Long-Acting and Selective Oxytocin Peptide Analogs Show Antidiabetic and Antiobesity Effects in Male Mice

AbstractOxytocin (OXT) has been shown to suppress appetite, induce weight loss, and improve glycemic control and lipid metabolism in several species, including humans, monkeys, and rodents. However, OXT’s short half-life in circulation and lack of receptor selectivity limit its application and efficacy. In this study, we report an OXT peptide analog (OXTGly) that is potent and selective for the OXT receptor (OXTR). OXT, but not OXTGly, activated vasopressin receptors in vitro and acutely increased blood pressure in vivo when administered IP. OXT suppressed food intake in mice, whereas OXTGly had a moderate effect on food intake when administered IP or intracerebroventricularly. Both OXT (IP) and OXTGly (IP) improved glycemic control in glucose tolerance tests. Additionally, both OXT (IP) and OXTGly (IP) stimulated insulin, glucagon-like peptide 1, and glucagon secretion in mice. We generated lipid-conjugated OXT (acylated-OXT) and OXTGly (acylated-OXTGly) and demonstrated that these molecules have significantly extended half-lives in vivo. Compared with OXT, 2-week treatment of diet-induced obese mice with acylated-OXT [subcutaneous(ly) (SC)] resulted in enhanced body weight reduction, an improved lipid profile, and gene expression changes consistent with increased lipolysis and decreased gluconeogenesis. Treatment with acylated-OXTGly (SC) also resulted in a statistically significant weight loss, albeit to a lesser degree compared with acylated-OXT treatment. In conclusion, we demonstrate that selective activation of the OXTR pathway results in both acute and chronic metabolic benefits, whereas potential activation of vasopressin receptors by nonselective OXT analogs causes physiological stress that contributes to additional weight loss.

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Effect of parenteral nutrition on protein turnover in endotoxaemic rats

Clinical Science ◽

10.1042/cs0760659 ◽

1989 ◽

Vol 76 (6) ◽

pp. 659-666 ◽

Cited By ~ 22

Author(s):

S. A. Ash ◽

G. E. Griffin

Keyword(s):

Skeletal Muscle ◽

Weight Loss ◽

Protein Synthesis ◽

Food Intake ◽

Parenteral Nutrition ◽

Total Parenteral Nutrition ◽

Intravenous Infusion ◽

Protein Turnover

1. Intravenous infusion of endotoxin into rats over 18 h caused a reduction in food intake to 20% of normal levels, weight loss, hypoalbuminaemia and a fall in rates of protein synthesis in vivo in heart and skeletal muscle. 2. Measurements of protein turnover in vitro in skeletal muscle of endotoxaemic animals, showed a 50% fall in protein synthesis rates and a 200% increase in rates of protein degradation. 3. Total parenteral nutrition was only partially able to reverse endotoxin-induced weight loss. Total parenteral nutrition did not reverse endotoxin-induced catabolism in cardiac or skeletal muscle, but was able to reverse the catabolism of protein in skeletal muscle produced by starvation. 4. Endotoxin treatment elevated rates of protein synthesis in vivo in liver. The combination of parenteral nutrition and endotoxaemia further increased the rate of protein synthesis in the liver. Parenteral nutrition did not influence endotoxin-induced hypoalbuminaemia.

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Effects of Bacterial CLPB Protein Fragments on Food Intake and PYY Secretion

Nutrients ◽

10.3390/nu13072223 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2223

Author(s):

Manon Dominique ◽

Nicolas Lucas ◽

Romain Legrand ◽

Illona-Marie Bouleté ◽

Christine Bôle-Feysot ◽

...

Keyword(s):

Food Intake ◽

Peptide Yy ◽

Molecular Mimicry ◽

Potential Effect ◽

In Vivo Studies ◽

Sprague Dawley ◽

E Coli ◽

In Vivo Effects

CLPB (Caseinolytic peptidase B) protein is a conformational mimetic of α-MSH, an anorectic hormone. Previous in vivo studies have already shown the potential effect of CLPB protein on food intake and on the production of peptide YY (PYY) by injection of E. coli wild type (WT) or E. coli ΔClpB. However, until now, no study has shown its direct effect on food intake. Furthermore, this protein can fragment naturally. Therefore, the aim of this study was (i) to evaluate the in vitro effects of CLPB fragments on PYY production; and (ii) to test the in vivo effects of a CLPB fragment sharing molecular mimicry with α-MSH (CLPB25) compared to natural fragments of the CLPB protein (CLPB96). To do that, a primary culture of intestinal mucosal cells from male Sprague–Dawley rats was incubated with proteins extracted from E. coli WT and ΔCLPB after fragmentation with trypsin or after a heat treatment of the CLPB protein. PYY secretion was measured by ELISA. CLPB fragments were analyzed by Western Blot using anti-α-MSH antibodies. In vivo effects of the CLPB protein on food intake were evaluated by intraperitoneal injections in male C57Bl/6 and ob/ob mice using the BioDAQ® system. The natural CLPB96 fragmentation increased PYY production in vitro and significantly decreased cumulative food intake from 2 h in C57Bl/6 and ob/ob mice on the contrary to CLPB25. Therefore, the anorexigenic effect of CLPB is likely the consequence of enhanced PYY secretion.

