bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Breeding and Exercise Affect Midbrain and PAG Volume
Authors: Lee Daisy C. , Ezzat Raymond Z. , Thompson Zoe , Schmill Margaret P. , Garland Theodore 
Published: June 2021

Inter‐specific comparative studies have shown that the size of brain structures is often correlated with behavioral propensities or capabilities. Life experiences can contribute to variation in brain‐behavior associations. For example, studies of rodents and humans have shown that environmental enrichment, exercise, and even video games can change the volume of structures within the brain, in as little as 7 days in rodents. More generally, exercise can favorably influence the brain by facilitating different neuroadaptive and neuroprotective processes that cause regions of the brain to change in size. One important region potentially influenced by exercise is the midbrain, which serves key functions in both movement and reward. Within the midbrain, an area of particular interest is the periaqueductal gray (PAG), which functions in suppressing pain and influences anxiety and fear. Another midbrain region, the red nucleus, is involved in limb motor coordination and is the site of origin for dopaminergic neurons. We investigated whether selective breeding for high voluntary exercise and/or wheel access had any significant impact on these regions. We studied 8 lines of mice: 4 selectively‐bred high runner (HR) lines and 4 non‐selected control (C) lines. 50 HR mice and 50 C mice were separated into two groups: wheel access or no wheel access for 10 weeks, beginning at weaning. After the 10 weeks, brains were dissected, sliced at 40 μm, Nissl stained, and photographed. These photographs were traced using ImageJ software to calculate the area, cell quantity, and region volume. Results from analysis of the whole midbrain volume indicate that it was not affected by wheel access but is larger in HR mice, the latter result confirming results of a previous study that used ex vivo magnetic resonance imaging of whole brains. Thus, under these conditions, a genetic history of selective breeding for high voluntary wheel running plays a greater role in affecting midbrain volume than does chronic physical exercise. Linetype and wheel access had an interactive effect on PAG volume: wheel access increased volume in C mice, but decreased it in HR mice, with no main effect of either linetype or wheel access. This result indicates an interesting relationship between selective breeding and exercise that may have implications for the modulation of pain and anxiety. Analysis of the red nucleus is in progress. Previous studies have shown that HR mice respond differently to dopamine‐targeting drugs; therefore, we hypothesize that HR mice may have evolved structural changes in this region.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Activation of μ‐opioid receptors in the rostral ventrolateral medulla blocks the sympathetic counter‐regulatory response to glucoprivation
Authors: Kakall Zohra M. , Farnham Melissa MJ. , Pilowsky Paul M. 
Published: June 2021

Intensive insulin therapy is the gold standard for managing serum glucose levels in patients with insulin‐deficient diabetes mellitus. Hypoglycaemia‐associated autonomic failure (HAAF) is a clinical syndrome characterised by the absence of a glucose counter‐regulatory response to hypoglycaemia or glucoprivation. The precise physiologic mechanisms underlying HAAF remain unknown. Recent data from human studies suggests activation of the endogenous opioid system during antecedent hypoglycaemia may contribute to unawareness of hypoglycaemia.Here, we aimed to determine whether or not activation of rostral ventrolateral medullary (RVLM) μ‐opioid receptors results in downstream sympathoinhibition, resulting in attenuated glucose production, and an impaired counter‐regulatory response following glucoprivation. Experiments were performed in sodium pentobarbital anaesthetised (65 mg/kg) male Sprague‐Dawley rats (250–350g).Bilateral activation of RVLM μ‐opioid receptors with DAMGO (8 mM, 50 nl) caused depression of adrenal sympathetic nerve activity (ASNA), that lasted at least 60 minutes (Δ−56.9 ± 9.8% vs saline: Δ1.7 ± 4.4%, P<0.05). In parallel, blood glucose levels were also reduced (Δ−0.8 ± 0.2 mM vs saline: Δ0.2 ± 0.3 mM, P<0.05). The counter‐regulatory response to glucoprivation (measured by ASNA efferent activity) induced by 2‐deoxyglucose was completely attenuated 60 minutes following DAMGO microinjections (Δ−4.4 ± 0.7% vs saline+2‐DG: Δ59.6 ± 8.0%, P<0.05). Bilateral μ‐opioid receptor activation also caused a significant decrease in mean arterial pressure (Δ−28.7 ± 6.1 mmHg vs saline: Δ−9.9 ± 7.3 mmHg, P<0.05) and heart rate (Δ−40.4 ± 14.9 bpm vs saline: Δ−11.1 ± 9.7 bpm, P<0.05).In conclusion, activation of RVLM μ‐opioid receptors reproduces features of HAAF (attenuated neural efferent response to glucoprivation). The mechanism underlying HAAF may include activation of RVLM μ‐opioid receptors to facilitate sympathoinhibition. Coupled with this sympathoinhibition, the reduced blood glucose levels may contribute to HAAF by increasing the threshold to elicit counter‐regulatory response.Support or Funding InformationNational Health and Medical Research Council of Australia, The University of Sydney, The Heart Research InstituteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evolutionarily‐Conserved Mechanisms of Nutrient Acquisition in the Primordial Vertebrate, the Pacific Hagfish
Authors: Weinrauch Alyssa , Glover Chris , Blewett Tamzin , Clifford Alexander , Goss Greg 
Published: June 2021

