID: 27306829 Free PMC Article
6. Phoenixin Activates Immortalized GnRH and Kisspeptin Neurons Through the Novel Receptor GPR173.
Treen AK, Luo V, Belsham DD.
Mol Endocrinol. 2016 Aug;30(8):872-88. doi: 10.1210/me.2016-1039. Epub 2016 Jun 6.
PMID: 27268078 Free PMC Article
7. Diet-induced cellular neuroinflammation in the hypothalamus: Mechanistic insights from investigation of neurons and microglia.
Tran DQ, Tse EK, Kim MH, Belsham DD.
Mol Cell Endocrinol. 2016 Dec 15;438:18-26. doi: 10.1016/j.mce.2016.05.015. Epub 2016 May 18.
8. Nitric Oxide Exerts Basal and Insulin-Dependent Anorexigenic Actions in POMC Hypothalamic Neurons.
Wellhauser L, Chalmers JA, Belsham DD.
Mol Endocrinol. 2016 Apr;30(4):402-16. doi: 10.1210/me.2015-1275. Epub 2016 Mar 1.
PMID: 26930171 Free PMC Article
9. Induction of Gnrh mRNA expression by the ω-3 polyunsaturated fatty acid docosahexaenoic acid and the saturated fatty acid palmitate in a GnRH-synthesizing neuronal cell model, mHypoA-GnRH/GFP.
Tran DQ, Ramos EH, Belsham DD.
Mol Cell Endocrinol. 2016 May 5;426:125-35. doi: 10.1016/j.mce.2016.02.019. Epub 2016 Feb 26.
10. Glucose Alters Per2 Rhythmicity Independent of AMPK, Whereas AMPK Inhibitor Compound C Causes Profound Repression of Clock Genes and AgRP in mHypoE-37 Hypothalamic Neurons.
Oosterman JE, Belsham DD.
PLoS One. 2016 Jan 19;11(1):e0146969. doi: 10.1371/journal.pone.0146969. eCollection 2016.
PMID: 26784927 Free PMC Article
11. Divergent Regulation of ER and Kiss Genes by 17β-Estradiol in Hypothalamic ARC Versus AVPV Models.
Treen AK, Luo V, Chalmers JA, Dalvi PS, Tran D, Ye W, Kim GL, Friedman Z, Belsham DD.
Mol Endocrinol. 2016 Feb;30(2):217-33. doi: 10.1210/me.2015-1189. Epub 2016 Jan 4.
PMID: 26726951 Free PMC Article
Department of Physiology, Medical Sciences Building
1 King's College Circle, University of Toronto
ON, M5S 1A8