Hypothalamic NPY-Y1R Interacts with Gonadal Hormones in Protecting Female Mice against Obesity and Neuroinflammation.

We previously demonstrated that Npy1rrfb mice, which carry the conditional inactivation of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with male mice showing metabolic, hormonal and behavioral effects and females being only marginally affected. Moreover, exposure of Npy1rrfb male mice to a high-fat diet (HFD) increased body weight growth, adipose tissue, blood glucose levels and caloric intake compared to Npy1r2lox male controls. We used conditional knockout Npy1rrfb and Npy1r2lox control mice to examine whether forebrain disruption of the Npy1r gene affects susceptibility to obesity and associated disorders of cycling and ovariectomized (ovx) female mice in a standard diet (SD) regimen or exposed to an HFD for 3 months. The conditional deletion of the Npy1r gene increased body weight and subcutaneous white adipose tissue weight in both SD- and HFD-fed ovx females but not in cycling females. Moreover, compared with ovx control females on the same diet regimen, Npy1rrfb females displayed increased microglia number and activation, increased expression of Neuropeptide Y (NPY)-immunoreactivity (IR) and decreased expression of proopiomelanocortin-IR in the hypothalamic arcuate nucleus (ARC). These results suggest that in the ARC NPY-Y1R reduces the susceptibility to obesity of female mice with low levels of gonadal hormones and that this effect may be mediated via NPY-Y1R ability to protect the brain against neuroinflammation.

Conditional Inactivation of Limbic Neuropeptide Y-1 Receptors Increases Vulnerability to Diet-Induced Obesity in Male Mice.

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1rrfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1rrfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance.

Sex-biased impact of endocrine disrupting chemicals on behavioral development and vulnerability to disease: Of mice and children.

Sex is a fundamental biological characteristic that influences many aspects of an organism's phenotype, including neurobiological functions and behavior as a result of species-specific evolutionary pressures. Sex differences have strong implications for vulnerability to disease and susceptibility to environmental perturbations. Endocrine disrupting chemicals (EDCs) have the potential to interfere with sex hormones functioning and influence development in a sex specific manner. Here we present an updated descriptive review of findings from animal models and human studies regarding the current evidence for altered sex-differences in behavioral development in response to early exposure to EDCs, with a focus on bisphenol A and phthalates. Overall, we show that animal and human studies have a good degree of consistency and that there is strong evidence demonstrating that EDCs exposure during critical periods of development affect sex differences in emotional and cognitive behaviors. Results are more heterogeneous when social, sexual and parental behaviors are considered. In order to pinpoint sex differences in environmentally-driven disease vulnerabilities, researchers need to consider sex-biased developmental effects of EDCs.

Developmental Exposure to a Mixture of Unconventional Oil and Gas Chemicals Increased Risk-Taking Behavior, Activity and Energy Expenditure in Aged Female Mice After a Metabolic Challenge.

Chemicals used in unconventional oil and gas (UOG) operations can act as endocrine disrupting chemicals and metabolic disruptors. Our lab has reported altered energy expenditure and activity in C57BL/6J mice that were preconceptionally, gestationally, and lactationally exposed via maternal drinking water to a laboratory-created mixture of 23 UOG chemicals from gestational day 1 to postnatal day 21 in 7-month-old female mice with no change in body composition. We hypothesized that allowing the mice to age and exposing them to a high fat, high sugar diet might reveal underlying changes in energy balance. To investigate whether aging and metabolic challenge would exacerbate this phenotype, these mice were aged to 12 months and given a high fat, high sugar diet (HFHSD) challenge. The short 3-day HFHSD challenge increased body weight and fasting blood glucose in all mice. Developmental exposure to the 23 UOG mixture was associated with increased activity and non-resting energy expenditure in the light cycle, increased exploratory behavior in the elevated plus maze test, and decreased sleep in 12 month female mice. Each of these effects was seen in the light cycle when mice are normally less active. Further studies are needed to better understand the behavioral changes observed after developmental exposure to UOG chemicals.

Correction to: Parma consensus statement on metabolic disruptors.

CORRECTION: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice.

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges.

Parma consensus statement on metabolic disruptors.

A multidisciplinary group of experts gathered in Parma Italy for a workshop hosted by the University of Parma, May 16-18, 2014 to address concerns about the potential relationship between environmental metabolic disrupting chemicals, obesity and related metabolic disorders. The objectives of the workshop were to: 1. Review findings related to the role of environmental chemicals, referred to as "metabolic disruptors", in obesity and metabolic syndrome with special attention to recent discoveries from animal model and epidemiology studies; 2. Identify conclusions that could be drawn with confidence from existing animal and human data; 3. Develop predictions based on current data; and 4. Identify critical knowledge gaps and areas of uncertainty. The consensus statements are intended to aid in expanding understanding of the role of metabolic disruptors in the obesity and metabolic disease epidemics, to move the field forward by assessing the current state of the science and to identify research needs on the role of environmental chemical exposures in these diseases. We propose broadening the definition of obesogens to that of metabolic disruptors, to encompass chemicals that play a role in altered susceptibility to obesity, diabetes and related metabolic disorders including metabolic syndrome.