bluuebunny/crossref_metadata_2025_split huggingface dataset:
High Casein Diet Differentially Alters FGF21 Levels in Plasma and Cardiac Tissue in Rats
Authors: Pettit‐Mee Ryan J , Cunningham Rory P , Sharma Naveen 
Published: November 2023

Fibroblast growth factor‐21 (FGF21) is a cytokine that has been demonstrated to regulate metabolism and have cardioprotective effects in response to obesity and other cardiac stressors. High protein diets have been used to reduce body fat and ameliorate metabolic disorders, however the effects of high protein diets on FGF21‐mediated signaling in cardiac tissue are not well known. We hypothesized that high protein diets will increase circulating levels of FGF21, leading to enhanced FGF21‐mediated signaling in cardiac tissue. Male Sprague‐Dawley rats were placed into one of three dietary groups: 1) control diet (20% of kcal from protein; CON; n=8), 2) high soy protein diet (40% of kcal from soy; SOY; n=8), or high casein protein diet (40% of kcal from casein; CAS; n=8). Food consumption and body mass were recorded weekly. After 15 weeks, blood was collected and hearts were excised after an overnight fast. Western immunoblotting was performed on cardiac homogenates and analyzed for: FGF21, FGF receptor‐1 (FGFR1), phospho‐FGFR1Tyr654, phospho‐ERK1/2Thr202/Tyr204, phospho‐AktSer473, phospho‐AMPKThr172, phospho‐p38 MAPKThr180/Tyr182, and 4‐hydroxynonenal (4‐HNE), a marker of oxidative stress. There was no difference in daily food intake or terminal body mass between dietary groups. Plasma concentrations of FGF21 were significantly (P<0.05) greater for CAS (742.1±149.9 pg/ml) compared to CON (213.6±37.7 pg/ml), determined by ELISA. FGF21 protein levels in the heart were significantly (P<0.05) lower for CAS compared to CON and SOY groups. Phospho‐AktSer473 was significantly (P<0.05) greater in SOY compared to CON and CAS groups. There were no other significant differences between dietary groups for any other analyte measured. These data indicate that high protein diets composed of differing protein sources have non‐uniform effects on plasma and cardiac levels of FGF21. Additionally, 15‐weeks of high protein diet consumption does not appear to alter body mass or FGF21‐mediated signaling in the rat heart.Support or Funding InformationCentral Michigan University Herbert H. and Grace A. Dow College of Health Proffesions, and the Office of Research and Graduate Studies Early Career Award.
Liraglutide Promotes Browning of White Adipose Tissue in Mice with Diet Induced Obesity
Authors: Oliveira Fernanda Cerqueira Barroso , Ribeiro Carolina Martins , Christ Camila Greice , Pereira Sidney Alcântara , Beserra Bruna Teles Soares , da Costa Silva Viana Janice , de Assis Rocha Neves Francisco , Coelho Michella Soares , Amato Angélica Amorim 
Published: November 2023

Liraglutide is a long‐acting glucagon‐like peptide 1 (GLP‐1) receptor agonist used as an anti‐hyperglycemiant agent in type 2 diabetes and recently approved as an anti‐obesity agent. The mechanisms underlying weight loss include delayed gastric emptying and induction of satiety, and there are data indicating it may also result in increased energy expenditure. Beige adipocytes are an inducible cell type in white adipose tissue (WAT), in a process so‐called browning of WAT. Upon appropriate stimuli, beige adipocytes are fully capable of executing thermogenesis.ObjectiveTo investigate the effects of liraglutide on browning of WAT in obese mice.MethodsMale C57Bl/6 mice with obesity induced by high fat diet (HFD) were randomly assigned into four groups and treated with saline (vehicle), the b3‐adrenergic agonist CL316,243, liraglutide or liraglutide and CL316,243. Liraglutide was administered intraperitoneally for 21 days (200 μg/kg, twice daily) and CL316,243 was administered intraperitoneally from day 17 to day 21 (1 mg/kg/d, once daily, for 5 days). Weight gain, energy intake and metabolic efficiency were determined. Two different WAT (inguinal and epidydimal) and the interscapular brown adipose tissue (BAT) depots were excised for determination of adiposity, histological analysis, oxygen consumption rates and relative expression of Ucp‐1 by RT‐qPCR.Results(p<0.05, ~ 5 mice/group): Liraglutide treatment reduced HFD‐induced body weight gain, energy intake, metabolic efficiency, visceral and subcutaneous adiposity (epidydimal and inguinal WAT depots), when compared to saline treatment. BAT mass decreased only in response to treatment with CL316,243, either alone or in combination with liraglutide. In all three adipose tissue depots, liraglutide treatment induced the expression of Ucp‐1 when compared to saline, and this effect was additive to that of treatment with CL316,243. Liraglutide significantly increased oxygen consumption rates in epidydimal WAT and interscapular BAT, compared saline treatment. In addition, in epidydimal WAT, inguinal WAT and interscapular BAT, the effect of liraglutide on oxygen consumption was additive to that of CL316,243 stimulation.ConclusionOur findings suggest that liraglutide treatment induces browning of WAT and increases the thermogenic capacity of both WAT and BAT. In addition, its effects seem additive to those of b3‐adrenergic signalling, a classical pathway of adaptive thermogenesis activation. This suggests that GLP‐1 receptor agonists may result in increased energy expenditure by activating thermogenic adipocytes, in addition to decreasing food intake, and opens new horizons to treat obesity.Support or Funding InformationCNPq/CAPES/FAPDF
Prior Exercise Training Alters the Response of White and Brown Adipose Tissue to Cold Stress
Authors: Knuth Carly M , Peppler Willem T , Trottier Sarah K , Townsend Logan K , Wright David C 
Published: November 2023

