ursodoxicoltaurine and Obesity

Adipose tissue is an organ with metabolic and endocrine activity. White, brown and ectopic adipose tissues have different structure, location, and function. Adipose tissue regulates energy homeostasis, providing energy in nutrient-deficient conditions and storing it in high-supply conditions. To attend to the high demand for energy storage during obesity, the adipose tissue undergoes morphological, functional and molecular changes. Endoplasmic reticulum (ER) stress has been evidenced as a molecular hallmark of metabolic disorders. In this sense, the ER stress inhibitor tauroursodeoxycholic acid (TUDCA), a bile acid conjugated to taurine with chemical chaperone activity, has emerged as a therapeutic strategy to minimize adipose tissue dysfunction and metabolic alterations associated with obesity. In this review, we highlight the effects of TUDCA and receptors TGR5 and FXR on adipose tissue in the setting of obesity. TUDCA has been demonstrated to limit metabolic disturbs associated to obesity by inhibiting ER stress, inflammation, and apoptosis in adipocytes. The beneficial effect of TUDCA on perivascular adipose tissue (PVAT) function and adiponectin release may be related to cardiovascular protection in obesity, although more studies are needed to clarify the mechanisms. Therefore, TUDCA has emerged as a potential therapeutic strategy for obesity and comorbidities.

Topics: Adipose Tissue; Adiposity; Humans; Obesity; Taurochenodeoxycholic Acid

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.

Topics: Animals; Bile Acids and Salts; Diabetes Mellitus; Endoplasmic Reticulum Stress; Humans; Liver Diseases; Neoplasms; Neurodegenerative Diseases; Obesity; Taurochenodeoxycholic Acid

In the context of obesity and its related maladies, the adipocyte plays a central role in the balance, or imbalance, of metabolic homeostasis. An obese, hypertrophic adipocyte is challenged by many insults, including surplus energy, inflammation, insulin resistance, and considerable stress to various organelles. The endoplasmic reticulum (ER) is one such vital organelle that demonstrates significant signs of stress and dysfunction in obesity and insulin resistance. Under normal conditions, the ER must function in the unique and trying environment of the adipocyte, adapting to meet the demands of increased protein synthesis and secretion, energy storage in the form of triglyceride droplet formation, and nutrient sensing that are particular to the differentiated fat cell. When nutrients are in pathological excess, the ER is overwhelmed and the unfolded protein response (UPR) is activated. Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress. This review will focus on the function of the ER under normal conditions in the adipocyte and the pathological effects of a stressed ER contributing to adipocyte dysfunction and a thwarted metabolic homeostasis.

Topics: Adipocytes; Animals; Cholesterol; Endoplasmic Reticulum; Humans; Inflammation; Lipid Metabolism; Metabolic Diseases; Obesity; Phenylbutyrates; Protein Folding; Proteins; Stress, Physiological; Taurochenodeoxycholic Acid

Insulin resistance is commonly associated with obesity. Studies conducted in obese mouse models found that endoplasmic reticulum (ER) stress contributes to insulin resistance, and treatment with tauroursodeoxycholic acid (TUDCA), a bile acid derivative that acts as a chemical chaperone to enhance protein folding and ameliorate ER stress, increases insulin sensitivity. The purpose of this study was to determine the effect of TUDCA therapy on multiorgan insulin action and metabolic factors associated with insulin resistance in obese men and women.. Twenty obese subjects ([means +/- SD] aged 48 +/- 11 years, BMI 37 +/- 4 kg/m2) were randomized to 4 weeks of treatment with TUDCA (1,750 mg/day) or placebo. A two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions and muscle and adipose tissue biopsies were used to evaluate in vivo insulin sensitivity, cellular factors involved in insulin signaling, and cellular markers of ER stress. RESULTS Hepatic and muscle insulin sensitivity increased by approximately 30% (P < 0.05) after treatment with TUDCA but did not change after placebo therapy. In addition, therapy with TUDCA, but not placebo, increased muscle insulin signaling (phosphorylated insulin receptor substrate(Tyr) and Akt(Ser473) levels) (P < 0.05). Markers of ER stress in muscle or adipose tissue did not change after treatment with either TUDCA or placebo.. These data demonstrate that TUDCA might be an effective pharmacological approach for treating insulin resistance. Additional studies are needed to evaluate the target cells and mechanisms responsible for this effect.

