taurochenodeoxycholic-acid and Insulin-Resistance

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

Various primary and secondary bile acids (BAs) may play pivotal roles in glucose/insulin metabolism. We investigated whether changes in specific BA subtypes were associated with long-term changes in glucose and insulin sensitivity.. This study included 515 adults with overweight or obesity who participated in a 2-year intervention study of weight-loss diets with different macronutrient intakes. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 months after the interventions. We analyzed associations of changes in BA subtypes with two-year changes in fasting glucose, insulin, and insulin resistance (HOMA-IR).. Greater decreases in primary and secondary BA subtypes induced by the interventions were significantly associated with greater reductions of fasting insulin and HOMA-IR at 6 months, showing various effects across the BA subtypes. The reductions of specific BA subtypes (chenodeoxycholate [CDCA], taurocholate [TCA], taurochenodeoxycholate [TCDCA], and taurodeoxycholate [TDCA]) were significantly related to improved glucose levels at 6 months. The initial (6-month) decreases in primary and secondary BA subtypes (glycochenodeoxycholate [GCDCA], TCDCA, and glycoursodeoxycholate [GUDCA]) were also significantly associated with long-term improvements in glucose and insulin metabolism over 2 years. We found significant interactions between dietary fat intake and changes in the BA subtypes for changes in glucose metabolism (P. Weight-loss diet-induced changes in distinct subtypes of circulating BAs were associated with improved glucose metabolism and insulin sensitivity in adults with overweight or obesity. Dietary fat intake may modify the associations of changes in BA metabolism with glucose metabolism.

Topics: Adult; Bile Acids and Salts; Blood Glucose; Diet, Reducing; Dietary Fats; Glucose; Glycochenodeoxycholic Acid; Humans; Insulin; Insulin Resistance; Obesity; Overweight; Taurochenodeoxycholic Acid

Conjugated bile acids are metabolised by upper small intestinal microbiota, and serum levels of taurine-conjugated bile acids are elevated and correlated with insulin resistance in people with type 2 diabetes. However, whether changes in taurine-conjugated bile acids are necessary for small intestinal microbiome to alter insulin action remain unknown.. We evaluated circulating and specifically brain insulin action using the pancreatic-euglycaemic clamps in high-fat (HF) versus chow fed rats with or without upper small intestinal healthy microbiome transplant. Chemical and molecular gain/loss-of-function experiments targeting specific taurine-conjugated bile acid-induced changes of farnesoid X receptor (FXR) in the brain were performed in parallel.. We found that short-term HF feeding increased the levels of taurochenodeoxycholic acid (TCDCA, an FXR ligand) in the upper small intestine, ileum, plasma and dorsal vagal complex (DVC) of the brain. Transplantation of upper small intestinal healthy microbiome into the upper small intestine of HF rats not only reversed the rise of TCDCA in all reported tissues but also enhanced the ability of either circulating hyperinsulinaemia or DVC insulin action to lower glucose production. Further, DVC infusion of TCDCA or FXR agonist negated the enhancement of insulin action, while genetic knockdown or chemical inhibition of FXR in the DVC of HF rats reversed insulin resistance.. Our findings indicate that FXR in the DVC is sufficient and necessary for upper small intestinal microbiome-mediated changes of TCDCA to alter insulin action in rats, and highlight a previously unappreciated TCDCA-FXR axis linking gut microbiome and host insulin action.

Topics: Animals; Brain; Brain Chemistry; Brain Stem; Diet, High-Fat; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Gene Knockdown Techniques; Glucose Clamp Technique; Insulin Resistance; Intestine, Small; Rats; Receptors, Cytoplasmic and Nuclear; Taurochenodeoxycholic Acid

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

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

Topics: Animals; Brain; Cognition; Cognitive Dysfunction; Computational Biology; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Energy Metabolism; Fasting; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gene Expression Regulation; Hippocampus; Indoles; Insulin Resistance; Male; Metabolome; Mice; Propionates; RNA, Ribosomal, 16S; Serotonin; Synapses; Taurochenodeoxycholic Acid

RING finger 186 (RNF186) is involved in the process of endoplasmic reticulum (ER)-stress-mediated apoptosis and inflammation of different cell types, such as HeLa cells and colon epithelial cells. However, the physiological and functional roles of RNF186 in peripheral tissues remain largely unknown. In the current study, we investigate the physiological function of RNF186 in the regulation of ER stress with respect to its biological roles in regulating insulin sensitivity in mouse primary hepatocytes. RNF186 expression is induced in the livers of diabetic, obese and diet-induced obese (DIO) mice. Mouse primary hepatocytes were isolated and treated with Ad-RNF186 or Ad-GFP. The results suggest that overexpression of RNF186 increases the protein levels of the ER stress sensors inositol requiring kinase 1 (IRE1) and C/EBP homologous protein (CHOP) protein, as well as the phosphorylation level of eukaryotic initiation factor 2α (eIF2α), in mouse primary hepatocytes. This effect impedes the action of insulin through c-Jun N-terminal kinase (JNK)-mediated phosphorylation of insulin receptor substrate 1 (IRS1). Furthermore, overexpression of RNF186 also significantly increases the levels of proinflammatory cytokines, including TNFα, IL-6 and MCP1. In addition, tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, alleviates the expression of ER stress markers induced by RNF186 overexpression. Taken together, the results of the present study show that overexpression of RNF186 induces ER stress and impairs insulin signalling in mouse primary hepatocytes, suggesting that RNF186 merits further investigation as a potential therapeutic target for treatment of insulin-resistance-associated metabolic diseases.