Brown adipose tissue is a thermogenic tissue bed that produces heat in conditions of cold environmental temperatures. While possessing much lower oxidative capacity than brown adipose tissue, recent findings have suggested that exercise training can increase the thermogenic capacity of white adipose tissue. What is not known is if exercise training can alter the response of an animal to cold stress. To address this question, male C57BL/6 mice were subject to either exercise training by voluntary wheel running (EX) or a sedentary (SED) intervention for 12 days. EX mice ran approximately 6km/day, which led to decreased body weight and increased glucose tolerance, while maintaining a similar pattern of food intake to SED. Mice were then further divided into groups that would be kept at room temperature (22°C) or a cold challenge of 4°C for 48‐hrs, thus we examined four groups in this study; (i) SED kept at room temperature (SRT), (ii) exercise trained kept at room temperature (EXRT), (iii) SED kept at 4°C (SC), and (iv) EX kept at 4°C (EXC). Rectal temperatures (Tb) of SC and EXC were lower than that of SRT and EXRT, and the initial drop in Tb of EXC was less than that observed in the SC 2‐hours following the start of the cold, however this difference was not maintained throughout the rest of the cold exposure. 48‐hrs of cold exposure led to reductions in body weight and epididymal and subcutaneous adipose tissue mass in the SED but not EX mice. Conversely, interscapular brown adipose tissue mass was increased following cold exposure in previously EX but not SED animals Taken together, our data demonstrates a unique effect of prior exercise on altering the response of adipose tissue to cold stress.Support or Funding InformationD.C.W. is a Tier II Canada Research Chair. This work was funded by an NSERC Discovery Grant to D.C.W.
Effect of Nonylphenol on Adiposity and Glucose Homeostasis in Mice with Diet Induced Obesity
Authors: Ribeiro Carolina Martins , Oliveira Fernanda Cerqueira Barroso , Pereira Sidney Alcântara , de Assis Rocha Neves Francisco , Coelho Michella Soares , Amato Angélica Amorim 
Published: November 2023

