TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice

Huang, Suling; Ma, Shan-yao; Ning, Man; Yang, Wei; Ye, Yangliang; Zhang, Lina; Shen, Jianhua; Liu, Ying

doi:10.1016/j.metabol.2019.07.003

Cited by 43 publications

(36 citation statements)

References 49 publications

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“…As expected, we did not observe alterations in insulin secretion during the OGTT between genotype or between treatment. It has been previously shown that enhanced TGR5 signaling improves insulin resistance in various tissues by decreasing inflammation [ 23 ] and lipotoxicity [ 16 ] and increasing energy expenditure [ 13 , 20 ], but the hepatocyte-specific effect of TGR5 signaling on insulin resistance has not been investigated. Therefore, we evaluated an index of insulin resistance in Tgr5 HEP+/+ and Tgr5 HEP −/− mice with and without Compound 18 treatment.…”

Section: Resultsmentioning

confidence: 99%

“…While our data are consistent with previous work demonstrating that TGR5 ablation contributes to metabolic dysregulation in mouse models [ 3 , 19 , 34 , 37 , 49 ], our data are the first to demonstrate that TGR5 signaling specifically within the hepatocyte plays a significant role in whole body glucose regulation. Until now, the role of TGR5 in the maintenance of glucose homeostasis and insulin sensitivity has been attributed to its effects on mitochondrial function in muscle and BAT and/or insulin release from the pancreas, enhanced by enteroendocrine L cell GLP-1 secretion [ 3 , 13 , 14 , 15 , 17 , 20 ]. For example, various TGR5 agonists have been shown to ameliorate glucose intolerance in obese and diabetic mice [ 3 , 13 , 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

“…A growing body of literature has highlighted the potential value of TGR5 agonists in the treatment of various metabolic and liver diseases [ 3 , 13 , 20 , 23 , 40 , 41 , 52 ]. However, the clinical development of TGR5 agonists is complicated by the wide range of effects associated with systemic TGR5 activation.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been demonstrated that TGR5 signaling increases energy expenditure by increasing the activity of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase, mitochondrial thermogenesis, and fat mass oxidation to enhance basal metabolic rate [ 13 , 18 , 19 ]. TGR5 signaling in adipocytes promotes beiging of white adipose tissue in mice [ 19 ] and enhances energy expenditure to improve glucose regulation [ 13 , 20 ]. Finally, TGR5 signaling in immune cells decreases inflammatory cytokine secretion [ 11 , 21 , 22 ], which likely decreases systemic inflammation to improve insulin sensitivity [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Compound 18 Improves Glucose Tolerance in a Hepatocyte TGR5-dependent Manner in Mice

et al. 2020

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The bile acid receptor, TGR5, is a key regulator of glucose homeostasis, but the mechanisms by which TGR5 signaling improves glucose regulation are incompletely defined. In particular, TGR5 has an increasingly appreciated role in liver physiology and pathobiology; however, whether TGR5 signaling within the liver contributes to its glucoregulatory effects is unknown. Therefore, we investigated the role of hepatocyte TGR5 signaling on glucose regulation using a hepatocyte-specific TGR5 knockout mouse model. Hepatocyte-specific Tgr5Hep+/+ and Tgr5Hep−/− mice were fed a high fat diet (HFD) for 7 weeks and then orally gavaged with three doses of a highly potent, TGR5-specific agonist, Compound 18 (10 mg/kg), or vehicle, over 72 h and underwent an oral glucose tolerance test (OGTT) after the last dose. Herein, we report that TGR5 mRNA and protein is present in mouse hepatocytes. Cumulative food intake, body weight, and adiposity do not differ between Tgr5Hep+/+ and Tgr5Hep−/− mice with or without treatment with Compound 18. However, administration of Compound 18 improves glucose tolerance in Tgr5HEP+/+ mice, but not in Tgr5Hep−/− mice. Further, this effect occurred independent of body weight and GLP-1 secretion. Together, these data demonstrate that TGR5 is expressed in hepatocytes, where it functions as a key regulator of whole-body glucose homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Compound 18 Improves Glucose Tolerance in a Hepatocyte TGR5-dependent Manner in Mice

et al. 2020

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“…Further, taurine conjugation of bile acids increases the affinity for TGR5, as compared to unconjugated bile acids; however, conjugation with glycine has a negligible impact on TGR5 affinity [32]. Based on the robust metabolic effects of TGR5 signaling, multiple synthetic [3,9,13,30,[33][34][35] and semi-synthetic [28] TGR5-specific agonists have been designed and synthesized, in addition to other natural ligands that have been identified [16,29].…”

Section: Hepatic Tgr5 Signaling and Expressionmentioning

confidence: 99%

TGR5 Signaling in Hepatic Metabolic Health

et al. 2020

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TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.

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Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

Ábrigo

González

Aguirre

et al. 2020

Journal Cellular Physiology

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Skeletal muscle atrophy is characterized by the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. An increase in the expression of two muscle-specific E3 ligases, atrogin-1 and MuRF-1, and oxidative stress are involved in muscle atrophy. Patients with chronic liver diseases (CLD) develop muscle wasting. Several bile acids increase in plasma during cholestatic CLD, among them, cholic acid (CA) and deoxycholic acid (DCA). The receptor for bile acids, TGR5, is expressed in healthy skeletal muscles. TGR5 is involved in the regulation of muscle differentiation and metabolic changes. In this paper, we evaluated the participation of DCA and CA in the generation of an atrophic condition in myotubes and isolated fibers from the muscle extracted from wild-type (WT) and TGR5-deficient (TGR5 −/−) male mice. The results show that DCA and CA induce a decrease in diameter, and myosin heavy chain (MHC) protein levels, two typical atrophic features in C 2 C 12 myotubes. We also observed similar results when INT-777 agonists activated the TGR5 receptor. To evaluate the participation of TGR5 in muscle atrophy induced by DCA and CA, we used a culture of muscle fiber isolated from WT and TGR5 −/− mice.

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TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice

Cited by 43 publications

References 49 publications

Compound 18 Improves Glucose Tolerance in a Hepatocyte TGR5-dependent Manner in Mice

Compound 18 Improves Glucose Tolerance in a Hepatocyte TGR5-dependent Manner in Mice

TGR5 Signaling in Hepatic Metabolic Health

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor

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