Topics: Animals; Chemokine CCL2; Diabetes Mellitus; Diet, High-Fat; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2B; Hep G2 Cells; Hepatocytes; Humans; Insulin; Insulin Resistance; Interleukin-6; Liver; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Obese; Protein Serine-Threonine Kinases; Taurochenodeoxycholic Acid; Transcription Factor CHOP; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases

Fibroblast growth factor 21 (FGF21) has recently emerged as a novel endocrine hormone involved in the regulation of glucose and lipid metabolism. However, the exact mechanisms whereby FGF21 mediates insulin sensitivity remain not fully understood. In the present study, FGF21was administrated in high-fat diet-induced obese mice and tunicamycin-induced 3T3-L1 adipocytes, and metabolic parameters, endoplasmic reticulum (ER) stress indicators, and insulin signaling molecular were assessed by Western blotting. The administration of FGF21 in obese mice reduced body weight, blood glucose and serum insulin, and increased insulin sensitivity, resulting in alleviation of insulin resistance. Meanwhile, FGF21 treatment reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress in adipose tissue of obese mice. Additionally, suppression of ER stress via the ER stress inhibitor tauroursodeoxycholic acid increased adiponectin expression and improved insulin resistance in obese mice and in tunicamycin-induced adipocytes. In conclusion, our results showed that the administration of FGF21 reversed suppression of adiponectin expression and restored insulin signaling via inhibiting ER stress under the condition of insulin resistance, demonstrating the causative role of ER stress in downregulating adiponectin levels.

Topics: 3T3 Cells; Adipocytes; Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cell Line; Diet, High-Fat; Endoplasmic Reticulum Stress; Fibroblast Growth Factors; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Signal Transduction; Taurochenodeoxycholic Acid; Tunicamycin

Endoplasmic reticulum (ER) stress is proposed as a novel link between elevated fatty acids levels, obesity and insulin resistance in liver and adipose tissue. However, it is unknown whether ER stress also contributes to lipid-induced insulin resistance in skeletal muscle, the major tissue responsible of insulin-stimulated glucose disposal. Here, we investigated the possible role of ER stress in palmitate-induced alterations of insulin action, both in vivo, in gastrocnemius of high-palm diet fed mice, and in vitro, in palmitate-treated C(2)C(12) myotubes. We demonstrated that 8 weeks of high-palm diet increased the expression of ER stress markers in muscle of mice, whereas ex-vivo insulin-stimulated PKB phosphorylation was not altered in this tissue. In addition, exposure of C(2)C(12) myotubes to either tuncamycine or palmitate induced ER stress and altered insulin-stimulated PKB phosphorylation. However, alleviation of ER stress by either TUDCA or 4-PBA treatments, or by overexpressing Grp78, did not restore palmitate-induced reduction of insulin-stimulated PKB phosphorylation in C(2)C(12) myotubes. This work highlights that, even ER stress is associated with palmitate-induced alterations of insulin signaling, ER stress is likely not the major culprit of this effect in myotubes, suggesting that the previously proposed link between ER stress and insulin resistance is less important in skeletal muscle than in adipose tissue and liver.

Topics: Animals; Butylamines; Diet; Dietary Fats; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Palmitates; Taurochenodeoxycholic Acid; Tunicamycin

Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA-induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X-box protein 1 (XBP-1s) only attenuates FFA-induced inflammation. PKR-like eukaryotic initiation factor 2α kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA-induced inflammation and insulin resistance. The key downstream target of FFA-induced ER stress is IκB kinase β (IKKβ), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA-induced activation of IKKβ and deficiency of IKKβ alleviates FFA-induced inflammation and insulin resistance. Consistently, overexpression of IKKβ in 3T3-L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKβ overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKβ expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high-fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA-induced inflammation and insulin resistance in adipocytes with PERK and IKKβ as the critical signaling components.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Dietary Fats; DNA-Binding Proteins; eIF-2 Kinase; Endoplasmic Reticulum; Fatty Acids, Nonesterified; I-kappa B Kinase; Inflammation; Insulin; Insulin Resistance; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Regulatory Factor X Transcription Factors; Signal Transduction; Taurochenodeoxycholic Acid; Transcription Factors; X-Box Binding Protein 1

Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D.

Topics: Animals; Blood Pressure; Blotting, Western; Body Weight; Diabetes Mellitus, Type 2; Eating; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Glucose Intolerance; Green Fluorescent Proteins; Hypothalamus; Immunoprecipitation; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Neurosecretory Systems; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; Stress, Physiological; Taurochenodeoxycholic Acid; Telemetry; Thapsigargin

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

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

Topics: Adipose Tissue; Animals; Blood Glucose; Cell Line, Tumor; Diabetes Mellitus, Type 2; Disease Models, Animal; eIF-2 Kinase; Endoplasmic Reticulum; Enzyme Activation; Eukaryotic Initiation Factor-2; Glucose; Glucose Tolerance Test; Homeostasis; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Liver; Mice; Mice, Obese; Phenylbutyrates; Phosphorylation; Receptor, Insulin; Signal Transduction; Taurochenodeoxycholic Acid