Nonylphenol (NP) is the predominant environmental biodegradation product of NP ethoxylates and is widely use in detergents, plastic products and paints. It is an endocrine disrupter found to compete with 17β‐estradiol for the binding site of estrogen receptor, due to their structural similarity. More recently, it was also identified as an environmental obesogenic, both in cell culture and in vivo. Acute exposure to NP has been found to induce the expression of adipogenesis and lipogenesis‐related genes in adipose tissue. Additionally, perinatal exposure to different concentrations of NP has resulted in increased body mass and adiposity in male and female offspring. However, the obesogenic potential of long‐term exposure to NP outside the perinatal period has not been investigated.ObjectiveTo investigate the effects of chronic exposure to NP on body weight, adiposity and glucose homeostasis in female C57BL/6 mice.MethodsFemale C57BL/6 mice were fed a high‐fat diet (HFD, 60% kcal as fat) from the 5th to 20th week of age. The animals were randomly divided into five groups (n=6) and treated with vehicle (drinking water) or NP 0.5 mg/kg/d or 2.5 mg/kg/d for 16 weeks (5th to 20th wk) or for 6 weeks (14th to 20th wk) in drinking water. Weight, weight gain, food and water consumption were measured. Two different white adipose tissue (WAT‐retroperitoneal and perigonadal) and one interscapular brown adipose tissue (BAT) depots were weighed. Glucose homeostasis was assessed by fasting glucose levels, glucose tolerance test (GTT), and insulin tolerance test (ITT).ResultsThere was a slight, but nonsignificant trend towards increased body weight and weight gain in response to NP treatment at doses of 0.5 mg/kg/d for 6 or 16 weeks and 2.5 mg/kg/d for 16 weeks when compared to vehicle. On the other hand, mice treated with NP 2.5 mg/kg/d for 6 weeks showed a trend towards decreased body weight. Treatment with NP did not affect energy intake, but increased water consumption when compared to vehicle. Fasting glucose levels at the 20th week were nonsignificantly decreased by NP treatment (0.5 mg/kg/d, 6 wk). However, there were no changes in glucose tolerance or insulin sensitivity. Visceral WAT, subcutaneous WAT and BAT mass remained unchanged in response to treatment with NF.ConclusionsOur findings suggest long‐term exposure of female mice to environmentally relevant NP concentrations, outside of the developmental period, does not affect glucose homeostasis or adiposity.Support or Funding InformationCNPq/CAPES/FAPDF
The effects of CTRP3 on lipid oxidation in adult mouse primary hepatocytes
Authors: Li Ying , Wright Gary L , Peterson Jonathan M 
Published: November 2023

C1q Tumor Necrosis Factor‐Related Protein (CTRP3) is an adipose tissue‐derived secreted factor, or adipokine, that contributes to the processes of metabolism and inflammation. Our previous work has demonstrated that CTRP3 inhibits hepatic lipid biogenesis, in vivo and in vitro. Additionally, recombinant CTRP3 treatment induced the up‐regulation of lipid oxidation in rat H4IIE hepatoma cell line (a liver‐like cell line). However, CTRP3‐induced increase to lipid utilization in primary hepatocytes has not been examined. Although the H4IIE can provide insight into hepatic metabolism, by design immortalized cell lines function very differently than the tissue from which they were derived. Therefore, we isolated primary hepatocytes from wildtype (WT) and transgenic mice which overexpress CTRP3 (CTRP3 Tg), to test the effects of elevated CTRP3 on hepatocyte metabolism (primary hepatocytes, ex vivo, mirror the physiological metabolism of in vivo hepatocytes). Real‐time oxygen consumption rates (OCR) of hepatocytes were recorded by Extracellular Flux Analyzer. Protein expression was measured by Western Blot. We found that OCR were unchanged between WT and CTRP3 Tg mice under standard conditions, after the addition of 100 μM palmitic acid, however, hepatocytes from CTRP3 Tg mice had a significant ~45% increase in OCR consistent with a shift of respiratory substrate from glucose to fatty acid. Further, primary hepatocytes from CTRP3 Tg mice had a 50% increase in Akt phosphorylation (Ser473) in response to insulin. In conclusion, this study confirmed that CTRP3 increases hepatic lipid oxidation, ex vivo, and has provided more evidence to support that lipid oxidation increased by CTRP3 relies on b‐oxidation of fatty acid in primary hepatocytes.Support or Funding InformationThis research was supported in part National Institute On Alcohol Abuse And Alcoholism of the National Institutes of Health under Award Number R03AA023612 and East Tennessee State University Research Development Committee (E82262). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Cold induced Ucp1 expression in brown and white adipose tissue of WFS1‐deficient mice
Authors: Ehrlich Marite , Ivask Marilin , Kõks Sulev 
Published: November 2023

