bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal Inflammation: A Potential Contributing Mechanism to High Fat Diet‐Induced Neuropathy
Authors: Umbaugh David S , Maciejewski J. Claire , Guilford Brianne L. 
Published: November 2023

Neuropathy, a debilitating complication of diabetes, has primarily been attributed to poor glycemic control, but has recently been associated with obesity and the metabolic syndrome in nondiabetic individuals. A robust body of evidence indicates that a high fat diet can induce signs of neuropathy in mice but the pathogenesis of high fat diet‐induced neuropathy remains unknown.PURPOSETo determine if neuronal inflammation is a potential initiating mechanism for the development of mechanical hypersensitivity and nerve fiber changes (signs of neuropathy) in high fat fed mice.METHODSMale C57Bl/6 mice were randomized to a standard (Std, 15% kcal from fat) or high fat diet (HF, 54% kcal from fat) for 2, 4, or 8 wks (n = 11–12 per group). Lumbar dorsal root ganglia were harvested and inflammatory mediators (IL‐1α, IL‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐10, IL‐12p70, IL‐17, MCP‐1, IFN‐γ, TNF‐α, MIP‐1α, GMCSF, RANTES) were quantified using a Multiplex ELISA and normalized to total protein. Neuropathy was characterized by the von Frey test for mechanical sensitivity at wk 0 and every other week thereafter. Hindpaw foot pad skin was harvested at end study and used to quantify intraepidermal nerve fiber density (IENFD) and a specific population of nociceptive nerve fibers (TrkA) via immunohistochemistry.RESULTSAfter 8 wks, HF had greater bodyweight (33.3 ± 1.0 vs. 26.7 ± 0.5 g, p < 0.001), fasting blood glucose (160.3 ± 9.4 vs. 138.5 ± 3.4 mg/dl, p < 0.05) and insulin (3.58 ± 0.46 vs. 0.82 ± 0.14 μg/L, p < 0.001) compared to Std. IL‐1α and IL‐5 were higher in HF compared to Std after 2 wks and 4 wks, respectively (IL‐1α: 4.8 ± 1.3 vs. 2.9 ± 0.6 pg/mg, p < 0.05; IL‐5: 5.8 ± 0.7 vs. 3.1 ± 0.5 pg/mg, p < 0.05). IENFD and TrkA fiber density were also higher in HF compared to Std after 4 wks (IENFD: 39.4 ± 1.2 vs. 32.2 ± 1.3 fibers/mm, p < 0.001; TrkA: 30.4 ± 1.8 vs. 22.4 ± 1.3 fibers/mm). There were no significant differences in hindpaw sensitivity for Std vs. HF at any time point.CONCLUSIONIncreased neuronal inflammation preceded and accompanied an increase in a specific population of nociceptive nerve fibers (TrkA) in the hindpaw footpads of high fat fed mice. Taken together, these data suggest that a diet high in fat may increase neuronal inflammation and initiate nerve fiber changes responsible for painful neuropathy in nondiabetic and/or diabetic patients.Support or Funding InformationSupported by Southern Illinois University Edwardsville Seed Grants for Transitional and Exploratory Projects
Heart‐Specific Disruption of Bmal1 Leads to Hepatic Insulin Resistance in Mice
Authors: Nakao Tomomi , Kohsaka Akira , Otsuka Tsuyoshi , Le Hue Thi , Thein Zaw Lin , Sato Fuyuki , Ihara Hayato , Muragaki Yasuteru , Maeda Masanobu 
Published: November 2023