Topics: Adiponectin; Adipose Tissue; Adult; Blood Glucose; Cholagogues and Choleretics; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Liver; Male; Middle Aged; Muscle, Skeletal; Obesity; Organ Specificity; Placebos; Taurochenodeoxycholic Acid; Triglycerides

Early childhood malnutrition may facilitate the onset of obesity and diabetes mellitus in adulthood which, when established, makes it more resistant to therapeutic interventions. The beneficial effects of tauroursodeoxycholic acid (TUDCA) in glucose homeostasis and body fat accumulation were analyzed in protein-restricted mice fed a high-fat diet (HFD). C57BL/6 mice were fed a control (14% protein [C]) or a protein-restricted (6% protein [R]) diet for 6 weeks. Afterward, mice received an HFD or not for 12 weeks (C mice fed an HFD [CH] and R mice fed an HFD [RH]). In the last 15 days of this period, half of the mice fed a HFD received i.p. PBS (groups CH and RH) or 300 mg/kg TUDCA (groups CHT and RHT). RH mice developed obesity, as demonstrated by the increase in fat accumulation, liver steatosis, and metabolic inflexibility. Additionally, showed glucose intolerance and insulin hypersecretion. TUDCA reduced adiposity and improve metabolic flexibility through increased HSL phosphorylation and CPT1 expression in eWAT and BAT, and reduced ectopic fat deposition by activating the AMPK/HSL pathway in the liver. Also, improved glucose tolerance and insulin sensitivity, normalizing insulin secretion by reducing GDH expression and increasing insulin peripheral sensitivity by greater expression of the IRβ in muscle and adipose tissue and reducing PEPCK liver expression. Our data indicate that TUDCA reduces global adiposity and improves glucose tolerance and insulin sensitivity in protein malnourished mice fed a HFD. Therefore, this is a possible strategy to reverse metabolic disorders in individuals with the double burden of malnutrition.

Topics: Adiposity; Animals; Diet, High-Fat; Glucose; Insulin; Insulin Resistance; Malnutrition; Mice; Mice, Inbred C57BL; Obesity; Taurochenodeoxycholic Acid

Bile acid tauroursodeoxycholic (TUDCA), formed from the association of ursodeoxycholic acid (UDCA) with taurine, has already been shown to increase mitochondrial biogenesis and cell survival, in addition to reduce reticulum stress markers in different cell types. However, its mechanism of action upon insulin secretion control in obesity is still unknown. In this sense, we seek to clarify whether taurine, associated with bile acid, could improve the function of the pancreatic β-cells exposed to fatty acids through the regulation of mitochondrial metabolism. To test this idea, insulin-producing cells (INS1-E) were exposed to a fatty acid mix containing 500 μM of each palmitate and oleate for 48 hours treated or not with 300 μM of TUDCA. After that, glucose-stimulated insulin secretion and markers of mitochondrial metabolism were evaluated. Our results showed that the fatty acid mix was efficient in inducing hyperfunction of INS1-E cells as observed by the increase in insulin secretion, protein expression of citrate synthase, and mitochondrial density, without altering cell viability. The treatment with TUDCA normalized insulin secretion, reducing the protein expression of citrate synthase, mitochondrial mass, and the mitochondrial membrane potential. This effect was associated with a decrease in the generation of mitochondrial superoxide and c-Jun N-terminal kinase (JNK) protein content. The findings are also consistent with the hypothesis that TUDCA normalizes insulin secretion by improving mitochondrial metabolism and redox balance. Thus, it highlights likely mechanisms of the action of this bile acid on the glycemic homeostasis reestablishment in obesity.

