The Bile Acid TUDCA Improves Beta-Cell Mass and Reduces Insulin Degradation in Mice With Early-Stage of Type-1 Diabetes

Bronczek, Gabriela Alves; Vettorazzi, Jean Franciesco; Soares, Gabriela Moreira; Kurauti, Mirian Ayumi; Santos, Cristiane dos; Bonfim, Maressa Fernandes; Carneiro, Everardo M.; Balbo, Sandra Lucinei; Boschero, Antônio Carlos; Júnior, José Maria Costa

doi:10.3389/fphys.2019.00561

Cited by 34 publications

(32 citation statements)

References 45 publications

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“…A previous study reported that treatment with 4-PBA ameliorated palmitate-induced β-cell dysfunction [24]. Treatment with TUDCA also prevented β-cell dysfunction and apoptosis in diabetic mice and potentiated glucose-stimulated insulin secretion in isolated mouse pancreatic islets [25][26][27][28]. In the present study, we showed that administration of 4-PBA reduced ER stress and thereby recovered adipsin expression in adipose tissues of HFD-fed obese mice.…”

Section: Discussionsupporting

confidence: 73%

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

et al. 2020

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Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.

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Section: Discussionsupporting

confidence: 73%

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

et al. 2020

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“…An increasing number of reports from experimental and clinical studies also indicate a higher prevalence of cardiac damage [98], obesity [99], vision impairment [23,100], and nephropathy [101,102] in diabetic patients. According to a growing number of data, ER stress is a key contributor to the pathology of diabetes and is associated with pancreatic beta cell loss and insulin resistance [103,104]. Moreover, the occurrence of ER stress has been demonstrated in pathology of obesity.…”

Section: Tudca In Diabetes and Obesitymentioning

confidence: 99%

“…Indeed, increasing evidence postulates that TUDCA evokes beneficial effects in the outcome of diabetes. Recent studies suggest that TUDCA is effective in e.g., increasing insulin sensitivity [99], potentiating insulin clearance [107], and increasing pancreatic beta-cell mass [103] in obese humans and murine models of obesity and diabetes. TUDCA has been demonstrated to prevent palmitate-induced apoptosis in rat pancreatic β-cell line INS-1 and to evoke beneficial effects on acinar cells in the experimental model of acute pancreatitis mostly by reducing ER stress [108,109].…”

Section: Tudca In Diabetes and Obesitymentioning

confidence: 99%

“…Nevertheless, defects in the expression of the UPR mediators such as ATF6 and XBP1 have been identified in β cells from both mouse models of type 1 diabetes as well as type 1 diabetic patients [112]. Administration of TUDCA led to the restoration of expression of the UPR mediators and resulted in reduced β cell apoptosis, increased β cell mass, higher β cell number per islet, and maintained insulin secretion together with marked reduction in blood glucose [103,112]. These data suggest that adequate maintenance of the UPR might be a pivotal factor for the preservation of β cells, and chemical restoration of imbalanced ER homeostasis can be used for therapeutic or preventive interventions in type 1 diabetes.…”

Section: Tudca In Diabetes and Obesitymentioning

confidence: 99%

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Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Kusaczuk

2019

Cells

140

125

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Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that has been used for centuries in Chinese medicine. Chemically, TUDCA is a taurine conjugate of ursodeoxycholic acid (UDCA), which in contemporary pharmacology is approved by Food and Drug Administration (FDA) for treatment of primary biliary cholangitis. Interestingly, numerous recent studies demonstrate that mechanisms of TUDCA functioning extend beyond hepatobiliary disorders. Thus, TUDCA has been demonstrated to display potential therapeutic benefits in various models of many diseases such as diabetes, obesity, and neurodegenerative diseases, mostly due to its cytoprotective effect. The mechanisms underlying this cytoprotective activity have been mainly attributed to alleviation of endoplasmic reticulum (ER) stress and stabilization of the unfolded protein response (UPR), which contributed to naming TUDCA as a chemical chaperone. Apart from that, TUDCA has also been found to reduce oxidative stress, suppress apoptosis, and decrease inflammation in many in-vitro and in-vivo models of various diseases. The latest research suggests that TUDCA can also play a role as an epigenetic modulator and act as therapeutic agent in certain types of cancer. Nevertheless, despite the massive amount of evidence demonstrating positive effects of TUDCA in pre-clinical studies, there are certain limitations restraining its wide use in patients. Here, molecular and cellular modes of action of TUDCA are described and therapeutic opportunities and limitations of this bile acid are discussed.

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“…injected. TUDCA was daily injected (1 injection/day), for 10 consecutive days, at a dose of 300 mg/Kg body weight, based on previous studies 24 , 28 , 29 . The rest of the mice, as well as the control mice, received PBS alone instead of TUDCA.…”

Section: Methodsmentioning

confidence: 99%

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer’s disease mice model

Zangerolamo

Solon

Soares

et al. 2021

Sci Rep

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

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The Bile Acid TUDCA Improves Beta-Cell Mass and Reduces Insulin Degradation in Mice With Early-Stage of Type-1 Diabetes

Cited by 34 publications

References 45 publications

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

Regulation of Adipsin Expression by Endoplasmic Reticulum Stress in Adipocytes

Tauroursodeoxycholate—Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer’s disease mice model

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