scholarly journals Obesity, POMC, and POMC-processing enzymes: surprising results from animal models

Endocrinology ◽  
2021 ◽  
Author(s):  
Iris Lindberg ◽  
Lloyd D Fricker
Keyword(s):  
Body Weight ◽  
Animal Models ◽  
Cleavage Site ◽  
Genetic Background ◽  
Rodent Species ◽  
Prohormone Convertases ◽  
Multiple Functions ◽  
Processing Enzymes ◽  
Melanocyte Stimulating Hormone ◽  
Inactivating Mutations

Abstract Peptides derived from proopiomelanocortin (POMC) are well established neuropeptides and peptide hormones that perform multiple functions, including regulation of body weight. In humans and some animals, these peptides include alpha- and beta-melanocyte stimulating hormone (MSH). In certain rodent species, no beta-MSH is produced from POMC due to a change in the cleavage site. Enzymes that convert POMC into MSH include prohormone convertases (PCs), carboxypeptidases (CPs), and peptidyl-alpha-amidating monooxygenase (PAM). Humans and mice with inactivating mutations in either PC1/3 or carboxypeptidase E (CPE) are obese, which was assumed to result from defective processing of POMC into MSH. However, recent studies have shown that selective loss of either PC1/3 or CPE in POMC-expressing cells does not cause obesity. These findings suggest that defects in POMC processing cannot alone account for the obesity observed in global PC1/3 or CPE mutants. We propose that obesity in animals lacking PC1/3 or CPE activity depends, at least in part, on deficient processing of peptides in non-POMC-expressing cells either in brain and/or the periphery. Genetic background may also contribute to the manifestation of obesity.

scholarly journals Sex-Specific Effects of Dietary Methionine Restriction on the Intestinal Microbiome

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 781 ◽  
Author(s):  
Katherine F. Wallis ◽  
Stepan B. Melnyk ◽  
Isabelle R. Miousse
Keyword(s):  
Body Weight ◽  
Animal Models ◽  
Intestinal Microbiota ◽  
Methylation Status ◽  
Intestinal Microbiome ◽  
Protein Methylation ◽  
Restricted Diet ◽  
Male And Female ◽  
Specific Effects ◽  
Methionine Restriction

Dietary methionine restriction is associated with improved health outcomes and an increase in lifespan in animal models. We have previously shown that an increase in dietary methionine induces alteration in the intestinal microbiome. The composition of the intestinal microbiota is a determinant of health and we, therefore, hypothesized that dietary methionine restriction would also induce changes in the murine microbiome. After one month on a methionine-restricted diet, five-month-old male and female C57BL/6 mice had decreased levels of serum methionine, without changes in body weight. We identified a decrease in the hepatic methylation status of animals fed a methionine-restricted diet compared to controls. This decrease was not associated with changes in DNA or protein methylation in the liver. In males, we saw an increase in families Bacteroidaceae and Verrucoccaceae (mostly A. mucinophila) and a decrease in Rumminococcaceae in animals fed a methionine-restricted diet compared to controls. In females, Bacteroidales family S24-7 was increased two-fold, while families Bacteroidaceae, Verrucoccaceae, Rumminococcaceae, and Rikenellaceae were decreased compared to controls. In summary, feeding a methionine-restricted diet for one month was associated with significant and sex-specific changes in the intestinal microbiome.

scholarly journals Activation of the Kexin from Schizosaccharomyces pombeRequires Internal Cleavage of Its Initially Cleaved Prosequence

1998 ◽  
Vol 18 (1) ◽  
pp. 400-408 ◽  
Author(s):  
Dale Powner ◽  
John Davey
Keyword(s):  
Cleavage Site ◽  
Secretory Pathway ◽  
Catalytic Domain ◽  
Activation Process ◽  
Processing Enzymes ◽  
Free Translation ◽  
A Cell ◽  
Internal Site ◽  
Primary Cleavage ◽  
Full Activation