Topics: Bile Acids and Salts; Citrate (si)-Synthase; Fatty Acids; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Obesity; Taurine; Taurochenodeoxycholic Acid

Aging is associated with glucose metabolism disturbances, such as insulin resistance and hyperinsulinemia, which contribute to the increased prevalence of type 2 diabetes (T2D) and its complications in the elderly population. In this sense, some bile acids have emerged as new therapeutic targets to treat TD2, as well as associated metabolic disorders. The taurine conjugated bile acid, tauroursodeoxycholic acid (TUDCA) improves glucose homeostasis in T2D, obesity, and Alzheimer's disease mice model. However, its effects in aged mice have not been explored yet. Here, we evaluated the actions of TUDCA upon glucose-insulin homeostasis in aged C57BL/6 male mice (18-month-old) treated with 300 mg/kg of TUDCA or its vehicle. TUDCA attenuated hyperinsulinemia and improved glucose homeostasis in aged mice, by enhancing liver insulin-degrading enzyme (IDE) expression and insulin clearance. Furthermore, the improvement in glucose-insulin homeostasis in these mice was accompanied by a reduction in adiposity, associated with adipocyte hypertrophy, and lipids accumulation in the liver. TUDCA-treated aged mice also displayed increased energy expenditure and metabolic flexibility, as well as a better cognitive ability. Taken together, our data highlight TUDCA as an interesting target for the attenuation of age-related hyperinsulinemia and its deleterious effects on metabolism.

Topics: Aged; Animals; Bile Acids and Salts; Diabetes Mellitus, Type 2; Glucose; Humans; Hyperinsulinism; Insulin; Male; Mice; Mice, Inbred C57BL; Obesity; Taurochenodeoxycholic Acid

Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.

Topics: Adipocytes, Beige; Adipogenesis; Animals; Cell Differentiation; Diet, High-Fat; Endoplasmic Reticulum Stress; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Obesity; Phenotype; Signal Transduction; Taurochenodeoxycholic Acid; Thermogenesis; Unfolded Protein Response

Bile salt hydrolase (BSH)-producing bacteria are negatively related to the body weight gain and energy storage of the host. We aimed to obtain a novel BSH-producing strain with excellent anti-obesity effect and explained its mechanism. Here, we selected a strain named Lactiplantibacillus plantarum H-87 (H-87) with excellent ability to hydrolyze glycochenodeoxycholic acid (GCDCA) and tauroursodeoxycholic acid (TUDCA) in vitro from 12 lactobacilli, and evaluated its anti-obesity effect in high-fat diet (HFD)-fed C57BL/6J mice. The results suggested that H-87 could inhibit HFD-induced body weight gain, fat accumulation, liver lipogenesis and injury, insulin resistance and dyslipidemia. In addition, H-87 could colonize in the ileum and hydrolyze GCDCA and TUDCA, reflected as changes in the concentrations of GCDCA, TUDCA, CDCA and UDCA in the ileum or liver. Furthermore, the study identified that H-87 reduced TUDCA and GCDCA levels in the ileum, which decreased the GLP-1 secretion by L cells to alleviate insulin resistance in HFD-fed mice. Furthermore, H-87 increased the CDCA level in the ileum and liver to activate FXR signaling pathways to inhibit liver lipogenesis in HFD-fed mice. In addition, the decrease of intestinal conjugated bile acids (TUDCA and GCDCA) also increased fecal lipid content and decreased intestinal lipid digestibility. In conclusion, H-87 could inhibit liver fat deposition, insulin resistance and lipid digestion by changing bile acid enterohepatic circulation, and eventually alleviate HFD-induced obesity.

Topics: Animals; Bile Acids and Salts; Diet, High-Fat; Dyslipidemias; Glycochenodeoxycholic Acid; Insulin Resistance; Lactobacillus plantarum; Lipid Metabolism; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Obesity; Taurochenodeoxycholic Acid

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.

Topics: Adiposity; Animals; Antiviral Agents; Autophagy; Autophagy-Related Protein 7; Body Weight; Cholagogues and Choleretics; Disease Models, Animal; Eating; Endoplasmic Reticulum Stress; Energy Metabolism; Feeding Behavior; Homeostasis; Hyperphagia; Hypothalamus; Leptin; Male; Metabolic Diseases; Mice; Mice, Inbred Strains; Mice, Knockout; Neuroendocrinology; Neurogenesis; Obesity; Pro-Opiomelanocortin; Taurochenodeoxycholic Acid

Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.

