Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.

[This corrects the article DOI: 10.1371/journal.pone.0266608.].

Addiction prioritizes drug use over innate needs by "hijacking" brain circuits that direct motivation, but how this develops remains unclear. Using whole-brain FOS mapping and in vivo single-neuron calcium imaging, we find that drugs of abuse augment ensemble activity in the nucleus accumbens (NAc) and disorganize overlapping ensemble responses to natural rewards in a cell-type-specific manner. Combining "FOS-Seq", CRISPR-perturbations, and snRNA-seq, we identify Rheb as a shared molecular substrate that regulates cell-type-specific signal transductions in NAc while enabling drugs to suppress natural reward responses. Retrograde circuit mapping pinpoints orbitofrontal cortex which, upon activation, mirrors drug effects on innate needs. These findings deconstruct the dynamic, molecular, and circuit basis of a common reward circuit, wherein drug value is scaled to promote drug-seeking over other, normative goals.

The nucleus accumbens (NAc) is a canonical reward center that regulates feeding and drinking but it is not known whether these behaviors are mediated by same or different neurons. We employed two-photon calcium imaging in awake, behaving mice and found that during the appetitive phase, both hunger and thirst are sensed by a nearly identical population of individual D1 and D2 neurons in the NAc that respond monophasically to food cues in fasted animals and water cues in dehydrated animals. During the consummatory phase, we identified three distinct neuronal clusters that are temporally correlated with action initiation, consumption, and cessation shared by feeding and drinking. These dynamic clusters also show a nearly complete overlap of individual D1 neurons and extensive overlap among D2 neurons. Modulating D1 and D2 neural activities revealed analogous effects on feeding versus drinking behaviors. In aggregate, these data show that a highly overlapping set of D1 and D2 neurons in NAc detect food and water reward and elicit concordant responses to hunger and thirst. These studies establish a general role of this mesolimbic pathway in mediating instinctive behaviors by controlling motivation-associated variables rather than conferring behavioral specificity.

Asthma currently affects more than 339 million people worldwide. In the present preliminary study, we examined the efficacy of a new, inhalable soluble epoxide hydrolase inhibitor (sEHI), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), to attenuate airway inflammation, mucin secretion, and hyper-responsiveness (AHR) in an ovalbumin (OVA)-sensitized murine model. Male BALB/c mice were divided into phosphate-buffered saline (PBS), OVA, and OVA+TPPU (2- or 6-h) exposure groups. On days 0 and 14, the mice were administered PBS or sensitized to OVA in PBS. From days 26–38, seven challenge exposures were performed with 30 min inhalation of filtered air or OVA alone. In the OVA+TPPU groups, a 2- or 6-h TPPU inhalation preceded each 30-min OVA exposure. On day 39, pulmonary function tests (PFTs) were performed, and biological samples were collected. Lung tissues were used to semi-quantitatively evaluate the severity of inflammation and airway constriction and the volume of stored intracellular mucosubstances. Bronchoalveolar lavage (BAL) and blood samples were used to analyze regulatory lipid mediator profiles. Significantly ( p < 0.05) attenuated alveolar, bronchiolar, and pleural inflammation; airway resistance and constriction; mucosubstance volume; and inflammatory lipid mediator levels were observed with OVA+TPPU relative to OVA alone. Cumulative findings indicated TPPU inhalation effectively inhibited inflammation, suppressed AHR, and prevented mucosubstance accumulation in the murine asthmatic model. Future studies should determine the pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (i.e., concentration/dose responses) of inhaled TPPU to explore its potential as an asthma-preventative or -rescue treatment.

Stress has pleiotropic physiologic effects, but the neural circuits linking stress to these responses are not well understood. Here, we describe a novel population of lateral septum neurons expressing neurotensin (LSNts) in mice that are selectively tuned to specific types of stress. LSNts neurons increase their activity during active escape, responding to stress when flight is a viable option, but not when associated with freezing or immobility. Chemogenetic activation of LSNts neurons decreases food intake and body weight, without altering locomotion and anxiety. LSNts neurons co-express several molecules including Glp1r (glucagon-like peptide one receptor) and manipulations of Glp1r signaling in the LS recapitulates the behavioral effects of LSNts activation. Activation of LSNts terminals in the lateral hypothalamus (LH) also decreases food intake. These results show that LSNts neurons are selectively tuned to active escape stress and can reduce food consumption via effects on hypothalamic pathways.

