Human alpha 2A-adrenergic receptor gene expressed in transgenic mouse adipose tissue under the control of its regulatory elements.

Catecholamines regulate white adipose tissue function and development by acting through beta- and alpha2-adrenergic receptors (ARs). Human adipocytes express mainly alpha 2A- but few or no beta 3-ARs while the reverse is true for rodent adipocytes. Our aim was to generate a mouse model with a human-like alpha2/beta-adrenergic balance in adipose tissue by creating transgenic mice harbouring the human alpha 2A-AR gene under the control of its own regulatory elements in a combined mouse beta 3-AR-/- and human beta 3-AR+/+ background. Transgenic mice exhibit functional human alpha 2A-ARs only in white fat cells. Interestingly, as in humans, subcutaneous adipocytes expressed higher levels of alpha2-AR than perigonadal fat cells, which are associated with a better antilipolytic response to epinephrine. High-fat-diet-induced obesity was observed in transgenic mice in the absence of fat cell size modifications. In addition, analysis of gene expression related to lipid metabolism in isolated adipocytes suggested reduced lipid mobilization and no changes in lipid storage capacity of transgenic mice fed a high-fat diet. Finally, the development of adipose tissue in these mice was not associated with significant modifications of glucose and insulin blood levels. Thus, these transgenic mice constitute an original model of diet-induced obesity for in vivo physiological and pharmacological studies with respect to the alpha2/beta-AR balance in adipose tissue

An updated radiocarbon-based ice margin chronology for the last deglaciation of the North American Ice Sheet Complex

The North American Ice Sheet Complex (NAISC; consisting of the Laurentide, Cordilleran and Innuitian ice sheets) was the largest ice mass to repeatedly grow and decay in the Northern Hemisphere during the Quaternary. Understanding its pattern of retreat following the Last Glacial Maximum is critical for studying many facets of the Late Quaternary, including ice sheet behaviour, the evolution of Holocene landscapes, sea level, atmospheric circulation, and the peopling of the Americas. Currently, the most up-to-date and authoritative margin chronology for the entire ice sheet complex is featured in two publications (Geological Survey of Canada Open File 1574 [Dyke et al., 2003]; ‘Quaternary Glaciations – Extent and Chronology, Part II’ [Dyke, 2004]). These often-cited datasets track ice margin recession in 36 time slices spanning 18 ka to 1 ka (all ages in uncalibrated radiocarbon years) using a combination of geomorphology, stratigraphy and radiocarbon dating. However, by virtue of being over 15 years old, the ice margin chronology requires updating to reflect new work and important revisions. This paper updates the aforementioned 36 ice margin maps to reflect new data from regional studies. We also update the original radiocarbon dataset from the 2003/2004 papers with 1541 new ages to reflect work up to and including 2018. A major revision is made to the 18 ka ice margin, where Banks and Eglinton islands (once considered to be glacial refugia) are now shown to be fully glaciated. Our updated 18 ka ice sheet increased in areal extent from 17.81 to 18.37 million km2, which is an increase of 3.1% in spatial coverage of the NAISC at that time. Elsewhere, we also summarize, region-by-region, significant changes to the deglaciation sequence. This paper integrates new information provided by regional experts and radiocarbon data into the deglaciation sequence while maintaining consistency with the original ice margin positions of Dyke et al. (2003) and Dyke (2004) where new information is lacking; this is a pragmatic solution to satisfy the needs of a Quaternary research community that requires up-to-date knowledge of the pattern of ice margin recession of what was once the world’s largest ice mass. The 36 updated isochrones are available in PDF and shapefile format, together with a spreadsheet of the expanded radiocarbon dataset (n = 5195 ages) and estimates of uncertainty for each interval

Glucose-sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

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 b-cells1, glucose excitation of neurons is driven by ATPmediated closure of ATP-sensitive potassium (KATP) channels2–5. Although b-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) neurons5 via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of KATP channels6,7. 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 production8. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesityinduced 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