Topics: Activating Transcription Factor 4; Adipogenesis; Adolescent; Adult; Alkaline Phosphatase; Body Mass Index; Cell Differentiation; Cell Proliferation; Cellular Senescence; Child; Endoplasmic Reticulum Stress; Female; Gene Expression Regulation, Developmental; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Obesity; Osteogenesis; Phenylbutyrates; Regenerative Medicine; Taurochenodeoxycholic Acid; Tissue Donors; Transcription Factor CHOP; Unfolded Protein Response; Young Adult

The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, and by combining metabolic, histologic, physiologic, pharmacologic, thermographic, and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high-fat diet or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Blotting, Western; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Acids, Nonesterified; Hypothalamus; Immunohistochemistry; Male; Obesity; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Taurochenodeoxycholic Acid; Temperature; Thermogenesis

Physical activity has profound benefits on health, especially on cardiometabolic wellness. Experiments in rodents with trained exercise have shown that exercise improves vascular function and reduces vascular inflammation by modulating the balance between nitric oxide (NO) and oxidative stress. However, the upstream regulator of exercise-induced vascular benefits is unclear. We aimed to investigate the involvement of peroxisome proliferator-activated receptor δ (PPARδ) in exercise-induced vascular functional improvement. We show that PPARδ is a crucial mediator for exercise to exert a beneficial effect on the vascular endothelium in diabetic mice. In db/db mice and high-fat diet-induced obese mice, 4 weeks of treadmill exercise restored endothelium-dependent vasodilation of aortas and flow-mediated vasodilation in mesenteric resistance arteries, whereas genetic ablation of Ppard abolished such improvements. Exercise induces AMPK activation and subsequent PPARδ activation, which help to reduce endoplasmic reticulum (ER) and oxidative stress, thus increasing NO bioavailability in endothelial cells and vascular tissues. Chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid decrease ER stress and protect against endothelial dysfunction in diabetic mice. The results demonstrate that PPARδ-mediated inhibition of ER stress contributes to the vascular benefits of exercise and provides potentially effective targets for treating diabetic vasculopathy.

Topics: Animals; Aorta; Blood Pressure; Diabetes Mellitus; Diabetic Angiopathies; Diet, High-Fat; Endoplasmic Reticulum Stress; Endothelium, Vascular; Male; Mesenteric Arteries; Mice; Mice, Knockout; Myography; Nitric Oxide; Obesity; Organ Culture Techniques; Oxidative Stress; Phenylbutyrates; Physical Conditioning, Animal; Receptors, Cytoplasmic and Nuclear; Taurochenodeoxycholic Acid; Vasodilation

The uroguanylin-GUCY2C gut-brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO).. Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ER(T2)-Rosa-STOP(loxP/loxP)-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain.. DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis.. These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression of intestinal uroguanylin impairs hypothalamic mechanisms regulating food consumption through loss of anorexigenic endocrine signaling. The correlative therapeutic paradigm suggests that, in the context of hormone insufficiency with preservation of receptor sensitivity, obesity may be prevented or treated by GUCY2C hormone replacement.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Caloric Restriction; Diet; Endoplasmic Reticulum Stress; Energy Intake; Fatty Liver; Gene Expression Regulation; Gene Silencing; Glucose Intolerance; Hormone Replacement Therapy; Intestinal Mucosa; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Natriuretic Peptides; Obesity; Postprandial Period; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Satiation; Signal Transduction; Taurochenodeoxycholic Acid; Tunicamycin