Anorexia Nervosa (AN) is an eating disorder characterized by severe voluntary food restriction1. Stress is known to be a precipitating factor in AN2-5, but the underlying biology linking stress to feeding is not well understood. Here we describe a novel population of stress-responsive neurons in the lateral septum (LS) that express neurotensin (NtsLS) and negatively regulate food intake. We used in vivo fiber photometry and chemo/optogenetics to show that NtsLS neurons are activated by stressful experiences, including active escape in a predator-induced stress paradigm, and specifically decrease food intake in mice, without altering anxiety or locomotor behaviors. These neurons co-express Glp1r, and pharmacologic or genetic manipulations of Glp1r signaling in the LS recapitulate the behavioral findings shown using chemo/optogenetics. Finally, we mapped the outputs of NtsLS neurons and show that activation of NtsLS neuronal terminals in the lateral hypothalamus (LH) also decrease food intake. Taken together, these results show that NTSLS neurons serve as a potential link between stress and anorexia and act by modulating hypothalamic pathways regulating feeding.

Associative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC > hippocampus > septal higher-order circuit that regulates feeding behavior.

With increasing prevalence of early-onset dietary-related diseases in Chinese young people, understanding their motives for food choice and the associated factors is particularly important for further behavioral interventions and food policy decisions. In our study, the food choice questionnaire was adopted, to measure Chinese young people's motives for food choice at an administrative division level in mainland China, and to understand physiological and socio-economic effects on the motives. Compared to ethical concern which was rated least important, sensory appeal, convenience and health were three most important motives ranked by people from Southwest, Southcentral, East, Northeast and North regions, while people from Northwest ranked familiarity as one of their most important motives. Canonical discriminant analysis indicated clear similarities and differences for each region of residence. Analysis of variance showed socio-economic factors played independent roles in food choice motives. However, physiological factors, including body mass index, waist-hip ratio, self and caregivers'health conditions didn't show any independent effects or interactions with socio-economic factors. Cluster analysis indicated that Chinese young people from six experimental regions were mainly grouped in five different motive-oriented clusters. Nearly 40 percent of young people were basically health-oriented food consumers. Together, it would be possible to alter motives for food choice towards health by changing some socio-economic factors, like level of education, monthly expenses. These data are important for further studies on health conditions and eating behaviors of Chinese young people distributed in different areas.

Multiple methods are used to separate high density lipoprotein (HDL) from plasma, including an array of density‐based ultracentrifugation methods, as well as dextran sulfate separation. Ultracentrifugation is the gold standard for lipoprotein isolation and has been used to assess HDL for decades. However, it is thought that the high sheer stress and high salt concentrations in density ultracentrifugation based methods may lead to the loss of specific molecular species in HDL. Moreover, none of the current methods have been optimized and validated for subsequent omic anaylsis. In this study, several HDL separation methods were optimized and validated, including multiple sequential flotation and gradient ultracentrifugation methods, and the dextran sulfate precipitation method. These methods were compared using a standard pooled HDL sample and analyses were completed in triplicate. Lipidomic, proteomic, and glycomic analyses were performed on the separated HDL using mass spectrometry. Our results show that there were differences between methods in the proteome, lipidome, and glycome of HDL indicating that the specific HDL isolation protocol influences the compositional analysis of HDL.

Objective: Enzymatic metabolism of polyunsaturated fatty acids leads to formation of bioactive lipid metabolites (LMs). Previous studies have shown that obesity leads to deregulation of LMs in adipose tissues. However, most previous studies have focused on a single or limited number of LMs, and few systematical analyses have been carried out.Methods: A LC-MS/MS-based lipidomics approach was used, which can analyze >100 LMs produced by cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) enzymes, to analyze the profile of LMs in high-fat diet-induced obesity in mice.Results: LC-MS/MS showed that high-fat feeding significantly modulated profiles of LMs in adipose tissues. Among the three major polyunsaturated fatty acid metabolizing pathways (cyclooxygenase, lipoxygenase, and CYP), CYP-derived fatty acid epoxides were the most dramatically altered LMs. Almost all types of fatty acid epoxides were reduced by 70% to 90% in adipose tissues of high-fat diet-fed mice. Consistent with the reduced levels of fatty acid epoxides, the gene expression of several CYP epoxygenases, including Cyp2j5, Cyp2j6, and Cyp2c44, was significantly reduced in adipose tissues of high-fat diet-fed mice.Conclusions: Results show that CYP-derived fatty acid epoxides are the most responsive LMs in high-fat diet-induced obesity, suggesting that these LMs could play critical roles in obesity.