Ucp1 expression in brown adipose tissue (BAT) is induced by cold temperatures and is fully consistent with temperature adaptation and thermogenesis. Transcription of the Ucp1 gene is increased within minutes of cold exposure. Beige adipocytes are mainly in the subcutaneous white adipose tissues (WAT) and they arise postnatally in response to chronic cold exposure. This process is often referred as the browning of WAT. The aim of this study was to compare the cold induced metabolic and Ucp1 expression differences between WFS1‐deficient mice and their wild‐type littermates.Experiments were performed with 2–3 months old male and female F2 hybrids (129S6/SvEvTac × 129S6/SvEvTac). Five to twelve WFS1‐deficient mice and wild‐type mice were used in the study. Mice were kept at 8–12°C up to 7 days and metabolic effect was measured with calorimetric cages (TSE Phenomaster). Ucp1 expression was measured in BAT and WAT with qPCR (Applied Biosystems).The results of measurements showed that WFS1‐deficient mice have significantly higher energy metabolism and higher Ucp1 expression in BAT and WAT after cold exposure.In conclusion, our results show that WFS1‐deficient mice have a stronger response to cold exposure and upregulation of Ucp1 in BAT and WAT. Thus suggesting that WFS1‐deficient mice have changes in regulation of thermogenesis that should be studied further.Support or Funding InformationThis work was supported by Institutional Research Funding IUT20‐46 of the Estonian Ministry of Education.
Long‐term Western Diet Feeding Causes Severe NASH and Cecal Dysbiosis in Juvenile Ossabaw Swine
Authors: Panasevich Matthew R , Meers Grace M , Linden Melissa A , Ibdah Jamal A , Booth Frank W , Perfield James W , Shankar Kartik , Rector R Scott 
Published: November 2023

Pediatric obesity and nonalcoholic fatty liver disease (NAFLD) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal model. Here we examined the effects of continued western diet (WD)‐feeding on NAFLD and cecal dysbiosis in juvenile Ossabaw swine. Female Ossabaw swine (5 weeks old) were fed WD (43.0% fat; 17.8% high fructose corn syrup; 2% cholesterol) or low‐fat control diet (CON; 10.5% fat) for 16 or 36 wks. We observed progressive obesity, lower physical activity, dyslipidemia, and systemic insulin resistance through 36 wks of WD feeding (P<0.05). In addition, WD‐fed pigs developed a progressive form of severe nonalcoholic steatohepatitis (NASH), with significant hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, fibrosis, and elevated liver enzymes. WD‐fed pigs also had elevated hepatic expression of inflammatory genes TNFα, TGFβ, IL‐1β, TLR4, TLR9, and F4/80 (P<0.05), as well as increased (P<0.05) hepatic protein content of fibrosis marker α‐SMA and JNK1 at 16 and 36 wks. WD feeding also significantly reduced hepatic OXPHOS proteins in complexes I, III and V at 16 and 36 weeks. Assessment of the microbiome in WD‐fed animals for 36 wks revealed dysbiosis showing higher (P<0.05) cecal relative abundance of Proteobacteria, and families and genera within (i.e. Enterobacteriaceae, Succinivibrionaceae, Desulfovrobrionaceae, Succinvibrio, and Desulfovbrio). Furthermore, LPS‐producing Desulfovbrionaceae and Desulfovbrio, were positively correlated with hepatic TLR4 expression (r=0.7997 and r=0.9130, P=0.01, respectively). Consistent with human high fat diet feeding and obesity and suggestive of increased energy harvest, long term WD‐feeding also resulted in an increased (P<0.05) Firmicutes to Bacteroidetes ratio and exhibited a tendency (r=0.6503, P=0.08) to be positively correlated with biochemical hepatic TAG concentrations. The changes observed in the microbiome are consistent with LPS‐induced transcriptional activation of pro‐inflammatory status in the liver and resemble the human NAFLD/NASH phenotype. Overall, WD‐fed Ossabaw swine developed cecal dysbiosis, a pro‐inflammatory signature, and NAFLD progressing to NASH similar to the pediatric/adolescent and young adult populations.Support or Funding InformationThis work was supported by grants from Mizzou Advantage, The Allen Foundation, and partially supported by VA Grant VHA‐CDA2 IK2BX001299.
CTRP3 Alters Lipid Profile in Response to Ethanol Feeding
Authors: DeGroat Ashley R. , Clark William Andrew , Hagood Kendra L. , Peterson Jonathan M. 
Published: November 2023