Sleep fragmentation (SF) is highly prevalent and may constitute an important contributing factor to excessive weight gain and the metabolic syndrome. Increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) leading to the attenuation of leptin receptor signaling in the hypothalamus leads to obesity and metabolic dysfunction.. Mice were exposed to SF and sleep control (SC) for varying periods of time during which ingestive behaviors were monitored. UPR pathways and leptin receptor signaling were assessed in hypothalami. To further examine the mechanistic role of ER stress, changes in leptin receptor (ObR) signaling were also examined in wild-type mice treated with the ER chaperone tauroursodeoxycholic acid (TUDCA), as well as in CHOP-/+ transgenic mice.. Fragmented sleep in male mice induced increased food intake starting day 3 and thereafter, which was preceded by increases in ER stress and activation of all three UPR pathways in the hypothalamus. Although ObR expression was unchanged, signal transducer and activator of transcription 3 (STAT3) phosphorylation was decreased, suggesting reduced ObR signaling. Unchanged suppressor of cytokine signaling-3 (SOCS3) expression and increases in protein-tyrosine phosphatase 1B (PTP1B) expression and activity emerged with SF, along with reduced p-STAT3 responses to exogenous leptin. SF-induced effects were reversed following TUDCA treatment and were absent in CHOP -/+ mice.. SF induces hyperphagic behaviors and reduced leptin signaling in hypothalamus that are mediated by activation of ER stress, and ultimately lead to increased PTP1B activity. ER stress pathways are therefore potentially implicated in SF-induced weight gain and metabolic dysfunction, and may represent a viable therapeutic target.

Topics: Animals; Eating; Endoplasmic Reticulum Stress; Heterozygote; Hyperphagia; Hypothalamus; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Signal Transduction; Sleep; Sleep Deprivation; STAT3 Transcription Factor; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Unfolded Protein Response

Our objective was to investigate the role of bile acids in hepatic steatosis reduction after vertical sleeve gastrectomy (VSG).. High fat diet (HFD)-induced obese C57Bl/6 mice were randomized to VSG, Sham operation (Sham), Sham operation with pair feeding to VSG (Sham-PF), or nonsurgical controls (Naïve). All mice were on HFD until sacrifice. Mice were observed postsurgery and data for body weight, body composition, metabolic parameters, serum bile acid level and composition were collected. Further hepatic gene expression by mRNA-seq and RT-PCR analysis was assessed.. VSG and Sham-PF mice lost equal weight postsurgery while VSG mice had the lowest hepatic triglyceride content at sacrifice. The VSG mice had elevated serum bile acid levels that positively correlated with maximal weight loss. Serum bile composition in the VSG group had increased cholic and tauroursodeoxycholic acid. These bile acid composition changes in VSG mice explained observed downregulation of hepatic lipogenic and bile acid synthetic genes.. VSG in obese mice results in greater hepatic steatosis reduction than seen with caloric restriction alone. VSG surgery increases serum bile acids that correlate with weight lost postsurgery and changes serum bile composition that could explain suppression of hepatic genes responsible for lipogenesis.

Topics: Animals; Bile Acids and Salts; Caloric Restriction; Cholic Acid; Diet, High-Fat; Down-Regulation; Fatty Liver; Gastroplasty; Gene Expression Profiling; Gene Expression Regulation; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Postprandial Period; Random Allocation; Taurochenodeoxycholic Acid; Triglycerides; Up-Regulation; Weight Loss

Bariatric surgery elevates serum bile acids. Conjugated bile acid administration, such as tauroursodeoxycholic acid (TUDCA), improves insulin sensitivity, whereas short-circuiting bile acid circulation through ileal interposition surgery in rats raises TUDCA levels. We hypothesized that bariatric surgery outcomes could be recapitulated by short circuiting the normal enterohepatic bile circulation. We established a model wherein male obese rats underwent either bile diversion (BD) or Sham (SH) surgery. The BD group had a catheter inserted into the common bile duct and its distal end anchored into the middistal jejunum for 4-5 weeks. Glucose tolerance, insulin and glucagon-like peptide-1 (GLP-1) response, hepatic steatosis, and endoplasmic reticulum (ER) stress were measured. Rats post-BD lost significantly more weight than the SH rats. BD rats gained less fat mass after surgery. BD rats had improved glucose tolerance, increased higher postprandial glucagon-like peptide-1 response and serum bile acids but less liver steatosis. Serum bile acid levels including TUDCA concentrations were higher in BD compared to SH pair-fed rats. Fecal bile acid levels were not different. Liver ER stress (C/EBP homologous protein mRNA and pJNK protein) was decreased in BD rats. Bile acid gavage (TUDCA/ursodeoxycholic acid [UDCA]) in diet-induced obese rats, elevated serum TUDCA and concomitantly reduced hepatic steatosis and ER stress (C/EBP homologous protein mRNA). These data demonstrate the ability of alterations in bile acids to recapitulate important metabolic improvements seen after bariatric surgery. Further, our work establishes a model for focused study of bile acids in the context of bariatric surgery that may lead to the identification of therapeutics for metabolic disease.

