BAD modulates counterregulatory responses to hypoglycemia and protective glucoprivic feeding.

Hypoglycemia or glucoprivation triggers protective hormonal counterregulatory and feeding responses to aid the restoration of normoglycemia. Increasing evidence suggests pertinent roles for the brain in sensing glucoprivation and mediating counterregulation, however, the precise nature of the metabolic signals and molecular mediators linking central glucose sensing to effector functions are not fully understood. Here, we demonstrate that protective hormonal and feeding responses to hypoglycemia are regulated by BAD, a BCL-2 family protein with dual functions in apoptosis and metabolism. BAD-deficient mice display impaired glycemic and hormonal counterregulatory responses to systemic glucoprivation induced by 2-deoxy-D-glucose. BAD is also required for proper counterregulatory responses to insulin-induced hypoglycemia as evident from significantly higher glucose infusion rates and lower plasma epinephrine levels during hyperinsulinemic hypoglycemic clamps. Importantly, RNA interference-mediated acute knockdown of Bad in the brain provided independent genetic evidence for its relevance in central glucose sensing and proper neurohumoral responses to glucoprivation. Moreover, BAD deficiency is associated with impaired glucoprivic feeding, suggesting that its role in adaptive responses to hypoglycemia extends beyond hormonal responses to regulation of feeding behavior. Together, these data indicate a previously unappreciated role for BAD in the control of central glucose sensing

Proof of principle for a high sensitivity search for the electric dipole moment of the electron using the metastable a(1)[^3\Sigma^+] state of PbO

The metastable a(1)[^3\Sigma^+] state of PbO has been suggested as a suitable system in which to search for the electric dipole moment (EDM) of the electron. We report here the development of experimental techniques allowing high-sensitivity measurements of Zeeman and Stark effects in this system, similar to those required for an EDM search. We observe Zeeman quantum beats in fluorescence from a vapor cell, with shot-noise limited extraction of the quantum beat frequencies, high counting rates, and long coherence times. We argue that improvement in sensitvity to the electron EDM by at least two orders of magnitude appears possible using these techniques.Comment: 5 pages, 3 figure

Cell Death Critical Control Points

AbstractProgrammed cell death is a distinct genetic and biochemical pathway essential to metazoans. An intact death pathway is required for successful embryonic development and the maintenance of normal tissue homeostasis. Apoptosis has proven to be tightly interwoven with other essential cell pathways. The identification of critical control points in the cell death pathway has yielded fundamental insights for basic biology, as well as provided rational targets for new therapeutics

Genetic requirement of BAD in the glucoprivic feeding response.

<p>Glucoprivic feeding response 4 hrs after i.p. administration of 2DG (150 mg/kg) or saline to <i>Bad </i>^−/−and <i>Bad </i>^+/+ mice (n = 11–12 per group). *p<0.05; **p<0.01, unpaired two tailed <i>t</i>-test.</p

Impaired counterregulatory responses to insulin-induced hypoglycemia in BAD-deficient mice.

<p>Plasma glucose levels (A) and glucose infusion rate (GIR) (B) in <i>Bad </i>^−/− and <i>Bad </i>^+/+ mice subjected to hyperinsulinemic hypoglycemic clamp analysis. Plasma glucagon (C) and epinephrine (D) levels at 30 min during the clamp period. *p<0.05; **p<0.01, <i>Bad </i>^−/− vs <i>Bad </i>^+/+ mice (n = 9 per group), unpaired two tailed <i>t</i>-test.</p

Glucagon secretion in response to glucose and arginine.

<p>(A) Glucagon secretion in primary <i>Bad </i>^−/− and <i>Bad </i>^+/+ islets. Data are mean ± s.e.m and represent cumulative values from 3 independent islet isolations. Glc, glucose. *p<0.05; **p<0.01, unpaired two tailed <i>t</i>-test (B) Glucagon secretion during L-arginine stimulation of <i>Bad </i>^−/− and <i>Bad </i>^+/+ mice (n = 4–7 per group). ***p<0.001, unpaired two tailed <i>t</i>-test.</p

BAD and KATP channels regulate neuron excitability and epileptiform activity

Brain metabolism can profoundly influence neuronal excitability. Mice with genetic deletion or alteration of Bad (BCL-2 agonist of cell death) exhibit altered brain-cell fuel metabolism, accompanied by resistance to acutely induced epileptic seizures; this seizure protection is mediated by ATP-sensitive potassium (KATP) channels. Here we investigated the effect of BAD manipulation on KATP channel activity and excitability in acute brain slices. We found that BAD’s influence on neuronal KATP channels was cell-autonomous and directly affected dentate granule neuron (DGN) excitability. To investigate the role of neuronal KATP channels in the anticonvulsant effects of BAD, we imaged calcium during picrotoxin-induced epileptiform activity in entorhinal-hippocampal slices. BAD knockout reduced epileptiform activity, and this effect was lost upon knockout or pharmacological inhibition of KATP channels. Targeted BAD knockout in DGNs alone was sufficient for the antiseizure effect in slices, consistent with a ‘dentate gate’ function that is reinforced by increased KATP channel activity