Daily balance of glucose metabolism is closely coupled with the function of the circadian clock in mammals. The molecular clock composed of a series of circadian clock genes resides in nearly all cells throughout the body, including cells in both metabolic and non‐metabolic tissues. Disruption of the molecular clock in metabolic tissues such as pancreas was shown to induce glucose intolerance. However, it remains unknown whether the clock in non‐metabolic tissues also plays an important role in maintaining systemic glucose metabolism. By studying mice with heart‐specific deletion of Bmal1, a core circadian clock gene, we demonstrate that clock function in the heart has a great influence on glucose tolerance. Heart‐specific disruption of Bmal1 not only results in a reduction in cardiac function but induces a significant increase in the blood glucose level in an age‐dependent manner. In addition, the insulin tolerance test reveals a decrease in insulin sensitivity in heart‐specific Bmal1 deficient mice, indicating that the increase in the blood glucose level observed in these mice is at least in part due to systemic insulin resistance. Importantly, the levels of mRNA expression of gluconeogenic genes in the liver of heart‐specific Bmal1 deficient animals are not suppressed by systemic administration of insulin, indicating that disruption of the molecular clock in the heart can induce hepatic insulin resistance. Taken together, our results suggest that, in addition to the clock function in major metabolic tissues, the function of the heart clock also has an impact on systemic glucose metabolism by altering hepatic insulin sensitivity.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant Number 25460316 and the Takeda Science Foundation.
The regulation of skeletal muscle insulin‐stimulated signaling by the MEK‐REDD1‐mTOR axis
Authors: Williamson David L , Dungan Cory M 
Published: November 2023

Recent findings in adipocytes suggest that mitogen‐activated protein kinase (MAPK)/extracellular‐regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate‐1 (IRS‐1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild‐type (WT) mice and 2) if rapamycin‐mediated mTOR inhibition is sufficient to improve IRS‐1 tyrosine phosphorylation in REDD1 knockout (KO) mice. REDD1 WT mice were injected with 10mg/kg BW of the MEK1/2 non‐competitive inhibitor, PD184352, 3 hours prior to acute insulin treatment (0.5 IU/kg BW). In separate studies, REDD1 KO mice were injected with 5mg/kg BW of the mTOR inhibitor, rapamycin, 3 hours prior to acute insulin treatment (0.5 IU/kg BW). Following the inhibitor treatment period, markers of insulin signaling activation (IRS‐1 Y1222, MEK1/2 S217/221, ERK1/2 T202/Y204), REDD1, and mTOR signaling activation (S6K1 T389, rpS6 S240/244) were examined in skeletal muscle collected before and after the 10 minute insulin treatment. PD184352 treatment reduced MEK/ERK phosphorylation and REDD1 protein expression, independent of insulin. This reduction in REDD1 protein expression was associated with elevated basal mTORC1 signaling activation and reduced insulin stimulated IRS‐1 phosphorylation. Conversely, rapamycin inhibited S6K1 and rpS6 activation, and significantly improved IRS‐1 and MEK1/2 phosphorylation in KO mice. These data affirm that REDD1 is required for normal insulin‐stimulated signaling, and that a subtle balance exists between MEK1/2, REDD1, and mTOR for the proper regulation of insulin signaling.Support or Funding InformationMark Diamond Foundation
Exercise‐induced Calmodulin dependent protein kinase (CaMK)II activation regulates saturated and unsaturated fatty acids in rat skeletal muscle
Authors: Mukwevho Emmanuel 
Published: November 2023

