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1.  Maternal exercise improves insulin sensitivity in mature rat offspring 
Purpose
Recent findings have shown the intrauterine environment can negatively influence long-term insulin sensitivity in the offspring. In an attempt to be pro-active, we set out to explore maternal voluntary exercise as an intervention in order to improve offspring insulin sensitivity and glucose homeostasis.
Methods
Female Sprague Dawley rats were split into sedentary and exercise groups with the exercise cohort having voluntary access to a running wheel in the cage prior to and during mating, pregnancy, and nursing. Female offspring were weaned into sedentary cages. Glucose tolerance tests and hyperinsulinemic–euglycemic clamp were performed in adult offspring to evaluate glucose regulation and insulin sensitivity.
Results
Adult female offspring born to exercised dams had enhanced glucose disposal during glucose tolerance testing (P < 0.05) as well as increased glucose infusion rates (P < 0.01) and whole body glucose turnover rates (P < 0.05) during hyperinsulinemic–euglycemic clamp testing compared to offspring from sedentary dams. Offspring from exercised dams also had decreased insulin levels (P < 0.01) and hepatic glucose production (P < 0.05) during the clamp procedure compared to offspring born to sedentary dams. Offspring from exercised dams had increased glucose uptake in skeletal muscle (P < 0.05) and decreased heart glucose uptake (P < 0.01) compared to offspring from sedentary dams in response to insulin infusion during the clamp procedure.
Conclusions
Exercise during pregnancy enhances offspring insulin sensitivity and improves offspring glucose homeostasis. This can decrease offspring susceptibility to insulin resistant related disease such as type 2 diabetes mellitus. Maternal exercise could be an easy, short–term, non–pharmacological method of preventing disease in future generations.
doi:10.1249/MSS.0b013e31827de953
PMCID: PMC3617068  PMID: 23247711
Pregnancy; running; programming; hyperinsulinemic-euglycemic clamp; rat
2.  Mineralocorticoid Receptor Agonists Induce Mouse Aortic Aneurysm Formation and Rupture in the Presence of High Salt 
Objective
Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in heart failure patients. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown.
Approach and Results
We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt or aldosterone and salt induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt or aldosterone and salt induced aortic aneurysm.
Conclusions
The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.
doi:10.1161/ATVBAHA.112.300820
PMCID: PMC3707291  PMID: 23661677
aneurysm; receptors; DOCA; salt; aldosterone
3.  Specific sequences in N termini of apolipoprotein A-IV modulate its anorectic effect 
Physiology & behavior  2013;120:136-142.
Rodent apoA-IV is expressed predominantly in small intestine and also expressed to a small extent in liver and hypothalamus. ApoA-IV has been shown to inhibit food intake in rats when injected centrally. In the current study, we hypothesize that a specific sequence within rat apoA-IV is responsible for mediating the anorectic effect. We use a bacterial expression system to generate truncation mutants (Δ249–371, Δ117–371 and Δ1–61) of rat apoA-IV and assess the ability of various regions of the molecule to inhibit food intake. The results indicate that a responsible sequence exists within the N-terminal 61 amino acids of rat apoA-IV. Synthetic peptides (1–30 EVTSDQVANVMWDYFTQLSNNAKEAVEQLQ, 1–15 EVTSDQVANVMWDYF and 17–30 QLSNNAKEAVEQLQ) were used to specify the region in between residues 1 and 30. A 14-mer peptide (17–30) encompassing this sequence was capable of reducing food intake in a dose-dependent manner whereas a peptide designed on a more C-terminal region (211–232) of apoA-IV (QEKLNHQMEGLAFQMKKNAEEL) failed to exhibit the dose-dependent anorectic effect. The isolation of this sequence provides a valuable tool for future work directed at identifying apoA-IV binding proteins and is a key step for exploring the potential of therapeutic manipulation of food intake via this pathway.
doi:10.1016/j.physbeh.2013.07.010
PMCID: PMC4054808  PMID: 23911688
Apolipoprotein A-IV; Food intake; Truncation mutation
4.  Resveratrol and cancer: focus on in vivo evidence 
Endocrine-Related Cancer  2014;21(3):R209-R225.
Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.
doi:10.1530/ERC-13-0171
PMCID: PMC4013237  PMID: 24500760
colon; mammary gland; obesity; phytoestrogen; prostate
5.  Perinatal Polychlorinated Biphenyl 126 Exposure Alters Offspring Body Composition 
Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants whose exposure levels are associated with various health hazards. We hypothesized that in utero and lactational exposure to PCBs can cause changes in body composition and obesity in a mouse model. Pregnant mice were exposed biweekly to two concentrations of PCB 126 via oral gavage. Maternal PCB exposure did not result in heavier offspring, however, dose-dependent and sex specific changes in body composition were observed. Female offspring displayed the most susceptibility to PCB-induced alterations in body composition, having less percent lean body mass and increased adiposity compared to females born to control dams, and these effects were largely dose-dependent. In contrast to females, and independent of the exposure level of PCB 126, male offspring had reduced lean body mass but no change in fat mass compared to males born to control dams. In conclusion, perinatal PCB 126 exposure did not affect body weight, but rather modulated body composition in a dose-dependent and gender-specific manner.
doi:10.3233/JPB-120072
PMCID: PMC3670830  PMID: 23741283
Programming; obesity; persistent organic pollutants; mice; aryl hydrocarbon receptor; coplanar
7.  The arcuate nucleus and NPY contribute to the antitumorigenic effect of calorie restriction 
Aging cell  2011;10(3):483-492.
Summary
Calorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR's antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate (MSG)-injected mice. While CR was protective in control mice challenged with a two-stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the MSG-treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite-suppressed mice. We propose that some of CR’s beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the arcuate nucleus of the hypothalamus (ARC) are involved in the translation of reduced intake to downstream physiological and functional benefits.
doi:10.1111/j.1474-9726.2011.00693.x
PMCID: PMC3094497  PMID: 21385308
calorie restriction; hypothalamus; MSG; neuroendocrine; NPY; tumorigenesis
8.  Regulation of SIRT6 protein levels by nutrient availability 
Febs Letters  2008;582(5):543-548.
Sirtuins have been shown to regulate life-span in response to nutritional availability. We show here that levels of the mammalian sirtuin, SIRT6, increased upon nutrient deprivation in cultured cells, in mice after fasting, and in rats fed a calorie-restricted diet. The increase in SIRT6 levels is due to stabilization of SIRT6 protein, and not via an increase in SIRT6 transcription. In addition, p53 positively regulates SIRT6 protein levels under standard growth conditions but has no role in the nutrient-dependent regulation of SIRT6. These observations imply that at least two sirtuins are involved in regulation of life-span by nutrient availability.
doi:10.1016/j.febslet.2008.01.019
PMCID: PMC3263697  PMID: 18242175
SIRT6; Sirtuin; Calorie restriction; Nutrient availability
9.  SRT1720 improves survival and healthspan of obese mice 
Scientific Reports  2011;1:70.
Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals.
doi:10.1038/srep00070
PMCID: PMC3216557  PMID: 22355589
10.  Oxidative Stress Accumulates in Adipose Tissue during Aging and Inhibits Adipogenesis 
PLoS ONE  2011;6(4):e18532.
Aging constitutes a major independent risk factor for the development of type 2 diabetes and is accompanied by insulin resistance and adipose tissue dysfunction. One of the most important factors implicitly linked to aging and age-related chronic diseases is the accumulation of oxidative stress. However, the effect of increased oxidative stress on adipose tissue biology remains elusive. In this study, we demonstrate that aging in mice results in a loss of fat mass and the accumulation of oxidative stress in adipose tissue. In vitro, increased oxidative stress through glutathione depletion inhibits preadipocyte differentiation. This inhibition of adipogenesis is at least in part the result of reduced cell proliferation and an inhibition of G1→S-phase transition during the initial mitotic clonal expansion of the adipocyte differentiation process. While phosphorylation of the retinoblastoma protein (Rb) by cyclin/cdk complexes remains unaffected, oxidative stress decreases the expression of S-phase genes downstream of Rb. This silencing of S phase gene expression by increased oxidative stress is mediated through a transcriptional mechanism involving the inhibition of E2F recruitment and transactivation of its target promoters. Collectively, these data demonstrate a previously unrecognized role of oxidative stress in the regulation of adipogenesis which may contribute to age-associated adipose tissue dysfunction.
