Food is a potent natural reward and food intake is a complex process. Reward and gratification associated with food consumption leads to dopamine (DA) production, which in turn activates reward and pleasure centers in the brain. An individual will repeatedly eat a particular food to experience this positive feeling of gratification. This type of repetitive behavior of food intake leads to the activation of brain reward pathways that eventually overrides other signals of satiety and hunger. Thus, a gratification habit through a favorable food leads to overeating and morbid obesity. Overeating and obesity stems from many biological factors engaging both central and peripheral systems in a bi-directional manner involving mood and emotions. Emotional eating and altered mood can also lead to altered food choice and intake leading to overeating and obesity. Research findings from human and animal studies support a two-way link between three concepts, mood, food, and obesity. The focus of this article is to provide an overview of complex nature of food intake where various biological factors link mood, food intake, and brain signaling that engages both peripheral and central nervous system signaling pathways in a bi-directional manner in obesity.

Myocardial Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in myocardial stress responses are incompletely understood. To address this issue, we sought to determine the transcriptional consequences of myocardial CaMKII inhibition after MI. We performed gene expression profiling in mouse hearts with cardiomyocyte-delimited transgenic expression of either a CaMKII inhibitory peptide (AC3-I) or a scrambled control peptide (AC3-C) following MI. Of the 8,600 mRNAs examined, 156 were substantially modulated by MI, and nearly half of these showed markedly altered responses to MI with CaMKII inhibition. CaMKII inhibition substantially reduced the MI-triggered upregulation of a constellation of proinflammatory genes. We studied 1 of these proinflammatory genes, complement factor B (Cfb), in detail, because complement proteins secreted by cells other than cardiomyocytes can induce sarcolemmal injury during MI. CFB protein expression in cardiomyocytes was triggered by CaMKII activation of the NF-κB pathway during both MI and exposure to bacterial endotoxin. CaMKII inhibition suppressed NF-κB activity in vitro and in vivo and reduced Cfb expression and sarcolemmal injury. The Cfb -/-mice were partially protected from the adverse consequences of MI. Our findings demonstrate what we believe is a novel target for CaMKII in myocardial injury and suggest that CaMKII is broadly important for the genetic effects of MI in cardiomyocytes.

ADAR2 is a double-stranded-RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-selective conversion of adenosine to inosine. Previous studies from our laboratory have demonstrated that ADAR2 can modify its own pre-mRNA to create a proximal 3 splice site containing a noncanonical adenosine-inosine dinucleotide. Alternative splicing to this proximal acceptor adds 47 nucleotides to the mature ADAR2 transcript, thereby resulting in the loss of functional ADAR2 protein expression due to premature translation termination in an alternate reading frame. To examine whether the editing of ADAR2 transcripts represents a negative autoregulatory strategy to modulate ADAR2 protein expression, we have generated genetically modified mice in which the ability of ADAR2 to edit its own pre-mRNA has been selectively ablated by deletion of a critical sequence (editing site complementary sequence [ECS]) required for adenosine-to-inosine conversion. Here we demonstrate that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous ⌬ECS mice and that ADAR2 protein expression is increased in numerous tissues compared to wild-type animals. The observed increases in ADAR2 protein expression correlate with the extent of ADAR2 autoediting observed with wild-type tissues and correspond to increases in the editing of ADAR2 substrates, indicating that ADAR2 autoediting is a key regulator of ADAR2 protein expression and activity in vivo.The conversion of adenosine to inosine (A to I) by RNA editing is a widespread posttranscriptional modification resulting from the hydrolytic deamination of selective adenosine residues that alters the nucleotide sequence of RNA transcripts from that encoded by genomic DNA. The majority of well-characterized A-to-I editing events involve nonsynonymous codon changes in mRNA sequences, resulting in the production of proteins with altered functional properties. In mammals, the most prominent examples of A-to-I editing have been described for transcripts encoding ionotropic glutamate receptor subunits (GluR), a voltage-gated potassium channel subunit (K v 1.1), and the 2C subtype of the serotonin receptor (5-HT 2C R), which lead to the production of channels with altered electrophysiological and ion permeation properties (6,27,37,38,43,54) and receptors with decreased G-protein coupling efficiency (5,10,46). A-to-I modifications have also been described for nontranslated RNA species and noncoding regions of RNA transcripts, suggesting that such RNA modifications may also affect other aspects of RNA function, including splicing, trafficking, translation efficiency, and transcript stability (1,7,35,42,45).The enzymes responsible for the site-specific deamination of A to I in mRNA transcripts are known as adenosine deaminases that act on RNA (ADARs) (2, 3, 34, 53). For mammals, three ADAR proteins (ADAR1, ADAR2, and ADAR3) and their corresponding genes have been identified (12,28,36,44). ADAR1 and ADAR2 have been shown to be ubiquitously expressed (44,50,59) an...

ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the sitespecific conversion of adenosine to inosine. To examine the physiologic consequences resulting from ADAR2 misexpression, we have generated mutant mice expressing either wildtype or deaminase-deficient ADAR2 transgenes under the control of the human cytomegalovirus promoter. Transgenic mice expressing either wild-type or inactive ADAR2 isoforms demonstrated adult onset obesity characterized by hyperglycemia, hyperleptinemia, and increased adiposity. Paired feeding analysis revealed that mutant mice on caloric restriction had a growth rate and body composition indistinguishable from wild-type littermates, indicating that the observed obesity predominantly results from hyperphagia rather than a metabolic derangement. The observation that expression of catalytically inactive ADAR2 also is capable of producing an obese phenotype in mutant animals suggests that ADAR2 may possess additional biological activities beyond those required for the site-selective deamination of adenosine or may interfere with the actions of other double-stranded RNA-specific binding proteins in the cell.The conversion of adenosine to inosine by RNA editing results in subtle alterations in the primary nucleotide sequence of mature mRNAs, thereby producing specific changes in amino acid coding potential that can affect the biological activity of the resulting protein(s) (1). The post-transcriptional conversion of adenosine to inosine is catalyzed by a family of double-stranded RNA (dsRNA) 2 -specific adenosine deaminases referred to as ADARs (adenosine deaminases that act on RNA) (2, 3) that contain variable amino termini, multiple copies of a dsRNA-binding domain (dsRBD) and conserved carboxyl-terminal sequences encoding a catalytic adenosine deaminase domain (3, 4). ADAR2, a member of the ADAR family, has been shown to be involved in the editing of numerous mammalian pre-mRNAs to affect subsequent protein function, including transcripts encoding glutamate-gated ion channels, a voltagegated potassium channel (K v 1.1), and the 2C subtype of serotonin receptor (5-7).Genetically modified mice lacking ADAR2 expression develop progressive seizures and die by postnatal day 21 due to a lack of editing (Q/R site) in transcripts encoding a subunit of the ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid subtype glutamate receptor (GluR-2) (8), demonstrating the critical role that ADAR2 plays in the normal development and function of the central nervous system. Multiple cDNA isoforms of ADAR2 have been identified in rats, mice, and humans resulting from alternative splicing events that affect protein expression and function (9 -11). Use of an alternative 3Ј-splice site near the 5Ј-end of the ADAR2 coding region produces a Ϫ1 frameshift to generate a truncated protein lacking the dsRBDs and catalytic deaminase domain required for editing activity (11). Use of this proximal 3Ј-acceptor is dependent upon the ability of ADAR2 to edit its own...

.-The present study tested the hypotheses that 1) nitric oxide (NO) is involved in attenuated responses to ANG II in female mice, and 2) there is differential expression of neuronal NO synthase (nNOS) in the subfornical organ (SFO) and paraventricular nucleus (PVN) in response to systemic infusions of ANG II in males vs. females. Aortic blood pressure (BP) was measured in conscious mice with telemetry im-), an inhibitor of NOS, was administrated into the lateral cerebral ventricle for 14 days before and during ANG II pump implantation. Central infusion of L-NAME augmented the pressor effects of systemic ANG II in females (⌬21.5 Ϯ 2.2 vs. ⌬9.2 Ϯ 1.5 mmHg) but not in males (⌬29.4 Ϯ 2.5 vs. ⌬30.1 Ϯ 2.5 mmHg). Central administration of, a selective nNOS inhibitor, also significantly potentiated the increase in BP induced by ANG II in females (⌬17.5 Ϯ 3.2 vs. ⌬9.2 Ϯ 1.5 mmHg). In gonadectomized mice, central L-NAME infusion did not affect the pressor response to ANG II in either males or females. Ganglionic blockade after ANG II infusion resulted in a greater reduction in BP in central L-NAME-or L-VNIO-treated females compared with control females. Western blot analysis of nNOS protein expression indicated that levels were ϳ12-fold higher in both the SFO and PVN of intact females compared with those in intact males. Seven days of ANG II treatment resulted in a further increase in nNOS protein expression only in intact females (PVN, to ϳ51-fold). Immunohistochemical studies revealed colocalization of nNOS and estrogen receptors in the SFO and PVN. These results suggest that NO attenuates the increase in BP induced by ANG II through reduced sympathetic outflow in females and that increased nNOS protein expression associated with the presence of female sex hormones plays a protective role against ANG II-induced hypertension in female mice. sex hormone; nitric oxide/nitric oxide synthase; blood pressure NITRIC OXIDE (NO) and angiotensin II (ANG II) are important agents that regulate arterial blood pressure (BP). Vasoconstriction produced by sympathoexcitatory effects contributes to ANG II-induced pressor responses (13, 17). Conversely, NO has a hypotensive action via vasodilation and sympathoinhibition (36, 39). It has been shown that interactions between ANG II and NO occur in a variety of tissues, including the central nervous system (CNS) (40, 58). For example, microinjection of either an NO synthase (NOS) inhibitor or ANG II into the lateral ventricle or the paraventricular nucleus (PVN) increases the discharge of renal sympathetic nerves and elevates arterial BP and heart rate (HR) (25, 28, 52). Central or peripheral blockade of NOS potentiates or prolongs the pressor response to ANG II (9, 31). Conversely, overexpression of neuronal NOS (nNOS) within the PVN by adenoviral gene transfer significantly attenuates ANG II pressor responses (28).There is evidence from human and animal studies that hypertension is delayed and attenuated in females compared with males (11). Previous studies from our laboratory (54) have sh...