CaMKII regulates many pathways involved in the regulation of various cellular and molecular mechanisms that result in myriad health benefits. Exercise is a key activator of CaMKII, and shown to improve many functional activities in individuals who exercise compared with those who do not exercise, however the mechanism involved not yet fully elucidated. Fatty acids play crucial role in the pathogenesis of metabolic diseases such as type 2 diabetes, obesity, and metabolic syndromes (MetS) (Haffner et al., 1992; Hanson et al., 2002). Since fatty acid have been implicated in the aetiology of metabolic disease, exercise through its activation of CaMKII can prove to be a vital tool in finding therapeutic modalities for treating of the metabolic syndrome.Lipids were analysed from rats muscle using GC×GC TOFMS. Palmitoleic acid and oleic acid which are monounsaturated fatty acids known to promote insulin sensitivity and improve glycaemic control were investigated. Levels of the exercise group showed ~2.0 fold increase compared with the non‐exercise (control) group. Abolishing CaMKII activity by administration of KN93 significantly decreased exercise‐induced Palmitoleic acid levels. Oleic acid levels of the exercise group were ~ 4.1 folds higher than the non‐exercise group and followed the same pattern as Palmitoleic acid. Lauric acid is a saturated fatty acid, which increases fatty acid needed for better health. The exercise group showed ~ 8.7 fold increase compared with the non‐exercise group of Lauric acid. The exercise + KN93 group significantly reduced induction by ~2.5 fold compared with the exercise group. On the other hand, Myristic acid and palmitic acid which are saturated fatty acids known to increase risk factors of metabolic syndrome. The myristic acid level of the exercise group decreased by ~3.4 fold compared with the control group, whereas the exercise + KN93 group significantly increased by ~4.3 compared with the exercise group.In conclusion, this study shows that CaMKII activation by exercise regulates saturated and unsaturated fatty acids. Therefore, CaMKII can reduce the risk factors of metabolic syndrome and type 2 diabetes.Support or Funding InformationNational Research Foundation of South Africa
Adipokines, Obesity, and Sex: Implications for the Central Control of Cardiovascular Function
Authors: Yosten Gina L. C. 
Published: November 2023

In addition to the storage of lipids, adipose tissue contributes to energy homeostasis by producing multiple adipokines, such as leptin and nesfatin‐1, that regulate food intake and energy expenditure. Plasma levels of these adipokines, which inhibit appetite, increase as a function of adipocyte mass, thus decreasing food intake during times of energy excess. In addition to modulating energy intake, adipokines also impact cardiovascular function, particularly through activation of the sympathetic nervous system. Like leptin, nesfatin‐1 interacts with the central melanocortin system to exert its hypertensive effects. Interestingly, melanocortin neurons are heavily influenced by sex hormones, particularly estrogen, which regulates the responsiveness and activity of these neurons. The functional implication of this observation is that females may respond to the hypertensive effects of adipokines, like nesfatin‐1, differently than males. We previously reported that male rats exhibit significant, dose‐related increases in blood pressure following injection of nesfatin‐1 into the lateral cerebroventricle, and that this effect could be blocked by pretreatment with a melanocortin receptor antagonist. In contrast, the hypertensive effect of nesfatin‐1 in females appears to be dependent upon sex hormone levels, as the response to nesfatin‐1 was significantly attenuated in rats in proestrus and estrus (high estrogen). As with males, the hypertensive effect of nesfatin‐1 in females in diestrus (low estrogen) was blocked by pretreatment with the melanocortin receptor antagonist, SHU9119. However, a completely sexually dimorphic effect was observed with respect to nesfatin‐1's effect on angiotensin II‐stimulated drinking and blood pressure. Whereas nesfatin‐1 significantly inhibited angiotensin II‐induced water drinking in males, nesfatin‐1 enhanced angiotensin II's effects on water drinking and blood pressure in females. We propose that these sex‐related differences in the hypertensive effects of nesfatin‐1 are due to the modulatory activity of estrogen on nesfatin‐1‐responsive melanocortin neurons, and that loss of estrogen, as observed in menopause, will lead to enhanced nesfatin‐1 signaling and hypertension. Future studies investigating the ability of chronically administered nesfatin‐1 to promote hypertension using telemetric monitoring of blood pressure will be necessary to evaluate whether persistently high nesfatin‐1 levels alter cardiovascular function.Support or Funding InformationNational Institutes of Health, HL121456
Functional Innervation of Rat Mesenteric Arteries Is Regulated by Thyroid Hormones
Authors: Ferrer Mercedes , Ruiz Mireya , Alameda M. Teresa , Sagredo Ana , Fernández‐Lamo Iván , Guadaño Ana 
Published: November 2023