doi:10.1371/journal.pone.0018532
PMCID: PMC3077372  PMID: 21533223
11.  Anti-oxidative and anti-inflammatory vasoprotective effects of caloric restriction in aging: role of circulating factors and SIRT1 
Endothelial-dysfunction, oxidative stress and inflammation are associated with vascular aging and promote the development of cardiovascular-disease. Caloric restriction (CR) mitigates conditions associated with aging, but its effects on vascular dysfunction during aging remain poorly defined. To determine whether CR exerts vasoprotective effects in aging, aortas of ad libitum (AL) fed young and aged and CR-aged F344 rats were compared. Aging in AL-rats was associated with impaired acetylcholine-induced relaxation, vascular oxidative stress and increased NF-κB-activity. Lifelong CR significantly improved endothelial function, attenuated vascular ROS production, inhibited NF-κB activity and down-regulated inflammatory genes. To elucidate the role of circulating factors in mediation of the vasoprotective effects of CR, we determined whether sera obtained from CR-animals can confer anti-oxidant and anti-inflammatory effects in cultured coronary-arterial endothelial cells (CAECs), mimicking the effects of CR. In CAECs cultured in the presence of AL-serum TNFα elicited oxidative-stress, NF-κB-activation and inflammatory gene expression. By contrast, treatment of CAECs with CR-serum attenuated TNFα-induced ROS generation and prevented NF-κB-activation and induction of inflammatory genes. siRNA-knockdown of SIRT1 mitigated the anti-oxidant and anti-inflammatory effects of CR-serum. CR exerts anti-oxidant and anti-inflammatory vascular effects, which are likely mediated by circulating factors, in part, via a SIRT1-dependent pathway.
doi:10.1016/j.mad.2009.06.004
PMCID: PMC2756526  PMID: 19549533
aging; oxidative stress; inflammation; calorie restriction; resveratrol
12.  JNK1 Phosphorylates SIRT1 and Promotes Its Enzymatic Activity 
PLoS ONE  2009;4(12):e8414.
SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways including the stress protection pathway. SIRT1 deacetylates a number of protein substrates, including histones, FOXOs, PGC-1α, and p53, leading to cellular protection. We identified a functional interaction between cJUN N-terminal kinase (JNK1) and SIRT1 by coimmunoprecipitation of endogenous proteins. The interaction between JNK1 and SIRT1 was identified under conditions of oxidative stress and required activation of JNK1 via phosphorylation. Modulation of SIRT1 activity or protein levels using nicotinamide or RNAi did not modify JNK1 activity as measured by its ability to phosphorylate cJUN. In contrast, human SIRT1 was phosphorylated by JNK1 on three sites: Ser27, Ser47, and Thr530 and this phosphorylation of SIRT1 increased its nuclear localization and enzymatic activity. Surprisingly, JNK1 phosphorylation of SIRT1 showed substrate specificity resulting in deacetylation of histone H3, but not p53. These findings identify a mechanism for regulation of SIRT1 enzymatic activity in response to oxidative stress and shed new light on its role in the stress protection pathway.
doi:10.1371/journal.pone.0008414
PMCID: PMC2793009  PMID: 20027304
13.  Characterization of Apolipoprotein A-IV in Brain Areas Involved in Energy Homeostasis 
Physiology & behavior  2008;95(1-2):161-167.
Apolipoprotein A-IV (apo A-IV) is a satiation protein synthesized in the small intestine and hypothalamus. To further understand its anorectic mechanisms, we used immunohistochemical techniques to characterize the distribution of apo A-IV in brain areas involved in energy homeostasis. Dense apo A-IV staining was detected in the arcuate (ARC) and ventromedial hypothalamic nuclei with less staining in cells in the paraventricular and dorsomedial nuclei. In the brainstem, apo A-IV staining was found in the nucleus of the solitary tract. Double staining immunohistochemistry revealed co-existence of apo A-IV with Neuronal Nuclei (a neuronal marker), but less with glial fibrillary acidic protein (a glial marker), in ARC, suggesting that apo A-IV is largely present in neurons. In the ARC, apo A-IV was co-localized with pro-opiomelanocortin (POMC), and apo A-IV administration stimulated hypothalamic POMC gene expression, suggesting that the brain apo A-IV system suppresses food intake by stimulating the ARC POMC system. To ascertain whether the apo A-IV detected in the brain is derived from the circulation, 125I-labeled recombinant rat apo A-IV was intravenously injected into mice. No increase of radioactive apo A-IV was found in the brain, consistent with a lack of uptake of co-injected 99mTc-labeled albumin, indicating that circulating apo A-IV is unable to cross the blood brain barrier. These data collectively support the hypothesis that apo A-IV, produced by neuronal cells, may exert its anorectic action by interacting with catabolic regulatory neuropeptides.
doi:10.1016/j.physbeh.2008.05.022
PMCID: PMC2574991  PMID: 18577393
Apolipoproteins; immunohistochemistry; blood brain barrier; neuropeptides
14.  Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan 
Cell metabolism  2008;8(2):157-168.
SUMMARY
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.
doi:10.1016/j.cmet.2008.06.011
PMCID: PMC2538685  PMID: 18599363

Results 1-14 (14)