Hagfish occupy the basal position of vertebrate phylogeny and are thus of interest for studies examining the evolution of vertebrate traits. Despite a morphologically basic digestive tract, the carnivorous hagfish can rapidly and effectively acquire nutrients from which they can persist off of for upwards of 11 months. Previous studies indicate that hagfish preferentially utilize carbohydrates and transition into fat‐fuelled energy sources as fasting progresses, yet few studies examine the mechanisms by which hagfish acquire nutrients. The aim of the present study was to examine and characterize the mechanisms of nutrient acquisition in the hindgut of the Pacific hagfish (Eptatretus stoutii), focusing on one molecule from each category of macronutrients: carbohydrates (glucose), fats (oleic acid) and proteins (alanyl‐alanine). Radiotracer fluxes across intestinal tissue demonstrated concentration‐dependent uptake indicative of regulated transport, for glucose (Km 0.37 mM, Jmax 8.48 nmol/cm2/h), oleic acid (Km 55 μM, Jmax 1131 pmol/cm2/h) and alanyl‐alanine (Km 1071 μM, Jmax 70 nmol/cm2/h). Pharmacological inhibition of glucose transporters (34% decrease with 200 μM cytochalasin‐b) and sodium‐glucose linked transporters (52–83% decrease with 0.0001–1μM phlorizin) suggest mechanisms akin to those in mammals exist in the hagfish hindgut. Further similarity in transport arises in that dipeptide transport is dependent upon sodium‐proton exchange, wherein a reduced sodium environment yields a 48% decrease in transport rates. While specific isoforms of mammalian fatty acid transporters demonstrate insulin sensitivity, hagfish oleic acid transport rates were unaffected by insulin application (average rate 2741± 262 pmol/cm2/h, N=10), despite a noted 71% decrease in plasma glucose concentration. Finally, feeding resulted in significant remodeling of the intestinal mucosa with hindgut absorptive microvilli lengthening by 125% post‐feeding. Correspondingly, an increased rate of transport was noted post‐feeding, with the degree of change dependent upon the substrate type. This study reveals evolutionarily‐conserved mechanisms of nutrient transport over a broad range of substrates in the oldest extant vertebrate and solidifies the applicability of hagfish as a model for studies of early vertebrate evolution.Support or Funding InformationSupported by NSERC Discovery Grants to GG (203736) and CG (251083)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mimicking Human Cmah Inactivation in Mice Increases Running Endurance and Muscle Respiratory Capacity: Implications for the Evolution of genus Homo
Authors: Okerblom Jonathan , Fletes William , Patel Hemal , Schenk Simon , Varki Ajit , Breen Ellen 
Published: June 2021