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Miltefosine Administration in Cats with Refractory Sporotrichosis

Acta Scientiae Veterinariae ◽

10.22456/1679-9216.83639 ◽

2018 ◽

Vol 46 (1) ◽

pp. 7

Author(s):

Francina Dos Santos Silva ◽

Simone Carvalho dos Santos Cunha ◽

Andrea Regina de Souza Baptista ◽

Vivian Dos Santos Baptista ◽

Kássia Valéria Gomes Coelho da Silva ◽

...

Keyword(s):

Weight Loss ◽

Sporothrix Schenckii ◽

Clinical Signs ◽

Public Health Problem ◽

Parasite Load ◽

Small Population ◽

Fungal Culture ◽

Cutaneous Lesions

Background: Sporotrichosis is a zoonosis caused by fungi of the Sporothrix schenckii complex. Cats have important zoonotic potential due to the high parasite load found in the cutaneous lesions. Refractory cases to antifungal therapy are increasing, becoming a public health problem. Miltefosine is a drug with high in vitro activity against Sporothrix brasiliensis. However, this efficacy has not been confirmed in vivo yet and administration has not been studied in the feline species. This study aimed to evaluate the effectiveness and safety of miltefosine administration in cats with resistant sporotrichosis.Materials, Methods & Results: Ten cats with refractory sporotrichosis were included in this study. Inclusion criteria were previous diagnosis for sporotrichosis associated with therapy with oral antifungals (itraconazole and/or potassium iodide) for more than one year, followed by one of these conditions: incomplete clinical remission, worsening of disease during treatment or recurrence after conventional treatment. Cats underwent clinical and dermatological examinations. Data on lifestyle and previous treatments were provided by the owners. Fungal culture and histochemical techniques were performed in all cats before miltefosine treatment. Blood samples were collected before and during the study for laboratory tests, such as blood count, blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT) and alkaline phosphatase, as well as serology for Feline Immunodeficiency (FIV) and Feline Leukemia (FeLV). Miltefosine was prescribed at a dosage of 2 mg/kg orally every 24 h. The animals were monitored by phone during the whole process and reassessed on days 0, 15, 30 and 45 of the treatment. Out of 10 cats, lesions were present on the nose in nine, ears in four, periocular areas in one and limbs in four. One cat received treatment for 45 days, six for 30 days, one for 21 days, one for 15 days and one for 3 days. One cat showed no response to the treatment and nine showed disease progression. Hyporexia and weight loss were the most frequent clinical signs related to miltefosine treatment, followed by sialorrhea, vomiting and diarrhea. Few adverse effects on hematology and biochemistry (mainly renal and hepatic parameters) were observed during the study. Hematocrit decrease was observed in four animals. However, only one cat had hematocrit decrease below normal values (anemia), which was already present before miltefosine administration. Other cats had a decrease of five points. Three cats showed elevation in leucometria and four in plasma protein. In relation to renal and hepatic biochemistry, one animal showed a BUN increase and another one showed a transient increase in ALT. Two animals started the treatment with increased ALT but had no problems during the study and values decreased even during the miltefosine administration.Discussion: Although two cats showed sialorrhea, most owners did not report difficulty in administering the drug orally, representing an advantage of this medication. Weight loss, secondary to gastrointestinal changes, was the most clinically relevant alteration. The most frequent hematological alteration was hematocrit decrease and only the animal that started the study with 20% hematocrit ended the study with anemia. Renal and hepatic parameters were not significant in the cats of this study. Miltefosine did not lead to sporotrichosis remission in this small population of cats, which reveals that, despite its in vitro efficacy against Sporothrix spp., the drug is not effective in vivo in the feline species. Further studies are needed to investigate the efficacy of this drug in a larger number of cats, and possible reasons for its in vivo ineffectiveness.

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Exposure to the Widely Used Pyrethroid Pesticide Deltamethrin, Does Not Exacerbate High Fat Diet Induced Obesity or Insulin Resistance in C57BL/6J Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.090 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A45-A46

Author(s):

Evangelia Evelyn Tsakiridis ◽

Marisa Morrow ◽

Andrea Llanos ◽

Bo Wang ◽

Alison Holloway ◽

...

