CNS Leptin and leptin receptors — actions on body weight balance, leptin resistance and glucose homeostasis
My entire professional activity is basic science, primarily using genetically modified mouse and cell models. Leptin is released from fat tissue into the circulation and acts in the brain to regulate a variety of processes and behaviors including inhibition of food intake and improvement of blood glucose balance. It turns out that obesity is associated with impaired leptin receptor signaling in the brain which may underlie the development of obesity. My research program aims to increase our understanding of molecular mechanisms underpinning this leptin resistance. We have discovery that SOCS3 is a negative regulator of leptin receptor signaling and that SOCS3 expression is elevated in the hypothalamus of obese rodents. This has provided a possible molecular mechanism causing common human obesity.
More recently my lab has initiated studies of leptin’s anti-diabetic actions that are also mediated by the brain. We have thus discovered a Leptin-LepRb-AgRP Neurons-MC4R-Glucagon-Glucose axis, which may be useful to identify novel anti-diabetes drug targets. In another set of studies we have discovered that the leptin receptor is expressed on neuronal dendriticfibers and signals in proximity to synaptic structures. In addition, the NMDA-receptor subunit, NR2B on AgRP/NPYneurons is required for normal energy balance, and may thus serve as a potential novel anti-obesity drug target. These findings will provide a basis f our future research program in the field of cross-talk between leptin receptors and receptors for classical neurotransmitters such as glutamate and GABA.
In summary, my lab is interested in the fields of leptin receptor signaling and function and its role in development of obesity and Type 2 diabetes. My research team aims to continue to use state-of-the-art innovative technology to achieve a better understanding of CNS regulation of body weight and blood glucose balance, and to identify brain processes that are defective in obesity and diabetes.
1. Huo L, Grill H, Bjorbaek C. Divergent regulation of POMC neurons by leptin in the NTS and the arcuate nucleus of the hypothalamus. Diabetes 2006, 55:567-73.
2. Shi H, Belinda C, Inouye K. Bjorbaek C, Flier JS. Over-expression of SOCS3 in Adipose Tissue Causes Local But Not Systemic Insulin Resistance. Diabetes 2006, 55:699-707.
3. Huo L, Maeng L, Bjorbaek C, Grill HJ. Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract (NTS) are Activated by Both Gastric Distension and Leptin. Endocrinology 2007, 148:2189-97.
4. Bjornholm M, Munzberg H, Leshan RL, Villanueva EC, Bates SH, Louis GW, Jones JC, Ishida-Takahashi R, Bjorbaek C, Myers MG. Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. J Clin Invest 2007, 117:1354-60.
5.Tu H, Kastin AJ, Bjorbaek C, Pan W. Urocortin trafficking in cerebral microvessel endothelial cells. J Mol Neurosci 2007, 31:171-82.
6. Huo L, Gamber K, Grill HJ, Bjorbaek C. Divergent Regulation of NTS Proglucagon Neurons by Leptin in Rats and Mice. Endocrinology 2008, 149:492-497. PMCID: PMC2219301
7.Huo L, Gamber K, Greeley S, Silva J, Huntoon N, Leng XH, Bjorbaek C. Leptin-dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons. Cell Metabolism 2009, 9:537-47 PMCID: PMC2730605
8. Backholer K, Bowden M, Gamber K, Bjørbæk C, Iqbal J, Clarke IJ Melanocortins mimic the effects of leptin to restore reproductive function in lean hypogonadotropic ewes.
Neuroendocrinology 2010, 91:27–40 PMCID: PMC2857620
9. Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjorbaek C. Over-expression of leptin receptors in POMC neurons promotes development of diet-induced obesity. PloS One 2012, 7:e30485 PMID:22276206
10. Huang H, Kong D, Byun KH, Ye C, Koda S, Lee DH, O h B-C, Lee SW, Kim MS, Lee B, Bjorbaek C, Lowell BB, Kim Y-B. Hypothalamic Rho-kinase Regulates Energy Balance by Targeting Leptin Receptor Signaling. Nature Neuroscience 2012, 15:1391-8 PMCID: PMC3458121