Compared to other primates, humans are exceptional long‐distance runners, a characteristic that emerged in genus Homo ~2 million years ago (mya), and is generally attributed to anatomical and physiological adaptations such as striding bipedalism and improved heat dissipation. Deletion of a critical exon in the CMAH gene also became fixed 2–3 mya in our ancestral lineage––eliminating CMAH enzymatic activity, which generates the major cell surface sialic acid Neu5Gc, by adding one oxygen atom to the Neu5Ac precursor. Modeling Cmah loss in mice suggested a fertility‐dependent role in emergence of genus Homo and its absence exacerbates human‐like muscular dystrophy phenotypes. Considering these seemingly disparate clues, we posited a role for CMAH loss in the evolution of the hominin endurance phenotype, and evaluated exercise capacity and skeletal muscle oxygen metabolism of Cmah−/− mice. Untrained Cmah−/− mice demonstrated an increased endurance during treadmill running and ran further and faster during 15 days of voluntary running, compared to WT littermates. Time to fatigue during repeated in situ contractions of hind limb muscles was >2‐fold higher in Cmah−/− mice, and a higher capillary‐to‐myofiber ratio was noted. Maximal ex vivo oxidative phosphorylation in muscle fibers was also higher in Cmah−/− mice, and relevant differences in metabolic pathways were noted. Taken together, these data suggest that CMAH loss likely triggered multiple adaptations in the genus Homo that improved skeletal muscle capacity for oxygen delivery and/or utilization––leading to enhanced aerobic capacity, and perhaps providing a selective advantage during the transition towards persistence hunting and other features of Homo.Support or Funding InformationThis work was supported by National Institutes of Health Grants R01GM32373 and R01AR060949This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comprehensive Lipidome and Proteome Analyses to Identify the Inflammatory and Cardiometabolic Fingerprints of Metabolically “Healthy” Versus “Unhealthy” Obese Subjects
Authors: Rajan Meenu Rohini , Sotak Matus , Barrenäs Fredrik , Tong Shen , Borkowski Kamil , Clark Madison , Fiehn Oliver , Newman John , Wallenius Ville , Lange Stephan , Börgeson Emma 
Published: June 2021

Study ObjectiveObesity‐related co‐morbidities pose a serious health care system burden. However, 30% of obese subjects do not present with cardiometabolic complications. Here we perform comprehensive lipidome and proteome analyses to identify inflammatory and cardiometabolic fingerprints that characterize metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) phenotypes.MethodsObese patients (BMI 35–50) donated plasma before undergoing bariatric surgery (clinicaltrial.gov NCT02322073). Patients were classified as MHO (n=5) versus MUO (n=9) according to International Diabetes Federation criteria. Metabolically healthy lean (MHL, n=14) subjects were age‐ and sex‐matched to the obese cohort. Plasma samples were analyzed for 480 protein biomarkers related to inflammation and cardiometabolic processes in a multiplexed array. Samples were also subjected to untargeted lipidomics and targeted oxylipin lipidomics analyses.ResultsGene‐ontology term analysis of the 15 proteins that were significantly decreased/elevated in MHO vs. MUO patients revealed differences in inflammation, metabolism, apoptosis and fibrosis signaling pathways. Furthermore, lipidomics show distinct differences in the lipid profile of MHO and MUO groups. The MUO group displayed increased levels of ceramides, which are implicated in development of insulin resistance and cardiovascular diseases. In contrast, the MHO group exhibited increased levels of anandamide and dihomo‐gamma‐linolenoyl ethanolamide, which are lipids associated with anti‐inflammatory effects. The MUO group also exhibited elevated levels of the cardiometabolic risk factor plasminogen activator inhibitor 1 (PAI‐1). Interestingly, MHO patients presented with increased levels of myeloblastin, which is a serine protease that degrades the PAI‐1–stabilizing protein vitronectin.ConclusionIn conclusion, we have performed a comprehensive lipidomic and proteomic fingerprinting of MHO and MUO subjects. Our analyses reveal clear stratification of the groups and identify lipid mediators that may be of possible therapeutic use as novel interventions for obesity‐associated pathophysiologies. Work is ongoing to explore the molecular mechanism by which the identified proteins and lipid mediators affect cardiometabolic health in obese patients.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of long‐term administration of heat‐processed onion (Allium cepa L.) extract on body weight, visceral fat accumulation, and plasma lipid profile in C57BL/6 mice fed high‐fat diets
Authors: Kang Hanna , Kim Tae‐Yang , Kang Yu‐Ri , Lee Jung‐Yun , Lee Jong‐Wook , Kwon Young‐In 
Published: June 2021

