Dr Alexandre Caron
2725 chemin Ste-Foy, room Y4255.5
Québec (QC) Canada, G1V 4G5
Biographical Sketch
Alexandre Caron obtained his PhD in Physiology-Endocrinology from Laval University in 2015. His graduate work with Drs. Denis Richard and Mathieu Laplante focused on understanding the role of DEP domain-containing mTOR-interacting protein (DEPTOR) in energy, glucose and lipid homeostasis. His graduate research also involved the study of the molecular mechanisms regulating non-shivering thermogenesis in brown adipose tissue. After graduating, Dr. Caron joined the laboratory of Dr. Joel Elmquist (Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center) first as a Diabetes Canada Postdoctoral Fellow and then as a Banting Postdoctoral Fellow. His postdoctoral work aimed at understanding how the central leptin-melanocortin system controls adipose metabolic and endocrine functions. He also developed an arsenal of genetic models allowing the manipulation of key autonomic receptors. In 2019, Dr. Caron received the NIDDK K99/R00 Award to perform studies aimed at better understanding the sympathetic regulation of liver metabolism. Under the mentorship of the chemist Dr. Shawn Burgess (Center for Human Nutrition, University of Texas Southwestern Medical Center), he started combining mouse genetics, chemogenetics and stable isotope approaches. In March 2020, he was appointed a position of Assistant Professor in Pharmacy at Laval University and established his laboratory at the Quebec Heart and Lung Institute.
Selected Scientific Contributions
1. Identification and characterization of DEPTOR in the central nervous system and investigation of its role in energy and glucose metabolism. During his PhD, Dr. Caron became interested in understanding how the hypothalamus controls energy balance and glucose homeostasis. His thesis aimed at elucidating the metabolic role of a novel endogenous inhibitor of mTOR signaling name DEPTOR. He was the first to characterize the distribution of DEPTOR in the rodent central nervous system, shedding the lights on the potential implication of
DEPTOR in the autonomic regulation of energy and glucose homeostasis. Using unique conditional transgenic mouse lines, he generated different models allowing systemic, hypothalamic, neuronal and liver-specific overexpression and deletion of DEPTOR. Dr. Caron found that hypothalamic overexpression of DEPTOR protects against diet-induced obesity and insulin resistance by improving neuronal insulin sensitivity. In order to determine the role of DEPTOR in discreet hypothalamic neurons, he thereafter showed that its overexpression in pro-opiomelanocortin (POMC) neurons affects glucose and lipid homeostasis through a fascinating brain-liver connection. He also discovered that loss of DEPTOR cell-autonomously increases oxidative metabolism in hepatocytes, resulting in a reduction in circulating glucose and hepatic glycogen content upon fasting.
• Caron A, et al. Journal of Comparative Neurology 523.1 (2015): 93-107.
• Caron A, et al. Molecular metabolism 5.2 (2016): 102-112.
• Caron A, et al. Am J of Physiology-Regulatory 310.11 (2016): R1322-R1331.
• Caron A, et al. Molecular metabolism 6.5 (2017): 447-458
• Caron A, et al. Physiological reviews 98.3 (2018): 1765-1803.
2. Revisiting the Central Leptin-Melanocortin system using modern genetic tools. A prevalent dogma in the field is that leptin signaling in pro-opiomelanocortin (POMC) is key in regulating energy balance and glucose homeostasis. This idea is based on global knock-out models, which were shown to lead to developmental compensation and off-targets. Moreover, the direct contribution of leptin-sensitive POMC neurons on glucose homeostasis has been difficult to dissect due to inevitable alterations of fat mass resulting from prenatal deletions. As such, dissociating the pathways involved in leptin’s and melanocortin’s effects on adiposity versus glucose homeostasis is key for the development of anti-obesity and anti-diabetes therapies. Dr. Caron used a tamoxifen-inducible POMC-CreERT2 transgenic mouse model to generate mice in which the leptin receptor expression is spatiotemporally-controlled in a neuron-specific fashion. Within one week of deleting leptin receptors from POMC neurons in adult mice, he observed impairment in hepatic glucose production, independent of changes in energy balance. This was one of the first study to clearly dissociate the effects of the leptin-melanocortin system on glucose homeostasis versus changes in energy balance. Moreover, this model is currently used to define the pathophysiologic progression of liver steatosis and insulin resistance, which may lead to important breakthrough on the molecular and temporal nature of non-alcoholic fatty liver disease.
• Caron A, et al. Elife 7 (2018): e33710.
3. Harnessing the power of chemogenetics to develop a library of transgenic models allowing the specific and spatiotemporal stimulation of GPCR signaling in peripheral organs. Chemical genetics, also known as chemogenetics, is an approach use to genetically engineer receptors that interact
with previously unrecognized small molecule chemical actuators. This approach has been used to create modified G-couple protein receptors (GPCRs), called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Originally developed to control neuronal activity, DREADDs are emerging as key tools for selective pharmacological control of GPCR signaling in any cell type or organ. Recently, Dr. Caron reported the generation of a novel chemogenetic approach allowing acute stimulation of GsPCR and GiPCR signaling in adipocytes in vivo and ex vivo. This innovative model revealed important, previously unappreciated complex interactions of GPCR signaling in adipose tissue and demonstrated the usefulness of chemogenetic technology to better understand cell and tissue function.
• Caron A, et al. Molecular metabolism 27 (2019): 11-21
Research Interests
Dr. Caron’s research is based on the conceptual framework that obesity and type 2 diabetes are diseases of the nervous system, consequent to miscommunication between the brain and metabolic organs. His laboratory studies the pathophysiological mechanisms that alter brain-organs communication in metabolic diseases and aims to identify new molecular and pharmacological targets in the brain and peripheral organs to improve energy and glucose metabolism. His work focusses on defining neuronal circuits involved in the control of hepatic glucose production and adipose lipid handling, and investigating autonomic receptor signaling pathways in metabolic organs. His objective is to make the fields of obesity and diabetes move forward and to directly impact on health research and clinical practices, by uncovering molecular and pharmacological targets for the treatment of metabolic disorders.