Food anticipatory activity on a calorie-restricted diet is independent of Sirt1

A number of studies have demonstrated that the Sirtuin family member, Sirt1, is a key integrator of growth, metabolism, and lifespan. Sirt1 directly interacts with and deacetylates key regulators of the circadian clock, positioning it to be an important link between feeding and circadian rhythms. In fact, one study suggests that Sirt1 is necessary for behavioral anticipation of limited daily food availability, a circadian process termed food anticipatory activity (FAA). In their study, mice overexpressing Sirt1 had enhanced FAA, while mice lacking Sirt1 had little to no FAA. Based on the supposition that Sirt1 was indeed required for FAA, we sought to use Sirt1 deletion to map the neural circuitry responsible for FAA. We began by inactivating Sirt1 using the cell-type specific Cre-driver lines proopiomelanocortin, but after observing no effect on body weight loss or FAA we then moved on to more broadly neuronal Cre drivers Ca2+/calmodulin-dependent protein kinase II and nestin. As neither of these neuronal deletions of Sirt1 had impaired FAA, we then tested 1) a broad postnatal tamoxifen-inducible deletion, 2) a complete, developmental knockout of Sirt1, and 3) a gene replacement, catalytically inactive, form of Sirt1; but all of these mice had FAA similar to controls. Therefore, our findings suggest that FAA is completely independent of Sirt1

Dopamine systems and biological rhythms: Let’s get a move on

How dopamine signaling regulates biological rhythms is an area of emerging interest. Here we review experiments focused on delineating dopamine signaling in the suprachiasmatic nucleus, nucleus accumbens, and dorsal striatum to mediate a range of biological rhythms including photoentrainment, activity cycles, rest phase eating of palatable food, diet-induced obesity, and food anticipatory activity. Enthusiasm for causal roles for dopamine in the regulation of circadian rhythms, particularly those associated with food and other rewarding events, is warranted. However, determining that there is rhythmic gene expression in dopamine neurons and target structures does not mean that they are bona fide circadian pacemakers. Given that dopamine has such a profound role in promoting voluntary movements, interpretation of circadian phenotypes associated with locomotor activity must be differentiated at the molecular and behavioral levels. Here we review our current understanding of dopamine signaling in relation to biological rhythms and suggest future experiments that are aimed at teasing apart the roles of dopamine subpopulations and dopamine receptor expressing neurons in causally mediating biological rhythms, particularly in relation to feeding, reward, and activity

Type 1 dopamine receptor (D1R)-independent circadian food anticipatory activity in mice.

Circadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R, conditionally deleting D1R in GABA neurons using Vgat-ires-Cre line. This conditional deletion mutant had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R, D1R KODrago. This result prompted us to re-test the original D1R KODrago line, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established the D1R KODrago knockout line from cryopreserved samples. The reestablished D1R KODrago-cryo had a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele of D1R created by the Knockout Mouse Project. This line of D1R KOKOMP mice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA

Food anticipatory activity on a calorie-restricted diet is independent of Sirt1

<div><p>A number of studies have demonstrated that the Sirtuin family member, Sirt1, is a key integrator of growth, metabolism, and lifespan. Sirt1 directly interacts with and deacetylates key regulators of the circadian clock, positioning it to be an important link between feeding and circadian rhythms. In fact, one study suggests that Sirt1 is necessary for behavioral anticipation of limited daily food availability, a circadian process termed food anticipatory activity (FAA). In their study, mice overexpressing Sirt1 had enhanced FAA, while mice lacking Sirt1 had little to no FAA. Based on the supposition that Sirt1 was indeed required for FAA, we sought to use Sirt1 deletion to map the neural circuitry responsible for FAA. We began by inactivating Sirt1 using the cell-type specific Cre-driver lines proopiomelanocortin, but after observing no effect on body weight loss or FAA we then moved on to more broadly neuronal Cre drivers Ca2+/calmodulin-dependent protein kinase II and nestin. As neither of these neuronal deletions of Sirt1 had impaired FAA, we then tested 1) a broad postnatal tamoxifen-inducible deletion, 2) a complete, developmental knockout of Sirt1, and 3) a gene replacement, catalytically inactive, form of Sirt1; but all of these mice had FAA similar to controls. Therefore, our findings suggest that FAA is completely independent of Sirt1.</p></div

Mouse strains used in this study.

