Research InterestsOur main focus has been to elucidate nutrient and hormone sensing mechanisms in the gut and the brain that regulate hepatic glucose production, hepatic VLDL-TG secretion and food intake to maintain glucose, lipid and energy homeostasis
Research Divisions: Endocrine and Diabetes Platform
Keywords: Nutrient sensing / Diabetes / Obesity.
Our main focus has been to elucidate nutrient and hormone sensing mechanisms in the gut and the brain that regulate hepatic glucose production, hepatic VLDL-TG secretion and food intake to maintain glucose, lipid and energy homeostasis. We have discovered nutrient sensing in the duodenum triggers hormonal signaling and a gut-brain-liver axis to inhibit glucose production and lower plasma glucose levels. We have identified intestinal signaling defects that are acquired by diabetes and obesity and have characterized novel molecular signaling pathways that can be activated to bypass intestinal signaling defects and restore glucose homeostasis. In addition, we have discovered that jejunual nutrient sensing is necessary for duodenal-jejunal bypasss to rapidly lower glucose levels in uncontrolled diabetes. Lastly, we have unveiled novel insulin, glucagon and nutrient signaling pathways in the brain that regulate hepatic glucose production, VLDL-TG secretion and food intake. In summary, our discoveries reveal molecular targets in the gut and the brain that may carry therapeutic potential to lower blood glucose and lipid levels and body weight in diabetes and obesity.
Publications and Awards
Duca FA et al. Glucoregulatory relevance of small intestinal nutrient sensing in physiology, bariatric surgery, and pharmacology. Cell Metab 2015 July 22.
Duca FA et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nature Medicine 21(5):506-11, 2015 (Highlighted in the Cover).
Cote CD et al. Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network. Nature Medicine 21(5):498-505, 2015 (Highlighted in the Cover).
Yue JT et al. A fatty acid-dependent hypothalamic-DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins. Nature Commun 2015 Jan 12;6:5970.
Rasmussen BA et al. Jejunal leptin-PI3K signaling lowers glucose production. Cell Metabolism 19(1):155-161, 2014
Mighiu PI, Yue JT et al. Hypothalamic glucagon signaling inhibits hepatic glucose production. Nature Medicine 19(6):766-772, 2013
Filippi BM et al. Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metabolism 16:500-510, 2012
Breen DM et al. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nature Medicine 18:950-955, 2012. (Live Interview at Nature Medicine Podcast: Time 16:06)
Yue JT and Lam TKT. Lipid sensing and insulin resistance in the brain. Cell Metabolism 15:646-655, 2012
Yue JT et al. Glycine normalizes hepatic triglyeride-rich VLDL secretion by triggering the CNS in high-fat fed rats. Circ Res 110:1345-54, 2012
Lam TKT: Neuronal regulation of homeostasis by nutrient sensing. Nature Medicine 16:392-395, 2010.
Cheung G et al. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metabolism 10:99-109, 2009 (Cover story, (TV Interview).
Wang P et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 452:1012-1016, 2008 (Named a 2008 Milestone in Canadian Health Research by Canadian Institutes of Health Research).
Caspi L et al. A balance of lipid-sensing mechanisms in the brain and liver. Cell Metabolism 6:99-104, 2007
Lam TKT et al. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309(5736):943, 2005.