In the previous study, it was found that Amadori rearrangement compounds‐rich heat‐processed onion reduced postprandial blood glucose increase by reducing absorption of glucose through inhibition of sucrase and α‐glucosidase in the small intestinal tract. This reduced absorption of carbohydrate might control body weight gain due to excessive carbohydrates consumption and induce calorie restriction. To investigate and prove the mechanism for the effects of heat‐processed onion extract (ONI_V) on body weight gain, body weight, plasma lipids, body fat mass, and lipid deposition were evaluated and compared to Garcinia cambogia (GC), a known competitive inhibitor of adenosine 5′‐triphosphate (ATP) citrate lyase in C57BL/6 mice model. Male C57BL/6 mice were fed high‐fat diet (60% kcal fat) with 2% ONI_V or GC used as a positive control. Supplementation of ONI_V effectively lowered the body weight gain, visceral fat accumulation, and plasma lipid concentrations. Compared to control, ONI_V increased the number of adipocytes with a smaller diameter. Interestingly, GC treatment did not change either adipocyte numbers or sizes although total weight of visceral fat pads was significantly reduced compared to control. These results indicate that ONI_V and GC may use different mechanisms in inhibiting weight gain under the current experimental conditions used in this study. Furthermore, ONI_V may reduce weight gain using a similar mechanism of anti‐diabetic drugs, thiazolidinediones (TZDs). TZDs in humans and animals have been shown to be a strong ligand for PPARγ, a nuclear transcription factor that enhances adipocyte differentiation, thereby increasing the number of adipocytes with smaller diameters, which is consistent with the effects of ONI_V observed in this study. According to the obtained results, ONI‐V may be effective not only in reducing weight gains, but also in ameliorating some of the metabolic abnormalities including hyperglycemia, oxidative stress, and inflammation associated with weight gain and obesity.Support or Funding InformationThis research was financially supported by the Ministry of Trade, Industry, and Energy (MOTIE), Korea, under the “Regional Specialized Industry Development Program” supervised by the Korea Institute for Advancement of Technology (KIAT).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Functional Impairment in the Corpus Cavernosum Related to a High Fat Diet is Prevented in Toll‐Like Receptor 9 Mutant Mice
Authors: Priviero Fernanda , Calmasini Fabiano Beraldi , McCarthy Cameron , Wenceslau Camilla Ferreira , Antunes Edson , Webb R. Clinton 
Published: June 2021

High fat diets lead to obesity and trigger inflammatory processes which are associated with an increase in the toll‐like receptor 9 (TLR9) signaling pathway in rodent models of non‐alcoholic fatty liver disease. Furthermore, TLR9 signaling plays a role in inflammation regulation of adipose tissue in obesity and metabolic syndrome. Erectile dysfunction (ED) has been correlated with increased inflammatory mediators. Since obesity induces ED, we hypothesize that the impaired function in the corpus cavernosum may be related to an increase in the TLR9 signaling in obese mice. The aim of this study was to evaluate the relaxation and contractile responses of the corpus cavernosum of wild type and TLR9 mutant mice made obese by a high fat diet. Four week old male C57BL/6 and TLR9 mutant mice were fed a high fat diet for 12 weeks. The corpus cavernosum was then mounted on strip myograph for functional evaluation. The contractile and relaxation responses of the corpus cavernosum were evaluated by electrical field stimulation (EFS) and concentration response curves to acetylcholine and phenylephrine. We observed that the relaxation induced by EFS was decreased in wild type obese mice. Deletion of TLR9 prevented this decrease. On the other hand, EFS‐induced contraction at 8 Hz was higher in the corpus cavernosum of obese wild type mice. However, this increase was prevented in TLR9 mutant mice. Furthermore, we observed that the contraction induced by KCl solution (120 mM) and maximal contraction induced by phenylephrine tended to be increased in wild type obese mice only. No changes were observed in the relaxation induced by acetylcholine or in the potency of phenylephrine. In conclusion, these data suggest that TLR9 signaling pathway contributes to erectile dysfunction induced by a high fat diet.Support or Funding InformationNIH: NHLBI001961FAPESP: 2016/20592‐8This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Estrogen Regulates Daily Metabolic Rhythms in Female Mice
Authors: Pendergast Julie S. , McGann Eric G. , Omotola Oluwabukola B. 
Published: June 2021