Thyroid hormones (THs) have been shown to affect cardiovascular function, and we previously demonstrated the modulatory action of THs on the function of rat aorta through different endothelial factors. On the other hand, innervation regulates the function of mesenteric arteries, which contribute to the control of peripheral vascular resistance. In view of these data, the aim of this study was to investigate whether THs influence the function of adrenergic and nitrergic innervations. For this purpose, endothelium‐denuded mesenteric artery segments from control and thyroidectomized male Wistar rats (4 months‐old) were used to analyze: (i) the contractile response induced by electrical field stimulation (EFS); (ii) the effect of the alpha‐adrenergic receptor antagonist, phentolamine, or the nitric oxide (NO)‐synthase inhibitor, L‐NAME, on the EFS‐induced response; (iii) the vasomotor response induced by noradrenaline (NA) and by the NO donor, sodium nitroprusside (SNP); and (iv) the basal and EFS‐induced NO release. The results showed that hypothyroidism increased the EFS‐ and NA‐induced contraction, while it did not modify the reduced EFS‐induced response after phentolamine incubation. Regarding nitrergic innervation, hypothyroidism reduced the EFS‐induced NO release as well as its vasodilator action, and L‐NAME failed to modify the EFS‐induced contraction. These findings suggest a preventive role of THs on noradrenergic and nitrergic function of rat mesenteric artery.Support or Funding InformationSupportedby grants (to M.F.) from the Fondo de Investigaciones Sanitarias (PI1100406), Comunidadde Madrid (S2013/ABI‐2783, “INSPIRA1‐CM”) and Fondo Europeo de DesarrolloRegional.
AT1 receptor blockade modifies MAPKs expression and attenuates myocardial remodeling in rats subjected to high‐fat diet‐induced obesity
Authors: Oliveira‐Junior Silvio Assis , Carvalho Marianna R , Ota Gabriel E , Morais Camila S , Pagan Luana U , Gomes Mariana J , Martinez Paula F , Fernandes Tiago , Oliveira Edilamar M , Okoshi Marina P , Okoshi Katashi , Campos Dijon H S , Cicogna Antonio C 
Published: November 2023

Although mitogen‐activated protein kinases (MAPKs) are involved in cardiac remodeling in several experimental models, their role is controversial in obesity. This study analyzed MAPKs expression and cardiovascular parameters in rats with diet‐induced obesity treated with angiotensin II type 1 (AT1) receptor blocker.MethodsWistar rats (n=48) were fed a control (2.9kcal/g) or a high‐fat (3.6kcal/g) diet for 20 weeks. After, rats were assigned to four groups: control (C); obese (OB); control‐losartan (LC); and obese‐losartan (LOB). Losartan was administered in drinking water (30mg/kg/day) for four weeks. Angiotensin‐converting enzyme activity (ACE) was determined in serum. Cardiovascular evaluation included systolic blood pressure (SBP), echocardiogram, myocardial morphometric study, myosin heavy chain composition, and myocardial protein levels of extracellular signal‐regulated kinase (ERK1/2) and c‐Jun amino‐terminal kinase (JNK) quantification by Western blot.Resultsmain results are presented in the Table.ConclusionThe angiotensin II blocker losartan attenuates cardiac remodeling and modulates MAPKs expression in rats with high‐fat diet induced‐obesity.Support or Funding InformationFinancial support: CNPq; FUNDECT/MS

