Hepatic Glucagon-Receptor Signaling Enhances Insulin-Stimulated Glucose Disposal in Rodents

Glucagon receptor (GCGR) agonists cause hyperglycemia but also weight loss. However, GLP1R/GCGR mixed agonists do not exhibit the diabetogenic effects often attributed to GCGR activity. Thus, we sought to investigate the effect of glucagon agonism on insulin action and glucose homeostasis. Acute GCGR agonism induced immediate hyperglycemia, followed by improved glucose tolerance and enhanced glucose-stimulated insulin secretion. Moreover, acute GCGR agonism improved insulin tolerance in a dose-dependent manner in both lean and obese mice. Improved insulin tolerance was independent of GLP1R, FGF21, and hepatic glycogenolysis. Moreover, we observed increased glucose infusion rate, disposal, uptake, and suppressed endogenous glucose production during euglycemic clamps. Mice treated with insulin and GCGR agonist had enhanced phosphorylation of hepatic AKT at Ser473; this effect was reproduced in isolated mouse primary hepatocytes and resulted in increased AKT kinase activity. These data reveal that GCGR agonism enhances glucose tolerance in part, by augmenting insulin action, with implications for the use of GCGR agonism in therapeutic strategies for diabetes

Earthquake swarms driven by aseismic creep in the Salton Trough, California

Author Posting. © American Geophysical Union, 2007. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 112 (2007): B04405, doi:10.1029/2006JB004596.In late August 2005, a swarm of more than a thousand earthquakes between magnitudes 1 and 5.1 occurred at the Obsidian Buttes, near the southern San Andreas Fault. This swarm provides the best opportunity to date to assess the mechanisms driving seismic swarms along transform plate boundaries. The recorded seismicity can only explain 20% of the geodetically observed deformation, implying that shallow, aseismic fault slip was the primary process driving the Obsidian Buttes swarm. Models of earthquake triggering by aseismic creep can explain both the time history of seismic activity associated with the 2005 swarm and the ∼1 km/h migration velocity exhibited by this and several other Salton Trough earthquake swarms. A combination of earthquake triggering models and denser geodetic data should enable significant improvements in time-dependent forecasts of seismic hazard in the key days to hours before significant earthquakes in the Salton Trough.This material is based upon work supported by the National Science Foundation under grant 0548785. R.B.L. was supported by a WHOI postdoctoral research fellowship

The BDNF val-66-met Polymorphism Affects Neuronal Morphology and Synaptic Transmission in Cultured Hippocampal Neurons from Rett Syndrome Mice

Brain-derived neurotrophic factor (Bdnf) has been implicated in several neurological disorders including Rett syndrome (RTT), an X-linked neurodevelopmental disorder caused by loss-of-function mutations in the transcriptional modulator methyl-CpG-binding protein 2 (MECP2). The human BDNF gene has a single nucleotide polymorphism (SNP)—a methionine (met) substitution for valine (val) at codon 66—that affects BDNF’s trafficking and activity-dependent release and results in cognitive dysfunction. Humans that are carriers of the met-BDNF allele have subclinical memory deficits and reduced hippocampal volume and activation. It is still unclear whether this BDNF SNP affects the clinical outcome of RTT individuals. To evaluate whether this BDNF SNP contributes to RTT pathophysiology, we examined the consequences of expression of either val-BDNF or met-BDNF on dendrite and dendritic spine morphology, and synaptic function in cultured hippocampal neurons from wildtype (WT) and Mecp2 knockout (KO) mice. Our findings revealed that met-BDNF does not increase dendritic growth and branching, dendritic spine density and individual spine volume, and the number of excitatory synapses in WT neurons, as val-BDNF does. Furthermore, met-BDNF reduces dendritic complexity, dendritic spine volume and quantal excitatory synaptic transmission in Mecp2 KO neurons. These results suggest that the val-BDNF variant contributes to RTT pathophysiology, and that BDNF-based therapies should take into consideration the BDNF genotype of the RTT individuals

