Activation of GLP-1 and Glucagon Receptors Regulates Bile Homeostasis Independent of Thyroid Hormone

2019 ◽  
Vol 12 (2) ◽  
pp. 139-146
Author(s):  
Vishal J. Patel ◽  
Amit A. Joharapurkar ◽  
Samadhan G. Kshirsagar ◽  
Brijesh K. Sutariya ◽  
Maulik S. Patel ◽  
...  
Keyword(s):  
Single Dose ◽  
Lipid Metabolism ◽  
Thyroid Hormone ◽  
Fibroblast Growth Factor 21 ◽  
Dose Treatment ◽  
Obesity And Diabetes ◽  
Serum T3 ◽  
Serum T4 ◽  
Glucagon Like Peptide 1 ◽  
Glucagon Receptors

Background: Balanced coagonists of glucagon-like peptide-1 (GLP-1) and glucagon receptors are emerging therapies for the treatment of obesity and diabetes. Such coagonists also regulate lipid metabolism, independent of their body weight lowering effects. Many actions of the coagonists are partly mediated by fibroblast growth factor 21 (FGF21) signaling, with the major exception of bile homeostasis. Since thyroid hormone is an important regulator of bile homeostasis, we studied the involvement of thyroid hormone in coagonist-induced changes in lipid and bile metabolism. Methods: We evaluated the effect of a single dose of coagonist Aib2 C24 chimera2 at 150 to 10000 µg/kg on tetraiodothyronine (T4) and triiodothyronine (T3) in high-fat diet-induced obese (DIO) mice and chow-fed mice. Repeated dose treatment of coagonist (150 µg/kg, subcutaneously) was assessed in four mice models namely, on lipid and bile homeostasis in DIO mice, propylthiouracil (PTU)-treated DIO mice, methimazole (MTM)-treated DIO mice and choline-deficient, L-amino acid-defined, highfat diet (CDAHFD)-induced nonalcoholic steatohepatitis (NASH). Results: Single dose treatment of coagonist did not alter serum T3 and T4 in chow-fed mice and DIO mice. Coagonist treatment improved lipid metabolism and biliary cholesterol excretion. Chronic treatment of GLP-1 and glucagon coagonist did not alter serum T3 in hypothyroid DIO mice and CDAHFDinduced NASH. Coagonist increased serum T4 in DIO mice after 4 and 40 weeks of treatment, though no change in T4 levels was observed in hypothyroid mice or mice with NASH. Conclusion: Our data demonstrate that coagonist of GLP-1 and glucagon receptors does not modulate bile homeostasis via thyroid signaling.

scholarly journals Balanced Coagonist of GLP-1 and Glucagon Receptors Corrects Dyslipidemia by Improving FGF21 Sensitivity in Hamster Model

Drug Research ◽  
2017 ◽  
Vol 67 (12) ◽  
pp. 730-736 ◽  
Author(s):  
Vishal Patel ◽  
Amit Joharapurkar ◽  
Samadhan Kshirsagar ◽  
Hiren Patel ◽  
Dheerendra Pandey ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Clinical Investigation ◽  
Repeated Dose ◽  
Hypolipidemic Effect ◽  
Hamster Model ◽  
Dose Treatment ◽  
Reduced Body ◽  
Obesity And Diabetes ◽  
Glucagon Receptors

AbstractHyperlipidemia is often associated with obesity and diabetes, and can lead to serious complications like atherosclerosis and fatty liver disease. Coagonist of GLP-1 and glucagon receptors is a therapy under clinical investigation for treatment of obesity and diabetes. In this study, we have characterized the mechanism of hypolipidemic effect of a balanced coagonist using high cholesterol-fed hamsters. Tyloxapol-induced hypertriglyceridemia, lipolysis in adipose tissue, and bile homeostasis were assessed after repeated dose treatment of the coagonist of GLP-1 and glucagon receptors (Aib2 C24 chimera 2, SC). Antagonists of GLP-1, glucagon, and FGF21 receptors were coadministered, and FGF21 sensitivity was determined in liver and adipose tissue. Repeated dose treatment of coagonist reduced cholesterol and increased FGF21 in blood and liver. Coagonist treatment reduced hepatic triglyceride secretion, increased lipolysis and reduced body weight. Antagonism of GLP-1 and glucagon receptors partially blocked the effect of the coagonist on lipid metabolism in circulation and liver, while FGF21 receptor antagonist completely abolished it. Glucagon and GLP-1 receptors antagonists blocked the action of coagonist on cholesterol excretion and bile flow in liver, but FGF21 antagonist was not effective. Treatment with the coagonist increased expression of FGF21, FGF21R and cofactor ßKlotho in liver and adipose. In conclusion, coagonist of GLP-1 and glucagon receptors improved lipid metabolism in liver of dyslipidemic hamsters. This effect is partially mediated by GLP-1 and glucagon receptors, and the improved FGF21 sensitivity could be the mechanism of hypolipidemic action of the coagonist of GLP-1/glucagon receptors.