Variables
C
OB
LC
LOB

Body adiposity (%)
4.64±0.95
7.62±1.55*
5.14±1.24
7.87±1.69†

ACE (UF×103/min/mg)
447±124
578±171*
577±98*
584±35

SBP (mmHg)
108±15
104±21
88±11*
78±21#

Heart rate (beats/min)
255±28
258±38
256±22
273±36

LV relative thickness
0.317±0.024
0.308±0.021
0.322±0.024
0.320±0.023

LVESd (mm)
4.37±0.51
4.86±0.66*
4.28±0.61
4.54±0.042

Ejection Fraction (%)
0.856±0.039
0.830±0.052*
0.855±0.044
0.835±0.034

CSA (μm2)
115.6±15.2
125.6±29.1
115.5±23.2
114.8±18.2

CIF (%)
1.02±0.36
1.70±0.77*
1.03±0.59
1.23±0.61

β/α‐MyHC
1.05±0.20
1.44±0.61*
1.00±0.25
1.41±0.17†

Total ERK 1/2
1.00±0.09
1.45±0.27*
1.18±0.26
0.91±0.49#

p‐ERK 1/2
1.00±0.60
0.69±0,16
0.82±0.13
0.93±0,93

Total JNK
1.00±0.27
1.01±0.37
0.90±0.22
0.18±0.10#†

p‐JNK
1.00±0.32
0.88±0.28
0.92±0.17
0.22±0.11#†

Values expressed as mean and standard deviation; LV relative thickness: left ventricular (LV) systolic posterior wall thickness‐to‐LV end‐diastolic diameter ratio; LVESd: LV end‐systolic diameter; CSA: cardiomyocyte cross‐sectional area; CIF: collagen interstitial fraction; β/α‐MyHC: ratio between LV β‐ and α‐MyHC isoforms;
p<0.05 vs C;
p<0.05 vs OB;
p<0.05 vs LC;
ANOVA and Tukey's test.
Transcriptional landscape of the major adipose depots during early life reveals unique pathways during development
Authors: Fainberg Hernan , Alhaddad Ahmad , Alagal Reham , Birtwistle Mark , Davies Graeme , Castellanos Marcos , May Sean , Sacks Harold , Budge Helen , Symonds Michael 
Published: November 2023

IntroductionThe anatomical and final functional architecture of each adipose tissue within the body is mainly determined by the pronounced changes in transcriptional processes during early postnatal life. To date this has not been examined using a bioinformatics approach that would be predicted to provide novel insights on fat development. In sheep there is a rapid transition from brown to white adipose tissue over the first month of life coincident with the loss of uncoupling protein 1 and the rapid growth of each fat depot.MethodsTo gain insight into the developmental origins of the molecular changes within fat in early life we conducted a multi‐region transcriptome analysis from five major (epicardial, subcutaneous, perirenal, sternal and omental) adipose depots sampled at 7 and 28 days of age from young sheep (n=6 per group).ResultsBy weighted gene co‐expression network analysis, we found that each developmental stage and fat depot can be segregated into a concise group with a small number of unique functional modules of co‐expressed genes. Each module exhibited temporal and spatial specificity and were associated with distinct biological processes. This indicates a consistent and a sequential order of transcriptional changes in each depot with age. These are indicative of different cellular origins, metabolism, environmental influence and functionality. In particular, we uncovered specific anatomical regional clusters of gene markers which were associated with distinctive cellular progenitor of brown adipocytes that were validated by cross‐age modular preservation. Furthermore, we observed an active repression in gene expression in sternal adipose tissue that appeared to be a depot‐autonomous effect. This could result in slower metabolism and potentially enable brown adipocyte trans‐differentiation.ConclusionsTogether, our results demonstrate that each adipose tissue depot follows an independent path of postnatal, which could be influenced by cell progenitor type as well as the immediate endocrine environment. Finally, we demonstrate that weighted gene co‐expression network analysis provides a valuable resource to dissect gene regulatory mechanisms.Support or Funding InformationThe Cardiometabolic Disease Research Foundation, Los Angeles, USA.
Brown Adipose Tissue Promotes Healthful Aging
Authors: Guers John J , Zhang Jie , Yoon Seonghun , Vatner Dorothy E , Vatne Stephen F 
Published: November 2023