Keyword(s):

Insulin Resistance ◽

Glycemic Control ◽

Metabolic Diseases ◽

Uncoupling Protein ◽

Diet Induced Obesity ◽

Brown Adipose ◽

Pyrethroid Pesticide ◽

First Time

Abstract Deltamethrin is a commonly used pesticide for the control of mosquito populations. Despite widespread use, the effects of deltamethrin on adiposity and glucose homeostasis have been equivocal with some studies showing increased, decreased and no effect on adiposity and glycemic control. However, no study to date has investigated the effect of deltamethrin in mice housed at thermoneutral temperatures, which is important for modelling metabolic diseases in rodents due to reduced thermal stress and constitutive activation of brown adipose tissue. In the current study we demonstrate for the first time that deltamethrin reduces uncoupling protein-1 expression in brown adipocytes cultured in vitro at concentrations as low as 1pm. Meanwhile, in-vivo deltamethrin does not appear to alter glycemic control or promote adiposity at exposures equivalent to 0.01, 0.1 or 1.0 mg/kg/day. Together, our study demonstrates environmentally relevant exposure to deltamethrin does not exacerbate diet induced obesity or insulin resistance.

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Digestion of timothy silage and hay in reindeer

Rangifer ◽

10.7557/2.18.1.1444 ◽

1998 ◽

Vol 18 (1) ◽

pp. 35

Author(s):

R. Moen ◽

M. A. Olsen ◽

Ø. E. Haga ◽

W. Sørmo ◽

T. H. Aagnes Utsi ◽

...

Keyword(s):

Food Intake ◽

Rangifer Tarandus ◽

Rumen Fluid ◽

Total Concentration ◽

Phleum Pratense ◽

Water Soluble ◽

Soluble Carbohydrates ◽

Energy Deficiency

Leafy timothy (Phleum pratense) silage (S), silage mixed with molasses (SM) and hay (H) were fed to nine male reindeer (Rangifer tarandus tarandus) calves in winter to investigate rumen function and digestion. Three calves were given S with 18.5% dry matter (DM), three were given SM (21.9% DM) and three were given H (85.0% DM). The content of water soluble carbohydrates (in % of DM) was 8.2% in S, 16.0% in SM and 8.5% in H. Median (range) daily DM food intake per kg BM was 12.9 (9-2-14.4) g in calves fed S, 19.0 (19-0-21.9) g in calves fed SM and 21.0 (19.2¬21.1) g in calves fed H. In vivo digestion of S and SM DM ranged from 78.5-83.1% compared to only 69-9-72.9% in calves fed H. In vitro DM digestion (IVDMD) of cellulose (median) incubated for 48 hours in rumen fluid was, however, significantly (F = 0.05) lower in calves fed S (24.4%) compared to calves fed SM (42.2%). Median IVDMD of cellulose (48 hours) in calves fed H was 36.4%. Total concentration of VFA (range) in the rumen fluid from reindeer fed H (99.7-113.6 mM) and was significantly (P<0.05) higher compared to animals fed S (57.7-85.9 mM) or SM (51.4-72.0 mM). Likewise, the pH of the rumen fluid (range) was significantly (P<0.05) lower in reindeer fed H (6.40-6.78) compared to animals fed S (6.97-7.30) or SM (6.79-7.27). Based on this study it is concluded that leafy timothy preserved as hay seems to be more suitable as emergency feed compared to silage. Supplementation of molasses to silage seems to stimulate food intake and ruminal cellulose digestion in reindeer. The lower intake of S compared to SM or H by reindeer may be explained by ruminal energy deficiency.

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Obestatin acts in brain to inhibit thirst

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00395.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R637-R643 ◽

Cited By ~ 91

Author(s):

Willis K. Samson ◽

Meghan M. White ◽

Christopher Price ◽

Alastair V. Ferguson

Keyword(s):

Food Intake ◽

Pituitary Gland ◽

Behavioral Activity ◽

Free Access ◽

Gene Encoding ◽

Gh Secretion ◽

Water Drinking ◽

Access To Water

Derived from the same prohormone, obestatin has been reported to exert effects on food intake that oppose those of ghrelin. The obestatin receptor GPR39 is present in brain and pituitary gland. Since the gene encoding those two peptides is expressed also in those tissues, we examined further the possible actions of obestatin in vivo and in vitro. Intracerebroventricular administration of obestatin inhibited water drinking in ad libitum-fed and -watered rats, and in food-and water-deprived animals. The effects on water drinking preceded and were more pronounced than any effect on food intake, and did not appear to be the result of altered locomotor/behavioral activity. In addition, obestatin inhibited ANG II-induced water drinking in animals provided free access to water and food. Current-clamp recordings from cultured, subfornical organ neurons revealed significant effects of the peptide on membrane potential, suggesting this as a potential site of action. In pituitary cell cultures, log molar concentrations of obestatin ranging from 1.0 pM to 100 nM failed to alter basal growth hormone (GH) secretion. In addition, 100 nM obestatin failed to interfere with the stimulation of GH secretion by GH-releasing hormone or ghrelin and did not alter the inhibition by somatostatin in vitro. We conclude that obestatin does not act in pituitary gland to regulate GH secretion but may act in brain to alter thirst mechanisms. Importantly, in rats the effects of obestatin on food intake may be secondary to an action of the peptide to inhibit water drinking.