Topics: Animals; Bariatric Surgery; Bile Acids and Salts; Endoplasmic Reticulum Stress; Glucagon-Like Peptide 1; Male; Obesity; Rats; Taurochenodeoxycholic Acid

To evaluate and compare the protective effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration in different models of retinal degeneration (RD) in mice.. Bbs(M390R/M390R) mice were injected subcutaneously twice a week, from P40 to P120, and rd10 mice were injected every 3 days from P6 to P38 with TUDCA or vehicle (0.15 M NaHCO(3)). Rd1 and rd16 mice were injected daily from P6 to P30 with TUDCA or vehicle. Retinal structure and function were determined at multiple time points by electroretinography (ERG), optical coherence tomography (OCT), and histology.. The amplitude of ERG b-waves was significantly higher in TUDCA-treated Bbs1 and rd10 animals than in controls. Retinal thickness on OCT was slightly greater in treated Bbs1 animals than in the controls. Histologically, outer segments were preserved, and the outer nuclear layer was significantly thicker in the treated Bbs1 and rd10 mice than in the controls. Bbs1(M390R/M390R) mice developed less obesity than the control Bbs1(M390R/M390R) while receiving TUDCA. The Rd1 and rd16 mice showed no improvement with TUDCA treatment, and the rd1 mice did not have normal weight gain during treatment.. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in Bbs1(M390R/M390R) mice, and prevented obesity assessed at P120. TUDCA treatment preserved ERG b-waves and the outer nuclear layer in the rd10 mice to P30. TUDCA is a prime candidate for treatment of humans with retinal degeneration, especially those with Bardet-Biedl syndrome, whom it may help not only with the vision loss, but with the debilitating obesity as well.

Topics: Animals; Bardet-Biedl Syndrome; Cholagogues and Choleretics; Disease Models, Animal; Electroretinography; Injections, Subcutaneous; Mice; Microtubule-Associated Proteins; Obesity; Retina; Retinal Degeneration; Retinitis Pigmentosa; Taurochenodeoxycholic Acid; Tomography, Optical Coherence

Obesity involves inflammation. MCP-1, an inflammatory chemokine, and MCP-1-induced protein (MCPIP) are known to induce adipogenesis that causes increase in the number of adipocytes. Here we elucidate the intermediate processes through which MCPIP induces adipogenesis. Forced expression of MCPIP in 3T3-L1 preadipocytes caused increased reactive oxygen/nitrogen species (ROS/RNS) production and inducible-nitric oxide synthase (iNOS) expression, endoplasmic reticulum stress (ER), as indicated by expression of ER chaperones and protein disulfide isomerase, and autophagy as indicated by expression of beclin-1 and cleavage of LC3. Treatment of ROS inhibitor, apocynin attenuated MCPIP induction of adipogenesis as measured by the induction of transcription factors involved in adipogenesis, adipocyte markers and lipid droplet accumulation. Inhibition of ER stress with taurursodeoxycholate or knockdown of inositol requiring enzyme 1 (IRE1) inhibited MCPIP induced autophagy and adipogenesis. Preadipocytes in adipogenesis-inducing cocktail manifested ER stress and autophagy. Knockdown of MCPIP attenuated these effects. MCPIP induced p38 activation and p38 inhibitor, SB203580, attenuated MCPIP-induced adipogenesis.

Topics: 3T3-L1 Cells; Acetophenones; Adipogenesis; Animals; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Endoribonucleases; Heat-Shock Proteins; Imidazoles; Mice; Nitric Oxide Synthase Type II; Obesity; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Pyridines; Reactive Nitrogen Species; Reactive Oxygen Species; Ribonucleases; RNA Interference; RNA, Small Interfering; Taurochenodeoxycholic Acid

Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-γ (PPARγ) and damage. When PPARγ was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARγ, and the PPARγ antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNβ (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARγ antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARγ and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.