The overall goal of this study is to evaluate the role of a novel adipose‐tissue derived cytokine, C1q TNF Related Protein 3 (CTRP3), in preventing Alcoholic Fatty Liver Disease (AFLD) and related complications. We have recently identified CTRP3 as a potential therapeutic treatment for Non‐Alcoholic Fatty Liver Disease (NAFLD). AFLD contributes to nearly half of all liver‐related mortalities, yet the effects of CTRP3 on AFLD have not been explored. To determine the impact of CTRP3 on AFLD we fed wildtype (WT) and CTRP3 transgenic (Tg) mice an ethanol diet ad libitum for 10 days followed by a gavage of a single dose of ethanol (5 g kg−1), also known as the chronic plus binge model or “The NIAAA model”. This model mimics the hepatic steatosis and liver injury seen with chronic alcohol consumption. Tg and WT littermates placed on isocaloric control diet (without the addition of ethanol) were used as experimental controls.ResultsEthanol feeding resulted in a significant increase in triglyceride accumulation in both WT and Tg mice, with no difference between WT and Tg mice fed the same diet. However, when the lipid content was examined control fed Tg mice had a higher percentage of linoleic acid (18:2Δ9,12) and a decrease in arachidonic acid (20:4Δ5,8,11,14) compared to WT. Whereas on the ethanol diet Tg mice had a ~45% increase in oleic acid (18:1Δ9) compared to ethanol‐fed WT. There was no difference in oleic acid concentration between control‐fed WT and Tg mice.ConclusionAlthough CTRP3 failed to reduce hepatic triglyceride levels in response to the NIAAA model of AFLD, CTRP3 significantly increased the concentration of the putative anti‐inflammatory and beneficial fatty acid (oleic acid). These findings indicate that although CTRP3 may not prevent alcohol‐induced hepatic steatosis, it may prevent secondary complications associated with AFLD.Support or Funding InformationThis research was supported in part National Institute On Alcohol Abuse And Alcoholism of the National Institutes of Health under Award Number R03AA023612, East Tennessee State University Research Development Committee (E82262)
Mechanisms of amelioration of NASH development by deletion of the orphan nuclear receptor SHP: interaction between bile acid and gut microbiota
Authors: Mifflin Ryan , Kim Chunki , Park Jung Eun , Lee Mikang , Shriver Leah , Barton Hazel , Lee Yoon Kwang 
Published: November 2023

Whole‐body deletion of small heterodimer partner (SHP, NR0B2), an orphan nuclear receptor, protects mice from diet‐induced obesity and hepatic steatosis upon feeding of a western diet (WD). Additionally, a six‐month WD regimen promoted the progression of nonalcoholic steatohepatitis (NASH) in wild type C57BL/6 mice (WT). Interestingly, SHP deletion was also protective in progression of NASH, demonstrated by lower expression of inflammatory and fibrotic genes, reduced oxidative stress, and less macrophage infiltration in the liver of SHP−/− mice. To clarify its role in hepatic fibrosis, mice were challenged with methionine and choline deficient (MCD) diet for four weeks. While WT mice developed fibrosis after the MCD diet regimen, no fibrotic phenotype was evident in SHP−/− mice when analyzed with qPCR and sirus red staining. Importantly, the observed protection against NASH was recapitulated in liver‐specific SHP‐null mice, suggesting that hepatic SHP plays a role in NASH development. Hepatic SHP is a critical component in bile acid (BA) synthesis through direct regulation of Cyp7a1 gene expression, which encodes the rate‐limiting enzyme in BA synthesis. Since a strong interrelationship between BA and the gut bacteria has been suggested, changes in BA composition possibly alters the composition of the gut microbiome, thereby affecting liver physiology significantly in the SHP−/− mice. Therefore, we performed 16s rDNA pyrosequencing using DNA extracted from fecal samples and ran a principal coordinate analysis (PCoA) with the obtained taxonomic composition. Indeed, mice lacking SHP display a distinctly different microbiome from WT mice, characterized by distinct PCoA clustering and a decreased abundance ratio of the Firmicutes phylum compared to the Bacteroidetes phylum. Using fluorescent staining, we found that the deletion of SHP does not result in loss of fecal bacterial abundance when fed WD. To confirm a potential effect of the gut microbiome on the liver phenotype, WT and SHP−/− mice were cohoused and challenged with WD. This cohousing abolished the protective phenotypes against body weight gain, hepatic inflammation and oxidative stress induced by WD feeding but not hepatic steatosis in the SHP−/− mice. In addition, cohousing also eliminated the distinctiveness in taxonomic composition of gut bacteria. These results suggest a relationship between SHP and the gut microbiome in the development of DIO, inflammation, and nonalcoholic steatohepatitis.Support or Funding InformationThis work had been supported by the National Institutes of Health 344 Grant R01DK093774 (to YKL)