<p>Mouse strains used in this study.</p

Testing FAA in forebrain and pan neuronal deletion mutants of Sirt1.

<p>(A) Mean body weights for <i>CamKII-Cre; Sirt1</i>^{<i>loxP/loxP</i>} and <i>Sirt1</i>^{<i>loxP/loxP</i>} littermate controls. CR diets began on Day 0. Mean high activity data for home cage behaviors at (B) Day -7 (n = 8 WT and n = 9 for KO), (C) Day 14 of CR (n = 6 WT and n = 9 KO), and (D) Day 28 (n = 7 WT and n = 8 KO) of CR are shown. (E) Mean total high activity, measured in seconds, over the entire 23.5h-24h video recording for <i>Sirt1</i>^{<i>loxP/loxP</i>} controls and CamKII-Cre;<i>Sirt1</i>^{<i>loxP/loxP</i>} (F) Mean fraction of normalized high activity in the 3h prior to mealtime; there were no differences between groups on all days. (G) Mean body weight for <i>Nestin-Cre; Sirt1</i>^{<i>loxP/loxP</i>} and <i>Sirt1</i>^{<i>loxP/loxP</i>} littermate controls. Mean high activity data for home cage behaviors at (H) Day -7 (n = 5 WT, n = 7 KO), (I) Day 14 (n = 4 WT, n = 4 KO) of CR, and (J) Day 28 (n = 5 WT, n = 7 KO) of CR are shown. (K) The amount of high activity in seconds for <i>Sirt1</i>^{<i>loxP/loxP</i>} and Nestin-Cre; <i>Sirt1</i>^{<i>loxP/loxP</i>} mice. On Day 7, the amount of total activity was greater for than <i>Nestin-Cre; Sirt1</i>^{<i>loxP/loxP</i>} compared to <i>Sirt1</i>^{<i>loxP/loxP</i>} controls (P = 0.0333). (L) Fraction of high activity measures between <i>Sirt1</i>^{<i>loxP/loxP</i>} and <i>Nestin-Cre; Sirt1</i>^{<i>loxP/loxP</i>} groups exhibit a greater amount of FAA in controls on Day 7 (P = 0.0333). For body weight data, statistical significance was determined using an unpaired T test. For behavioral data, statistical significance was determined using the Mann-Whitney Test. * denotes p<0.05.</p

Interventional treatment in diabetics in the era of drugeluting stents and compliance to the ESC guidelines: Lessons learned from the Euro Heart Survey Programme

Aims: The objective of the study is to determine the demographics and the in-hospital outcome of diabetic and non-diabetic patients treated with percutaneous coronary interventions (PCI) in Europe, to report the type of equipment and technology used for PCI procedures in diabetics and to clarify whether the treatment of diabetic patients complies with current European Society of Cardiology (ESC) guidelines. Methods and results: A total of 14,458 patients treated with PCI were enrolled from 29 member countries of the ESC between June 2005 and January 2006. Data were collected on patient characteristics and treatment, using new Cardiology Audit and Registration Data standards. In total, 3,603 patients (24.9%) were diabetic. Diabetics were older, more often female and had a higher body mass index than non-diabetics. Diabetics had higher rates of hypercholesterolaemia and hypertension, while current smokers were more frequent in the non-diabetics. Diabetics also had significantly higher rates of previous cardiovascular events. Clopidogrel was administered only in 48.1% of diabetic patients before PCI, while IIb/IIIa inhibitors were 22.9% during PCI. At discharge, there was a major adjustment of treatment with increases in the use of Beta-blocker (80.4%), angiotensin converting enzyme inhibitor (ACEI, 71.3%) and statins (89.8%) compared with on admission (Beta-blocker 60.9%, ACEI 55.0%, statin 63.1%). Inhospital mortality was higher in diabetics (1.8% vs 1.2%) although the in-hospital MACCE rate was not significantly different (3.6% vs 3.0%, p=0.09). Conclusions: Diabetic patients treated with PCI were older with more comorbidity. According to ESC guideline, the under-usage of clopidogrel, GP IIb/IIIa inhibitors should be improved. PCI is now taken as a good opportunity to adjust the use of appropriate medication. © Europa Edition. All rights reserved