ABSTRACT Members of the kexin family of processing enzymes are responsible for the cleavage of many proproteins during their transport through the secretory pathway. The enzymes themselves are made as inactive precursors, and we investigated the activation process by studying the maturation of Krp1, a kexin from the fission yeastSchizosaccharomyces pombe. Using a cell-free translation-translocation system prepared from Xenopuseggs, we found that Krp1 is made as a preproprotein that loses the presequence during translocation into the endoplasmic reticulum. The prosequence is also rapidly cleaved in a reaction that is autocatalytic and probably intramolecular and is inhibited by disruption of the P domain. Prosequence cleavage normally occurs at Arg-Tyr-Lys-Arg102↓ (primary cleavage site) but can occur at Lys-Arg82 (internal cleavage site) and/or Trp-Arg99 when the basic residues are removed from the primary site. Cleavage of the prosequence is necessary but not sufficient for activation, and Krp1 is initially unable to process substrates presented in trans. Full activation is achieved after further incubation in the extract and is coincident with the addition of O-linked sugars. O glycosylation is not, however, essential for activity, and the crucial event appears to be cleavage of the initially cleaved prosequence at the internal site. Our results are consistent with a model in which the cleaved prosequence remains noncovalently associated with the catalytic domain and acts as an autoinhibitor of the enzyme. Inhibition is then relieved by a second (internal) cleavage of the inhibitory prosequence. Further support for this model is provided by our finding that overexpression of a Krp1 prosequence lacking a cleavable internal site dramatically reduced the growth rate of otherwise wild-type S. pombecells, an effect that was not seen after overexpression of the normal, internally cleavable, prosequence or prosequences that lack the Lys-Arg102 residues.

Abstract 228: Alterations of Cardiac Morphology and Function Caused by Cardio-Thoracic Surgery in Small Animal Models of Heart Disease

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Peter Nordbeck ◽  
Leoni Bönhof ◽  
Karl-Heinz Hiller ◽  
Sabine Voll ◽  
Paula Arias ◽  
...  
Keyword(s):  
Body Weight ◽  
Heart Disease ◽  
Animal Models ◽  
Right Ventricular ◽  
Small Animal ◽  
Cardiac Morphology ◽  
Small Animal Models ◽  
And Function

Background: Surgical procedures in small animal models of heart disease, such as artificial ligation of the coronary arteries for experimental myocardial infarction, can evoke alterations in cardiac morphology and function. Such alterations might induce artificial early or long term effects in vivo that might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies in small animal models of heart disease. Methods: Female Wistar rats were matched for weight and distributed to sham left coronary artery ligation or untreated control. Cardiac parameters were then investigated in vivo by high-field MRI over time after the surgical procedure, determining left and right ventricular morphology and function. Additionally, the time course of several metabolic and inflammatory blood parameters was determined. Results: Rats after sham surgery showed a lower body weight for up to 8 weeks after the intervention compared to healthy controls. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in the sham operated rats compared to the controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed prolonged metabolic and inflammatory changes after surgery not related to cardiac disease. Conclusion: There is a small distinct impact of cardio-thoracic surgical procedures on the global integrity of the organism, which in the long term also includes circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective studies and transferring the findings to conditions in patients.

scholarly journals Efficacy of Nitazoxanide againstCryptosporidium parvum in Cell Culture and in Animal Models

1998 ◽  
Vol 42 (8) ◽  
pp. 1959-1965 ◽  
Author(s):  
Cynthia M. Theodos ◽  
Jeffrey K. Griffiths ◽  
Jennifer D’Onfro ◽  
Alexandra Fairfield ◽  
Saul Tzipori
Keyword(s):  
Cell Culture ◽  
Clinical Trials ◽  
Body Weight ◽  
Animal Models ◽  
Cryptosporidium Parvum ◽  
Combined Treatment ◽  
Parasite Burden ◽  
Parasite Growth ◽  
Gnotobiotic Piglet