Benefit of Combined Triiodothyronine (LT3) and Thyroxine (LT4) Treatment in Athyreotic Patients Unresponsive to LT4 Alone

2011 ◽  
Vol 120 (02) ◽  
pp. 121-123 ◽  
Author(s):  
D. Solter ◽  
M. Solter
Keyword(s):  
Thyroid Hormone ◽  
Combination Therapy ◽  
Genetic Basis ◽  
Normal Range ◽  
Serum T3 ◽  
Serum T4 ◽  
Serum Tsh ◽  
Tsh Levels

AbstractDespite some reports, the usefulness of levothyroxine ( LT4) and levotriiodothyronine (LT3) combination therapy in hypothyroidism remains controversial. The objective of this paper is to study a benefit of additional LT3 in athyreotic patients who failed to normalize TSH on LT4 alone even with hyperthyroid serum T4 values.In a survey of 200 athyreotic patients treated between 2006 and 2009, about 7% failed to normalize serum TSH levels following treatment with LT4, though serum T4 values in the hyperthyroid range were achieved. These patients (characterized by serum T4≥160 nmol/L and TSH≥5.0 mIU/L), were additionally treated with 10 μg b. i. d LT3. LT3 and LT4 combination therapy resulted in decreased serum TSH levels into the normal range (12.8 vs. 1.22 mIU/L; p<0.01) and reduced LT4 dose (153.3 vs. 117.5 μg; p<0.01) required for normalization of serum T4 values (170.6 vs. 123.3 nmol/L; p<0.01). Serum T3 values were higher (1.3 vs. 2.26 nmol/L; p<0.01) than those during monotherapy with LT4.Our results indicate a subpopulation of athyreotic patients that could significantly benefit from combined LT4 + LT3 therapy in restoring normal TSH and thyroid hormone patterns. Further research should be undertaken to provide a genetic basis for these findings.

scholarly journals Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus

2018 ◽  
Vol 9 (6) ◽  
pp. 80-91 ◽  
Author(s):  
Vishal J Patel ◽  
Amit A Joharapurkar ◽  
Samadhan G Kshirsagar ◽  
Brijesh K Sutariya ◽  
Maulik S Patel ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Injury ◽  
Murine Models ◽  
Obesity And Diabetes ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Glucagon Receptors

scholarly journals β-Blocker inhibits myocardial infarction-induced brown adipose tissue D2 activation and maintains a low thyroid hormone state in rats

2018 ◽  
Author(s):  
Fernando A. C. Seara ◽  
Iracema G. Araujo ◽  
Güínever E. Império ◽  
Michelle P. Marassi ◽  
Alba C. M. Silva ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Cardiac Function ◽  
Brown Adipose Tissue ◽  
Sham Group ◽  
Low T3 ◽  
Brown Adipose ◽  
Serum T3 ◽  
Serum T4

AbstractConsidering the recognized role of thyroid hormones on the cardiovascular system during health and disease, we hypothesized that type 2 deiodinase (D2) activity, the main activation pathway of thyroxine (T4)-to-triiodothyronine (T3), could be an important site to modulate thyroid hormone status, which would then constitute a possible target for β-adrenergic blocking agents in a myocardial infarction (MI) model induced by left coronary occlusion in rats. Despite a sustained and dramatic fall in serum T4 concentrations (60-70%), the serum T3 concentration fell only transiently in the first week post-infarction (53%) and returned to control levels at 8 and 12 weeks after surgery compared to Sham group (P<0.05). Brown adipose tissue (BAT) D2 activity (fmoles T4/min.mg ptn) was dramatically increased by approximately 77% in the 8th week and approximately 100% in the 12th week in the MI group compared to that of the Sham group (P<0.05). Beta-blocker treatment (propranolol given in the drinking water, 0.5 g/L) maintained a low T3 state in MI animals, dampening both BAT D2 activity (44% reduction) and serum T3 (66% reduction in serum T3) compared to that of the non-treated MI group 12 weeks after surgery (P<0.05). Propranolol improved cardiac function (assessed by echocardiogram) in MI group compared to MI-non treated one by 40 and 57 % 1 and 12 weeks after treatment respectively (P<0.05). Our data suggest that the beta-adrenergic pathway may contribute to BAT D2 hyperactivity and T3 normalization after MI in rats. Propranolol treatment maintains low T3 state and improves cardiac function additionally.