Topics: Animals; Antiviral Agents; Blotting, Western; Endoplasmic Reticulum; Fatty Liver; Liver Transplantation; Male; Obesity; Organ Preservation; PPAR gamma; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rats, Zucker; Reperfusion Injury; Taurochenodeoxycholic Acid; Toll-Like Receptor 4; Transplantation, Isogeneic; Unfolded Protein Response

Adipose tissue plays a central role in maintaining metabolic homeostasis under normal conditions. Metabolic diseases such as obesity and type 2 diabetes are often accompanied by chronic inflammation and adipose tissue dysfunction. In this study, we observed that endoplasmic reticulum (ER) stress and the inflammatory response occurred in adipose tissue of mice fed a high-fat diet for a period of 16 weeks. After 16 weeks of feeding, ER stress markers increased and chronic inflammation occurred in adipose tissue. We found that ER stress is induced by free fatty acid (FFA)-mediated reactive oxygen species (ROS) generation and up-regulated gene expression of inflammatory cytokines in 3T3-L1 adipocytes. Oral administration to obese mice of chemical chaperons, which alleviate ER stress, improved chronic inflammation in adipose tissue, followed by the suppression of increased body weight and improved insulin signaling. These results indicate that ER stress plays important pathophysiological roles in obesity-induced adipose tissue dysfunction.

Topics: 3T3-L1 Cells; Adipose Tissue; Administration, Oral; Animals; Body Weight; Butylamines; Chronic Disease; Cytokines; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Acids, Nonesterified; Inflammation; Insulin; Male; Mice; Mice, Inbred C57BL; Obesity; Reactive Oxygen Species; Signal Transduction; Taurochenodeoxycholic Acid; Up-Regulation

ER stress is involved in the pathophysiology of obesity although little is known about the role of ER stress on obesity-associated cardiac dysfunction. This study was designed to examine the effect of ER chaperone tauroursodeoxycholic acid (TUDCA) on obesity-induced myocardial dysfunction. Adult lean and ob/ob obese mice were treated with TUDCA (50mg/kg/day, p.o.) or vehicle for 5 weeks. Oral glucose tolerance test (OGTT) was performed. Echocardiography, cardiomyocyte contractile and intracellular Ca(2+) properties were assessed. Sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity and protein expression of intracellular Ca(2+) regulatory proteins were measured using (45)Ca(2+) uptake and Western blot analysis, respectively. Insulin signaling, ER stress markers and HSP90 were evaluated. Our results revealed that chronic TUDCA treatment lowered systolic blood pressure and lessened glucose intolerance in obese mice. Obesity led to increased diastolic diameter, cardiac hypertrophy, compromised fractional shortening, cardiomyocyte contractile (peak shortening, maximal velocity of shortening/relengthening, and duration of contraction/relaxation) and intracellular Ca(2+) properties, all of which were significantly attenuated by TUDCA. TUDCA reconciled obesity-associated decrease in SERCA activity and expression, and increase in serine phosphorylation of IRS, total and phosphorylated cJun, ER stress markers Bip, peIF2α and pPERK. Obesity-induced changes in phospholamban and HSP90 were unaffected by TUDCA. In vitro finding revealed that TUDCA ablated palmitic acid-induced cardiomyocyte contractile dysfunction. In summary, these data depicted a pivotal role of ER stress in obesity-associated cardiac contractile dysfunction, suggesting the therapeutic potential of ER stress as a target in the management of cardiac dysfunction in obesity.