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Custom Repair of Mandibular Bone Defects with 3D Printed Bioceramic Scaffolds

Journal of Dental Research ◽

10.1177/0022034517734846 ◽

2017 ◽

Vol 97 (1) ◽

pp. 68-76 ◽

Cited By ~ 36

Author(s):

H. Shao ◽

M. Sun ◽

F. Zhang ◽

A. Liu ◽

Y. He ◽

...

Keyword(s):

Weight Loss ◽

Alveolar Bone ◽

Bone Defects ◽

Linear Shrinkage ◽

Tris Buffer ◽

Bone Tissue Regeneration ◽

3 Dimensional ◽

Flexural Resistance

Implanting artificial biomaterial implants into alveolar bone defects with individual shape and appropriate mechanical strength is still a challenge. In this study, bioceramic scaffolds, which can precisely match the mandibular defects in macro and micro, were manufactured by the 3-dimensional (3D) printing technique according to the computed tomography (CT) image. To evaluate the stimulatory effect of the material substrate on bone tissue regeneration in situ in a rabbit mandibular alveolar bone defect model, implants made with the newly developed, mechanically strong ~10% Mg-substituted wollastonite (Ca90%Mg10%SiO3; CSi-Mg10) were fabricated, implanted into the bone defects, and compared with implants made with the typical Ca-phosphate and Ca-silicate porous bioceramics, such as β-tricalcium phosphate (TCP), wollastonite (CaSiO3; CSi), and bredigite (Bred). The initial physicochemical tests indicated that although the CSi-Mg10 scaffolds had the largest pore dimension, they had the lowest porosity mainly due to the significant linear shrinkage of the scaffolds during sintering. Compared with the sparingly dissolvable TCP scaffolds (~2% weight loss) and superfast dissolvable (in Tris buffer within 6 wk) pure CSi and Bred scaffolds (~12% and ~14% weight loss, respectively), the CSi-Mg10 exhibited a mild in vitro biodissolution and moderate weight loss of ~7%. In addition, the CSi-Mg10 scaffolds showed a considerable initial flexural strength (31 MPa) and maintained very high flexural resistance during soaking in Tris buffer. The in vivo results revealed that the CSi-Mg10 scaffolds have markedly higher osteogenic capability than those on the TCP, CSi, and Bred scaffolds after 16 wk. These results suggest a promising potential application of customized CSi-Mg10 3D robocast scaffolds in the clinic, especially for repair of alveolar bone defects.

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Downregulation of CTRP-3 by Weight Loss In Vivo and by Bile Acids and Incretins in Adipocytes In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21218168 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8168

Author(s):

Andreas Schmid ◽

Jonas Gehl ◽

Miriam Thomalla ◽

Alexandra Hochberg ◽

Anja Kreiß ◽

...

Keyword(s):

Weight Loss ◽

Bile Acid ◽

Bile Acids ◽

Serum Levels ◽

Receptor Expression ◽

Low Calorie Diet ◽

Calorie Diet ◽

Bile Acid Receptor

The adipokine CTRP-3 (C1q/TNF-related protein-3) exerts anti-inflammatory and anti-diabetic effects. Its regulation in obesity and during weight loss is unknown. Serum and adipose tissue (AT) samples were obtained from patients (n = 179) undergoing bariatric surgery (BS). Moreover, patients (n = 131) participating in a low-calorie diet (LCD) program were studied. CTRP 3 levels were quantified by ELISA and mRNA expression was analyzed in AT and in 3T3-L1 adipocytes treated with bile acids and incretins. There was a persistent downregulation of CTRP-3 serum levels during weight loss. CTRP-3 expression was higher in subcutaneous than in visceral AT and serum levels of CTRP-3 were positively related to AT expression levels. A rapid decrease of circulating CTRP-3 was observed immediately upon BS, suggesting weight loss-independent regulatory mechanisms. Adipocytes CTRP-3 expression was inhibited by primary bile acid species and GLP 1. Adipocyte-specific CTRP-3 deficiency increased bile acid receptor expression. Circulating CTRP-3 levels are downregulated during weight loss, with a considerable decline occurring immediately upon BS. Mechanisms dependent and independent of weight loss cause the post-surgical decline of CTRP-3. The data strongly argue for regulatory interrelations of CTRP-3 with bile acids and incretin system.

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