ABSTRACT Nitazoxanide (NTZ), a drug currently being tested in human clinical trials for efficacy against chronic cryptosporidiosis, was assessed in cell culture and in two animal models. The inhibitory activity of NTZ was compared with that of paromomycin (PRM), a drug that is partially effective against Cryptosporidium parvum. A concentration of 10 μg of NTZ/ml (32 μM) consistently reduced parasite growth in cell culture by more than 90% with little evidence of drug-associated cytotoxicity, in contrast to an 80% reduction produced by PRM at 2,000 μg/ml (3.2 mM). In contrast to its efficacy in vitro, NTZ at either 100 or 200 mg/kg of body weight/day for 10 days was ineffective at reducing the parasite burden in C. parvum-infected, anti-gamma-interferon-conditioned SCID mice. Combined treatment with NTZ and PRM was no more effective than treatment with PRM alone. Finally, NTZ was partially effective at reducing the parasite burden in a gnotobiotic piglet diarrhea model when given orally for 11 days at 250 mg/kg/day but not at 125 mg/kg/day. However, the higher dose of NTZ induced a drug-related diarrhea in piglets that might have influenced its therapeutic efficacy. As we have previously reported, PRM was effective at markedly reducing the parasite burden in piglets at a dosage of 500 mg/kg/day. Our results indicate that of all of the models tested, the piglet diarrhea model most closely mimics the partial response to NTZ treatment reported to occur in patients with chronic cryptosporidiosis.

scholarly journals Long-Term Oral Administration ofCapsicum baccatumExtracts Does Not Alter Behavioral, Hematological, and Metabolic Parameters in CF1 Mice

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Aline Rigon Zimmer ◽  
Bianca Leonardi ◽  
Eduardo Rigon Zimmer ◽  
Eduardo Kalinine ◽  
Diogo Onofre de Souza ◽  
...  
Keyword(s):  
Body Weight ◽  
Animal Models ◽  
Oral Administration ◽  
Biochemical Markers ◽  
Antioxidant Properties ◽  
Relative Weight ◽  
Total Phenolic ◽  
Phenolic Contents ◽  
First Time

Our group showed that crude ethanol (CE) and butanol (BUT) extracts ofCapsicum baccatumpresented anti-inflammatory and antioxidant properties. Furthermore, the flavonoid and total phenolic contents were positively correlated with both of these properties observed forC. baccatumextracts. The present study demonstrated that 60 days of oral administration of CE and BUT (200 mg/kg) in mice did not cause significant differences in the following parameters evaluated: hematological profile, body weight and relative weight of visceral organs, systemic lipid profile, glucose homeostasis (GTT), kidney and hepatic biochemical markers, and spontaneous locomotion and anxiety-like behavior. Altogether, these results indicate for the first time that the long-term oral administration ofC. baccatumextracts does not affect specific aspects of CF1 mice physiology, suggesting their safety, building up the venue to test their efficacy in animal models underlying persistent activation of oxidative and inflammatory pathways.

scholarly journals A novel method optimizing the normalization of cardiac parameters in small animal models: the importance of dimensional indexing

2019 ◽  
Vol 316 (6) ◽  
pp. H1552-H1557 ◽  
Author(s):  
Quint A. J. Hagdorn ◽  
Guido P. L. Bossers ◽  
Anne-Marie C. Koop ◽  
Arnold Piek ◽  
Tim R. Eijgenraam ◽  
...  
Keyword(s):  
Body Weight ◽  
Animal Models ◽  
Animal Experiments ◽  
Three Dimensional ◽  
Small Animal ◽  
Left Ventricular ◽  
Heart Weight ◽  
Small Animal Models ◽  
Rats And Mice ◽  
Tibia Length

For indexing cardiac measures in small animal models, tibia length (TL) is a recommended surrogate for body weight (BW) that aims to avoid biases because of disease-induced BW changes. However, we question if indexing by TL is mathematically correct. This study aimed to investigate the relation between TL and BW, heart weight, ventricular weights, and left ventricular diameter to optimize the current common practice of indexing cardiac parameters in small animal models. In 29 healthy Wistar rats (age 5–34 wk) and 116 healthy Black 6 mice (age 3–17 wk), BW appeared to scale nonlinearly to TL1 but linearly to TL3. Formulas for indexing cardiac weights were derived. To illustrate the effects of indexing, cardiac weights between the 50% with highest BW and the 50% with lowest BW were compared. The nonindexed cardiac weights differed significantly between groups, as could be expected ( P < 0.001). However, after indexing by TL1, indexed cardiac weights remained significantly different between groups ( P < 0.001). With the derived formulas for indexing, indexed cardiac weights were similar between groups. In healthy rats and mice, BW and heart weights scale linearly to TL3. This indicates that not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept in which cardiac parameters should not all be indexed to the same measure but one-dimensional measures to BW1/3 or TL1, two-dimensional measures to BW2/3 or TL2, and three-dimensional measures to BW or TL3. NEW & NOTEWORTHY In healthy rats and mice, body weight (BW) scales linearly to tibia length (TL) to the power of three (TL3). This indicates that for indexing cardiac parameters, not TL1 but TL3 is the optimal surrogate for BW. New formulas for indexing heart weight and isolated ventricular weights are provided, and we propose a concept of dimensionally consistent indexing. This concept is proposed to be widely applied in small animal experiments.

