Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity
By L. Parton, C. Ye, R. Coppari, P. Enriori, Brian J. Choi, Chen-Yu Zhang, Chun Xu, C. Vianna, N. Balthasar, Charlotte E. Lee and 3 more. Nature, 2007
715 citations recorded by the source corpus.
A subset of neurons in the brain, known as ‘glucose-excited’ neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic β-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (KATP) channels. Although β-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of KATP channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
Subfields: Endocrine and Autonomic Systems, Physiology, Surgery
View Paper: https://www.semanticscholar.org/paper/db6fa1ebdee3b51dd1ddb453c36514988ffd5a30
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Endocrine and Autonomic Systems
In Physiology
In Surgery
Citations in the corpus
- Obesity and Leptin Resistance: Distinguishing Cause from Effect (2010, background): “Second, DIO animals tend to reduce their food intake and body weight when switched to a less palatable diet (52).”
- Sugar for the brain: the role of glucose in physiological and pathological brain function (2013, background): “In the hypothalamus, pro-opiomelanocortin (POMC) [59], melanin concentrating hormone (MCH) [60], and neuropeptide Y (NPY) / agouti-related peptide (AgRP) neurons sense peripheral glucose levels and regulate energy metabolism in an antagonistic fashion [49].”
- Mitochondrial ROS signaling in organismal homeostasis. (2015, background): “For example, superoxide can directly alter the activity of potassium channels (Avshalumov and Rice, 2003), which play important roles in glucose sensing by hypothalamic neurons and under regulatory control by UCP2 (Parton et al., 2007).”
- Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons (2011, neutral): “, 2008), we used immunodetectable hrGFP, expressed from POMC-hrGFP (Parton et al., 2007) and NPY-hrGFP (van den Pol et al.”
- Evaluating the glucose tolerance test in mice. (2008, background): “Finally, there is no consistency on the amount of glucose administered, with studies using 1 (5, 25, 27) or 2 g/kg (7, 15, 18, 23, 32) or both doses to determine glucose tolerance in their genetically modified mice (13, 29).”