Brown adipose tissue (BAT) increases thermogenesis and metabolism and protects against the cold. The mouse model of Receptor for G Protein Signaling 14 (RGS14) knockout (KO) has increased BAT, as assessed by a greater BAT mass and brown adipocyte size than wild type littermates and lives 17% longer than wild type (WT) littermates, and is not only protected against the cold, but has improved glucose tolerance and exercise capacity. Thermogenic function was improved in RGS14 KO as reflected by a lower reduction, <0.05, in basal body temperature in response to a cold environment (4° C) in RGS14 KO (−3.0 ± 0.5%) than WT (−7.1 ± 0.4%). Twenty‐four hour oxygen consumption, measured by indirect calorimetry, was greater in RGS14 KO (87 ± 3.2 ml/kg/min), than WT mice (76 ± 3.2 ml/kg/min; p <0.05). Maximal treadmill exercise capacity, measured as distance, was greater in RGS14 KO mice (814 ± 64 m) than their WT littermates (597 ± 24 m; p<0.05). Glucose tolerance, as assessed by the area under the curve in a glucose tolerance test in response to glucose load, was also protected in RGS14 KO mice (7,376 ± 712) compared to their WT littermates (AUC: 10,907 ± 1208; p <0.05). The goal of this investigation was to determine if BAT could be the mechanism mediating these salutary effects. Accordingly, we transplanted BAT from RGS14 KO to their WT littermates. Thermogenic function was improved in BAT recipients (−5.2 ± 0.3 %) when compared to BAT donors (−7.4 ± 0.6 %; p<0.05). Oxygen consumption was greater in BAT recipients (71 ± 5 ml/kg/min) than donor mice (57 ± 4 ml/kg/min; p <0.05). BAT recipient mice ran a greater distance (569 ± 28 m) than BAT donors (424 ± 29 m; p <0.05). BAT recipients also had improved glucose tolerance with lower areas under the glucose curves (7,010 ± 1,193) than their BAT donors (11,013 ± 1685; p <0.05). Thus WT receiving the BAT transplant exhibit improved cold tolerance, glucose tolerance and exercise capacity, similar to what is observed in RGS14 KO with intact BAT, and the RGS14 KO BAT donors lose their protection and have a phenotype similar to WT. These findings suggest that BAT mediates a number of novel mechanisms important for healthful aging.Support or Funding InformationThis work is supported by NIH grant: R01HL124282
Modulation of Hepatic Mineral Concentrations in Bile Acid‐Induced Fatty Liver
Authors: HORI SHOTA , Tanaka Yasutake , Tsuneki Ikuya , Hanai Taketo , Hara Hiroshi , Shimizu Hidehisa , Ishizuka Satoshi 
Published: November 2023

Background & AimsBile acids (BAs) promote lipid absorption as a detergent and a high fat diet consumption promotes its secretion. In our previous study, we found that a diet supplemented with cholic acid (CA), a major primary BA increasing during aging, induces non‐obese fatty liver in rats. The CA‐induced fatty liver seems represent some symptoms at an early stage of fatty liver. On the other hand, hepatic iron is associated with severity of fatty liver disease but little is known about the roles of iron in the early stage of fatty liver development. Thus, we investigated whether distribution of minerals in the body is involved in the CA‐induced fatty liver.MethodsRats were fed diets either with or without CA‐supplementation for 13 weeks. BAs were analyzed in portal vein, liver, and cecum with LC‐MS. Mineral concentrations (Fe, Ca, Mg, Mn, Zn, and Cu) in liver, aorta plasma, renal cortex, and feces were analyzed with ICP‐MS. Several parameters associated with fatty liver were analyzed.ResultsCecal concentration of deoxycholic acid, the secondary BAs from CA, increased significantly in the CA‐fed rats. In the portal plasma, significant increases in CA and taurocholic acid (TCA) levels were observed in the CA‐fed rats. Prominent increases in the concentration of TCA and taurodeoxycholic acid as well as lipid accumulation were found in the liver of the CA‐fed rats. A significant decrease was observed in hepatic Fe in the CA‐fed rats, whereas there were significant increases of Ca, Mg, and Mn in the liver. Principal component analysis indicated hepatic iron concentration was closely associated with the lipid accumulation in the liver. No significant difference was observed in concentration of ferritin in aorta plasma between two groups although Fe concentration in aorta plasma decreased significantly in the CA‐fed rats, suggesting decrease in the amount of functional iron in the CA‐fed rats.ConclusionIron deficiency is reported to cause a variety of changes in host energy metabolism such as increases of glucose uptake and lipogenesis as well as decreases of β‐oxidation in the liver. Therefore, the decrease of hepatic functional iron in the CA‐fed rats may be involved in the development of the lipid accumulation.