Systemic glucose homeostasis is substantially regulated by central autonomic circuits and there is a high risk of developing type 2 diabetes if autonomic dysfunction is present. Therefore, without a full understanding of the mechanisms governing the preautonomic neurons, there is a barrier to the understanding of the control of glycemic status. The overall long term goal of this proposal is to elucidate the fundamental relationship between central autonomic control and glucose homeostasis. The paraventricular nucleus (PVN) of the hypothalamus is a critical command center controlling autonomic outflow and, thereby, influencing glucose and energy homeostasis. Since impaired glucose homeostasis in diabetic patients involves central circuits controlling autonomic output, the immediate objective of this proposal is to identify transient receptor potential vanilloid type 1 (TRPV1)-dependent mechanisms involved in the regulation of preautonomic PVN neurons in the control of glycemic status using in vivo and in vitro approaches. The involvement of TRPV1 in diabetes has been established and recent studies from my laboratory have indicated that TRPV1 is a vital controller of preautonomic PVN neurons through increasing excitatory neurotransmitter release. Furthermore, this TRPV1- dependent excitation of liver-related PVN neurons was absent in a diabetic mouse model. Our preliminary observations demonstrate that activation of TRPV1 in the PVN lowers systemic blood glucose levels in control mice likely through increasing glucose uptake of the muscle and decreasing gluconeogenesis by the liver. These observations lead to the central hypothesis that preautonomic PVN neurons receive TRPV1-expressing inputs and these inputs are integrated into a coordinated autonomic output signal to generate an appropriate glycemic response. The proposed in vivo studies will determine the effect of TRPV1 activation in PVN circuits on autonomic endpoints. The effect of TRPV1 activation in PVN on glucose homeostasis will be determined using hyperinsulinemic-euglycemic clamp studies in conscious mice, and on blood pressure and heart rate using telemetry. Systems level studies using optogenetics will determine the effect of selective stimulation and inhibition of TRPV1 inputs on glucose homeostasis using TRPV1cre mice. Whole-cell, patch-clamp studies will reveal the cellular effects of activation and inhibition of TRPV1 inputs on PVN neurons, and we will identify preautonomic neuronal populations in the PVN regulated by TRPV1-expressing projections. Furthermore, the effect of TRPV1 activation on neurotransmission will be determined using photostimulation in TRPV1cre mice. These studies will define the role of central TRPV1 action on whole body glucose homeostasis through preautonomic PVN neurons, and will differentiate the importance of pre- and postsynaptic locations of TRPV1 on this system. The outcomes of the proposed studies hold the promise of opening innovative clinical strategies and drug targets for the improvement of glycemic status in diabetic patients via autonomic control.

Public Health Relevance

This research is relevant to public health because of the increasing prevalence of type 2 diabetes. The proposed studies focus on the regulation of the systemic glucose homeostasis via the brain and will determine the contribution of central TRPV1 to the regulation of glucose homeostasis. Exploring these mechanisms can lead to novel strategies to improve glucose homeostasis through centrally directed therapies.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tulane University
Schools of Medicine
New Orleans
United States
Zip Code
Yu, Sangho; Cheng, Helia; Fran├žois, Marie et al. (2018) Preoptic leptin signaling modulates energy balance independent of body temperature regulation. Elife 7:
Navarro, Guadalupe; Allard, Camille; Morford, Jamie J et al. (2018) Androgen excess in pancreatic ? cells and neurons predisposes female mice to type 2 diabetes. JCI Insight 3:
Gao, Hong; Molinas, Adrien J R; Miyata, Kayoko et al. (2017) Overactivity of Liver-Related Neurons in the Paraventricular Nucleus of the Hypothalamus: Electrophysiological Findings in db/db Mice. J Neurosci 37:11140-11150
Bruce, Kimberley D; Zsombok, Andrea; Eckel, Robert H (2017) Lipid Processing in the Brain: A Key Regulator of Systemic Metabolism. Front Endocrinol (Lausanne) 8:60
Anwar, Imran J; Miyata, Kayoko; Zsombok, Andrea (2016) Brain stem as a target site for the metabolic side effects of olanzapine. J Neurophysiol 115:1389-98
Zsombok, Andrea; Derbenev, Andrei V (2016) TRP Channels as Therapeutic Targets in Diabetes and Obesity. Pharmaceuticals (Basel) 9:
O'Hare, James D; Zsombok, Andrea (2016) Brain-liver connections: role of the preautonomic PVN neurons. Am J Physiol Endocrinol Metab 310:E183-9
Derbenev, Andrei V; Zsombok, Andrea (2016) Potential therapeutic value of TRPV1 and TRPA1 in diabetes mellitus and obesity. Semin Immunopathol 38:397-406
Zsombok, Andrea (2015) Alarming evidence: high fat diet alters brainstem circuits prior to the development of obesity. J Physiol 593:1
Rezai-Zadeh, Kavon; Yu, Sanghou; Jiang, Yanyan et al. (2014) Leptin receptor neurons in the dorsomedial hypothalamus are key regulators of energy expenditure and body weight, but not food intake. Mol Metab 3:681-93

Showing the most recent 10 out of 11 publications