The Role of beta-Hydroxybutyrate in Glucagon Receptor Stimulated Food Intake Suppression in Obese Mice

Glucagon’s counterregulatory role to insulin action is well known, but its broader therapeutic potential is an evolving research interest. We have reported that chronic glucagon receptor (GCGR) activation decreases body weight (BW) and food intake (FI) while increasing beta-Hydroxybutyrate (bHB), a known ketone body. Recent studies suggest that ketone esters similarly reduce food intake in mice. The primary objective of this study was to determine if decreases in FI seen in DIO mice treated with GCGR agonist (IUB288) are mediated by bHB. C57Bl6/J mice were fed High Fat Diet (HFD, 58% fat + sucrose) for 12 weeks, to stimulate diet induced obesity. Mice were assigned into groups matched for food intake; Vehicle-Vehicle, Vehicle-IUB288, Trimetazidine-Vehicle, Trimetazidine-IUB288, (n=3). Mice were treated with or without Trimetazidine, 15 mg/kg (TMZ), an inhibitor of ketogenesis, for two days prior to four days of IUB288 or vehicle injections. Following a ten-day wash out period, the study was repeated using 30 mg/kg. FI and BW were measured daily, and plasma bHB were measured at baseline and study conclusion. IUB288 reduced FI and BW in both TMZ and vehicle treated mice. Surprisingly bHB concentration was elevated post-treatment in both 15 mg/kg and 30 mg/kg TMZ treated mice. In both experiments, the administered dosage of TMZ was insufficient to block IUB288-stimulated bHB. The results provide neither evidence for, or against, bHB FI suppression in DIO mice. Future studies will utilize a larger dosage of TMZ, or administration of a different inhibitor of ketogenesis

Glucagon's metabolic action in health and disease

Discovered almost simultaneously with insulin, glucagon is a pleiotropic hormone with metabolic action that goes far beyond its classical role to increase blood glucose. Albeit best known for its ability to directly act on the liver to increase de novo glucose production and to inhibit glycogen breakdown, glucagon lowers body weight by decreasing food intake and by increasing metabolic rate. Glucagon further promotes lipolysis and lipid oxidation and has positive chronotropic and inotropic effects in the heart. Interestingly, recent decades have witnessed a remarkable renaissance of glucagon’s biology with the acknowledgment that glucagon has pharmacological value beyond its classical use as rescue medication to treat severe hypoglycemia. In this article, we summarize the multifaceted nature of glucagon with a special focus on its hepatic action and discuss the pharmacological potential of either agonizing or antagonizing the glucagon receptor for health and disease

Glucagon receptor signaling regulates weight loss via central KLB receptor complexes

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon’s weight loss effects. FGF21 signaling requires an obligate coreceptor (β-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome

Earthquake Seismology: An Introduction and Overview

This introductory chapter covers the science of earthquake seismology: the study of earthquakes using seismic waves. In it, we touch on some of the many interesting and varied research questions that earthquake seismology seeks to address. We begin by reviewing the basic understanding of where, why, and how earthquakes occur in the context of the theory of plate tectonics. Earthquakes have had, and will continue to have, an important impact on human affairs, so it is natural to note some of the more significant earthquakes in history, as gauged by different measures, while doing this. From here, we delve into more quantitative aspects of earthquake source theory and how seismologists use the radiated wave field to understand the mechanics of earthquakes and faulting. The wide range of temporal and spatial scales that are important to the faulting process mean that there are necessarily a wide range of approaches and perspectives in the study of earthquakes. In this overview chapter, we can only give them cursory treatment, but subsequent chapters explore these different perspectives in detail. We end the overview by introducing research issues in the closely related fields of tsunami generation, Nuclear Test Ban Treaty verification, and earthquake risk mitigation. All of these are closely intertwined with the science of earthquake seismology