Influence of Cigarette Smoking on Thyroid Hormone Levels

1987 ◽  
Vol 6 (6) ◽  
pp. 507-509 ◽  
Author(s):  
A. Karakaya ◽  
N. Tunçel ◽  
G. Alptuna ◽  
Z. Koçer ◽  
G. Erbay
Keyword(s):  
Thyroid Hormone ◽  
Cigarette Smoking ◽  
Smoking Behaviour ◽  
Hormone Levels ◽  
Serum T3 ◽  
Serum T4 ◽  
Thyroid Hormone Levels ◽  
Substantial Change ◽  
Heavy Smokers

1 Serum triiodothyronine (T3), thyroxine (T4) and thyrotropin (TSH) concentrations and urinary thiocyanate levels were examined in healthy smokers and non-smokers as an indicator of smoking behaviour. Smokers were subdivided into moderate and heavy. 2 Significant differences in urinary thiocyanate levels were apparent between all three groups. For heavy smokers, serum T3 concentrations were significantly above the values found in non-smokers. Increased serum T3 levels were not accompanied by a substantial change in serum T4 and TSH concentrations.

scholarly journals Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 315-325 ◽  
Author(s):  
Julia Müller ◽  
Steffen Mayerl ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Anita Boelen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Elevated Serum ◽  
Normal Serum ◽  
Monocarboxylate Transporter ◽  
Cellular Transport ◽  
Tissue Specific ◽  
Serum T3 ◽  
Serum T4 ◽  
Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

Let-7e-5p Regulates GLP-1 Content and Basal Release From Enteroendocrine L Cells From DIO Male Mice

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Sandra Handgraaf ◽  
Rodolphe Dusaulcy ◽  
Florian Visentin ◽  
Jacques Philippe ◽  
Yvan Gosmain
Keyword(s):  
Compensatory Mechanism ◽  
L Cells ◽  
Low Fat Diet ◽  
Obesity And Diabetes ◽  
Basal Release ◽  
Glucagon Like Peptide 1 ◽  
Cell Transcriptome ◽  
Microarray Analyses

Abstract Characterization of enteroendocrine L cells in diabetes is critical for better understanding of the role of glucagon-like peptide-1 (GLP-1) in physiology and diabetes. We studied L-cell transcriptome changes including microRNA (miRNA) dysregulation in obesity and diabetes. We evaluated the regulation of miRNAs through microarray analyses on sorted enteroendocrine L cells from control and obese glucose-intolerant (I-HFD) and hyperglycemic (H-HFD) mice after 16 weeks of respectively low-fat diet (LFD) or high-fat diet (HFD) feeding. The identified altered miRNAs were studied in vitro using the mouse GLUTag cell line to investigate their regulation and potential biological functions. We identified that let-7e-5p, miR-126a-3p, and miR-125a-5p were differentially regulated in L cells of obese HFD mice compared with control LFD mice. While downregulation of let-7e-5p expression was observed in both I-HFD and H-HFD mice, levels of miR-126a-3p increased and of miR-125a-5p decreased significantly only in I-HFD mice compared with controls. Using miRNA inhibitors and mimics we observed that modulation of let-7e-5p expression affected specifically GLP-1 cellular content and basal release, whereas Gcg gene expression and acute GLP-1 secretion and cell proliferation were not affected. In addition, palmitate treatment resulted in a decrease of let-7e-5p expression along with an increase in GLP-1 content and release, suggesting that palmitate acts on GLP-1 through let-7e-5p. By contrast, modulation of miR-125a-5p and miR-126a-3p in the same conditions did not affect content or secretion of GLP-1. We conclude that decrease of let-7e-5p expression in response to palmitate may constitute a compensatory mechanism contributing to maintaining constant glycemia in obese mice.

scholarly journals The glucocorticoid receptor: cause of or cure for obesity?

2016 ◽  
Vol 310 (4) ◽  
pp. E249-E257 ◽  
Author(s):  
Kezia John ◽  
Joseph S. Marino ◽  
Edwin R. Sanchez ◽  
Terry D. Hinds
Keyword(s):  
Lipid Metabolism ◽  
Glucocorticoid Receptor ◽  
Chronic Exposure ◽  
Mineralocorticoid Receptor ◽  
Acute Treatment ◽  
Glucocorticoid Hormones ◽  
Future Studies ◽  
Obesity And Diabetes ◽  
Metabolic Conditions ◽  
Insufficient Knowledge

Glucocorticoid hormones (GCs) are important regulators of lipid metabolism, promoting lipolysis with acute treatment but lipogenesis with chronic exposure. Conventional wisdom posits that these disparate outcomes are mediated by the classical glucocorticoid receptor GRα. There is insufficient knowledge of the GC receptors (GRα and GRβ) in metabolic conditions such as obesity and diabetes. We present acute models of GC exposure that induce lipolysis, such as exercise, as well as chronic-excess models that cause obesity and lipid accumulation in the liver, such as hepatic steatosis. Alternative mechanisms are then proposed for the lipogenic actions of GCs, including induction of GC resistance by the GRβ isoform, and promotion of lipogenesis by GC activation of the mineralocorticoid receptor (MR). Finally, the potential involvement of chaperone proteins in the regulation of adipogenesis is considered. This reevaluation may prove useful to future studies on the steroidal basis of adipogenesis and obesity.

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