1272Effect of age, genetic background and experimental conditions on left atrial monophasic action potential duration, effective refractory period and activation time in Langendorff-perfused murine hearts

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
J Obergassel ◽  
S N Kabir ◽  
M O"reilly ◽  
L C Sommerfeld ◽  
C O"shea ◽  
...  
Keyword(s):  
Body Weight ◽  
Action Potential ◽  
Genetic Background ◽  
Left Atrial ◽  
Coronary Flow ◽  
Weight Ratio ◽  
Monophasic Action Potential ◽  
Heart Weight ◽  
Body Weight Ratio ◽  
Experimental Conditions

Abstract Funding Acknowledgements Supported by EU [CATCH ME] 633196, British Heart Foundation FS/13/43/30324, AA/18/2/34218 LF, PK, DFG FA413 LF, Studienstiftung to JO. Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The range of normal values for left atrial action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) is not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify factors that influence these electrophysiological parameters in wildtype (WT) mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analyzed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6 ± 0.25 months, range 2.47-17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1D). LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Age effects were compared in groups. Atrial ERP was significantly longer in mice ≤ 3 months compared to all older mice. Atrial ERP was also significantly prolonged (+ 3.4ms, + 13.5%) in female mice compared to males (Figure 1B). Conclusion This dataset summarizes left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We confirm that cycle length, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Abstract Figure 1

scholarly journals Effect of mushrooms on obesity in animal models: study protocol for a systematic review and meta-analysis

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Denise Grotto ◽  
Isabella Ferreira Camargo ◽  
Katia Kodaira ◽  
Lauren Giustti Mazzei ◽  
Juliana Castro ◽  
...  
Keyword(s):  
Systematic Review ◽  
Weight Loss ◽  
Body Weight ◽  
Animal Models ◽  
Meta Analysis ◽  
Experimental Studies ◽  
Body Weight Loss ◽  
Preclinical Research ◽  
Medicinal Mushrooms ◽  
Aquatic Mammal

Abstract Background Obesity and its consequences are worldwide epidemic problem; therefore, studies with strategies and mechanisms that favor weight loss to improve outcomes in health are necessary. Effects of mushrooms on body weight are uncertain. The aim of this systematic review is to determine the efficacy of mushrooms in weight loss in animal preclinical models. Method This is a systematic review of preclinical studies of animal models of obesity (any type of non-aquatic mammal), which were exposed to edible and medicinal mushrooms orally in comparison with the control. The following databases will be used: MEDLINE (PubMed), Web of Science, BIOSIS, SCOPUS, and gray literature. There will be no restriction of language, date, or publication status. The primary outcome will be body weight loss. And the secondary outcomes include the total amount of food consumed by the animals, analysis of metabolic parameters, inflammatory mediators, mortality for any causes, and any adverse effect reported. A team of reviewers will select, in pairs and independently, the titles and abstracts, extract data from qualifying studies, and assess bias risk (using SYstematic Review Centre for Laboratory animal Experimentation SYRCLE’s risk of bias tool and the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist). The standardized mean difference (SMD) will be calculated to measure treatment effect, with 95% confidence intervals (95% CI). The heterogeneity between-study will be calculated by I2 inconsistency values and Cochran’s Q statistical test, where I2 > 50% and/or p < 0.10 suggest high heterogeneity meta-analyses of random effects will be conducted as possible. Discussion Although many experimental studies about the effects of mushrooms on obesity have already been published, there is still no consensus in the literature. This study will provide evidences of preclinical research on mushrooms and their relation to body weight loss in animal models of obesity, being non-aquatic mammals. Also, this systematic review will show the limitations and strengths of the studies available in the literature, as well as it will to encourage the financing of new studies by public health managers and governmental entities. Systematic review registration PROSPERO (CRD42019125299).

Sign in / Sign up

Export Citation Format

Share Document