Topics: Animals; Blood Pressure; Blotting, Western; Calcium; Cells, Cultured; Echocardiography; Endoplasmic Reticulum; Glucose Tolerance Test; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardial Contraction; Myocytes, Cardiac; Obesity; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Taurochenodeoxycholic Acid

Obesity impairs adiponectin expression, assembly, and secretion, yet the underlying mechanisms remain elusive. The aims of this study were 1) to determine the molecular mechanisms by which obesity impairs adiponectin multimerization and stability, and 2) to determine the potential role of disulfide-bond-A oxidoreductase-like protein (DsbA-L), a recently identified adiponectin interactive protein that promotes adiponectin multimerization and stability in obesity-induced endoplasmic reticulum (ER) stress and adiponectin downregulation.. Tauroursodeoxycholic acid (TUDCA), a chemical chaperone that alleviates ER stress, was used to study the mechanism underlying obesity-induced adiponectin downregulation in db/db mice, high-fat diet-induced obese mice, and in ER-stressed 3T3-L1 adipocytes. The cellular levels of DsbA-L were altered by RNAi-mediated suppression or adenovirus-mediated overexpression. The protective role of DsbA-L in obesity- and ER stress-induced adiponectin downregulation was characterized.. Treating db/db mice and diet-induced obese mice with TUDCA increased the cellular and serum levels of adiponectin. In addition, inducing ER stress is sufficient to downregulate adiponectin levels in 3T3-L1 adipocytes, which could be protected by treating cells with the autophagy inhibitor 3-methyladenine or by overexpression of DsbA-L.. ER stress plays a key role in obesity-induced adiponectin downregulation. In addition, DsbA-L facilitates adiponectin folding and assembly and provides a protective effect against ER stress-mediated adiponectin downregulation in obesity.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Adipose Tissue, White; Animals; Autophagy; Cell Differentiation; Down-Regulation; Drug Tolerance; Endoplasmic Reticulum; Gene Expression Regulation; Insulin; Male; Mice; Mice, Obese; Obesity; Reference Values; Taurochenodeoxycholic Acid

Leptin has not evolved as a therapeutic modality for the treatment of obesity due to the prevalence of leptin resistance in a majority of the obese population. Nevertheless, the molecular mechanisms of leptin resistance remain poorly understood. Here, we show that increased endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in the hypothalamus of obese mice inhibits leptin receptor signaling. The genetic imposition of reduced ER capacity in mice results in severe leptin resistance and leads to a significant augmentation of obesity on a high-fat diet. Moreover, we show that chemical chaperones, 4-phenyl butyric acid (PBA), and tauroursodeoxycholic acid (TUDCA), which have the ability to decrease ER stress, act as leptin-sensitizing agents. Taken together, our results may provide the basis for a novel treatment of obesity.

Topics: Animals; Endoplasmic Reticulum; Hypothalamus; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phenylbutyrates; Receptors, Leptin; Signal Transduction; Taurochenodeoxycholic Acid; Tunicamycin

Endoplasmic reticulum (ER) stress is associated with obesity-induced insulin resistance, yet the underlying mechanisms remain to be fully elucidated. Here we show that ER stress-induced insulin receptor (IR) down-regulation may play a critical role in obesity-induced insulin resistance. The expression levels of IR are negatively associated with the ER stress marker C/EBP homologous protein (CHOP) in insulin target tissues of db/db mice and mice fed a high-fat diet. Significant IR down-regulation was also observed in fat tissue of obese human subjects and in 3T3-L1 adipocytes treated with ER stress inducers. ER stress had little effect on IR tyrosine phosphorylation per se but greatly reduced IR downstream signaling. The ER stress-induced reduction in IR cellular levels was greatly alleviated by the autophagy inhibitor 3-methyladenine but not by the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). Inhibition of autophagy prevented IR degradation but did not rescue IR downstream signaling, consistent with an adaptive role of autophagy in response to ER stress-induced insulin resistance. Finally, chemical chaperone treatment protects cells from ER stress-induced IR degradation in vitro and obesity-induced down-regulation of IR and insulin action in vivo. Our results uncover a new mechanism underlying obesity-induced insulin resistance and shed light on potential targets for the prevention and treatment of obesity-induced insulin resistance and type 2 diabetes.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Autophagy; Disease Models, Animal; Down-Regulation; Endoplasmic Reticulum; Humans; Insulin Resistance; Leupeptins; Mice; Mice, Inbred Strains; Obesity; Phosphorylation; Receptor, Insulin; Taurochenodeoxycholic Acid; Tyrosine