One‐third of women are obese. Moreover, after menopause, women are increasingly susceptible to obesity comorbidities such as metabolic syndrome and cardiovascular disease, suggesting that estrogen regulates these processes. Shift work, which disrupts circadian rhythms, also increases the risk of obesity and cardiovascular disease in women. In this study, we sought to examine the role of estrogen in regulating daily rhythms associated with the development of obesity. The circadian system controls daily, 24‐h rhythms of behavior and physiology such as the sleep‐wake cycle and the eating rhythm. Our lab previously found that high‐fat diet feeding in male mice, which caused diet‐induced obesity, also disrupted daily rhythms of eating behavior. Male mice typically had robust eating rhythms (eating consolidated during the night) on low‐fat diet (LFD). However, when placed on high‐fat diet (HFD), male mice ate arrhythmically throughout the day. Since previous studies demonstrated that female mice were resistant to diet‐induced obesity, we aimed to determine whether daily metabolic rhythms were also protected from the effects of high‐fat feeding in females. Female C57BL/6J mice (6 weeks old) were ovariectomized and implanted subcutaneously with either a physiological dose of 17β‐estradiol or vehicle (sesame oil) in silastic tubing. At 7 weeks old, females were single‐housed in cages in light‐tight boxes in 12L:12D and fed LFD (10% kcal fat) for 1 week and then HFD (45% kcal fat) for 1 week. Locomotor activity and eating behavior rhythms were continuously measured with infrared sensors and video cameras, respectively. Body weight, food intake, body composition and fasting blood glucose were also measured. Consistent with previous studies, we found that estrogen replacement in ovariectomized mice inhibited HFD‐induced weight gain and adiposity in females. In contrast to males, whose daily rhythm of eating behavior was abrogated during high‐fat feeding, intact females had robust eating behavior rhythms on high‐fat diet. However, after ovariectomy, females had low‐amplitude or arrhythmic eating behavior during high‐fat feeding. The robust daily rhythm of eating behavior was rescued in ovariectomized females with estrogen replacement. Our data show that estrogen confers robust, high‐amplitude eating behavior rhythms during high‐fat feeding in female mice. Notably, these females are also protected from diet‐induced obesity. Together, our data show that regulation of daily metabolic rhythms is markedly different in males and females.Support or Funding InformationThis study was funded by National Institutes of Health grants R03DK098321, P20GM103527, K01DK098321, and P30DK058404, and the University of Kentucky.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sexually Dimorphic Ano2 Expression in Nodose Neurons Determines CCK‐mediated Satiation and Obesity in Heterozygote Male Mice
Authors: Lu Yongjun , Wang Runping , Cicha Michael Z. , Chapleau Mark W. , Abboud Francois M. 
Published: June 2021

The gut peptide cholecystokinin (CCK) contributes to neurally mediated post prandial satiety. Our previous results indicate that high fat diet downregulates the CCK‐sensitive anoctamins (Ano1 and Ano2) that function as calcium‐activated chloride channels (CaCCs) in intestinal vagal afferents. Using Cre‐loxP system, we generated heterozygote (HET) Nav1.8CreAno2fl/WT mice. The endogenous Scn10a promoter drives Cre expression (Nav1.8Cre) selectively in sensory neurons of the nodose, dorsal root and trigeminal ganglia where loxP sites flanked Ano2 exon 12. The male HET mice exhibited an obese phenotype and decreased sensitivity to CCK. To assess the Ano2 expression in HET vs. control (Nav1.8Cre+/−) mice, we first did qRT‐PCR on whole nodose ganglia obtained under anesthesia at 50 weeks of age and found no significant difference in Ano2 mRNA expression (n=4, p>0.05). Ano2 gene may be expressed in non‐neuronal cells of nodose ganglia while Cre expression is selective to neurons. We measured Ano2 mRNAs in nodose neurons cultured for 16–18 hours using single cell qRT‐PCR. Cre positive neurons were 57% (12 of 21) in HET and 74% (29 of 39) in control, indicating a lower efficiency of Cre expression in HET. Correspondingly, Ano2 positive neurons were 48% (10 of 21) and 62% (24 of 39), respectively, indicating the Ano2 allelic deletion in HET. The combined Cre and Ano2 positivity in HET was 29% (6 of 21) vs. 54% (21 of 39) in control. Most importantly the Ano2 mRNA levels in HET neurons (n=10) were 20% of the levels measured in control neurons (n=24, p<0.05) (0.20±0.16 vs. 1.00±0.57). The Ano2 expression in individual nodose neurons of female mice did not show a reduction or even higher in HET (n=27) vs. control (n=28) (2.58±1.48 vs. 1.42±1.27, p>0.05). The female HET mice remained CCK sensitive indicating a sexual dimorphism. We conclude that differences in expression of Ano2 mRNA support our findings of CCK insensitivity and selective obesity in male but not female HET mice (HL14388).Support or Funding InformationNIH HL14388This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.