Tissue Endoplasmic Reticulum Stress Research Articles

Maternal obesity during pregnancy leads to adipose tissue ER stress in mice via miR-126-mediated reduction in Lunapark

Aims/hypothesisLevels of the microRNA (miRNA) miR-126-3p are programmed cell-autonomously in visceral adipose tissue of adult offspring born to obese female C57BL/6J mice. The spectrum of miR-126-3p targets and thus the consequences of its dysregulation for adipocyte metabolism are unknown. Therefore, the aim of the current study was to identify novel targets of miR-126-3p in vitro and then establish the outcomes of their dysregulation on adipocyte metabolism in vivo using a well-established maternal obesity mouse model.MethodsmiR-126-3p overexpression in 3T3-L1 pre-adipocytes followed by pulsed stable isotope labelling by amino acids in culture (pSILAC) was performed to identify novel targets of the miRNA. Well-established bioinformatics algorithms and luciferase assays were then employed to confirm those that were direct targets of miR-126-3p. Selected knockdown experiments were performed in vitro to define the consequences of target dysregulation. Quantitative real-time PCR, immunoblotting, histology, euglycaemic–hyperinsulinaemic clamps and glucose tolerance tests were performed to determine the phenotypic and functional outcomes of maternal programmed miR-126-3p levels in offspring adipose tissue.ResultsThe proteomic approach confirmed the identity of known targets of miR-126-3p (including IRS-1) and identified Lunapark, an endoplasmic reticulum (ER) protein, as a novel one. We confirmed by luciferase assay that Lunapark was a direct target of miR-126-3p. Overexpression of miR-126-3p in vitro led to a reduction in Lunapark protein levels and increased Perk (also known as Eif2ak3) mRNA levels and small interference-RNA mediated knockdown of Lunapark led to increased Xbp1, spliced Xbp1, Chop (also known as Ddit3) and Perk mRNA levels and an ER stress transcriptional response in 3T3-L1 pre-adipocytes. Consistent with the results found in vitro, increased miR-126-3p expression in adipose tissue from adult mouse offspring born to obese dams was accompanied by decreased Lunapark and IRS-1 protein levels and increased markers of ER stress. At the whole-body level the animals displayed glucose intolerance.Conclusions/interpretationConcurrently targeting IRS-1 and Lunapark, a nutritionally programmed increase in miR-126-3p causes adipose tissue insulin resistance and an ER stress response, both of which may contribute to impaired glucose tolerance. These findings provide a novel mechanism by which obesity during pregnancy leads to increased risk of type 2 diabetes in the offspring and therefore identify miR-126-3p as a potential therapeutic target.Graphical abstract

Maternal obesity affects offspring

Physiology Alterations in cellular homeostasis can cause endoplasmic reticulum (ER) stress and activation of the stress pathway—the unfolded protein response. Obesity in mice induces ER stress in tissues and the hypothalamus, a brain region that plays a role in many important functions, including controlling food intake and energy expenditure. Park et al. found that diet-induced obesity in pregnant mice resulted in postnatal ER stress in the pancreas and hypothalamus of offspring. These mice had increased food intake, adiposity, and body weight and showed disrupted development of specific hypothalamic neurons associated with energy homeostasis. Treatment of offspring with an ER stress–relieving drug reversed these effects. This suggests that in mice, maternal physiology has important nutritional programming effects on offspring. PLOS Biol. 18 , e3000296 (2020).

Study progress of adipose tissue endoplasmic reticulum stress and childhood obesity-related type 2 diabetes

In recent years, the incidence of childhood obesity has also increased year by year as people′s living standards keep improving.Over-accumulation of adipose tissue in children with obesity not only affects growth and development, but also increases the risk of certain related metabolic diseases such as insulin resistance and type 2 diabetes.It has been recognized that adipose tissue is the main site of obesity-induced endoplasmic reticulum stress and plays an important role in the development of insulin resistance and type 2 diabetes.As the largest human endocrine organ, adipose tissue will be considered as a key target for the treatment of obesity-related metabolic diseases in children.Now, the mechanism of insulin resistance and type 2 diabetes in children with obesity caused by endoplasmic reticulum stress in adipose tissue were briefly reviewed, and the role of adipose tissue in the development of obesity-associated type 2 diabetes was deeply understanded.It is beneficial for people to actively promote the prevention and treatment of childhood obesity and provide new ideas for clinical treatment of child-related metabolic diseases. Key words: Adipose tissue; Endoplasmic reticulum stress; Child; Obesity; Insulin resistance; Type 2 diabetes

Amiodarone-induced adipose tissue endoplasmic reticulum stress and lipolysis may contribute to hepatic lipid accumulation

Amiodarone-induced adipose tissue endoplasmic reticulum stress and lipolysis may contribute to hepatic lipid accumulation

Effects of vitamin D3 on endoplasmic reticulum stress in adipose tissue and insulin resistance induced by high fat diet in mice

Objective To study the effect of vitamin D3 on adipose tissue endoplasmic reticulum stress and insulin resistance induced by high fat diet in mice. Methods Eighty male C57BL/6 mice were divided into control group(n=20)and experimental group(n=60), fed with common food and high fat diet, respectively. After the establishment of the obesity model, the experimental mice were divided into control group, low-dose(50 IU/kg)vitamin D3 group(VitD-L), and high-dose(250 IU/kg)vitamin D3 group(VitD-H). After the mice were fed for 1 week, Western blot was used to detect the expressions of immunoglobulin heavy chain-binding protein(Bip), phosphorylated inositol-requiring enzyme 1(p-IRE1), phosphorylated protein kinase R(PKR)-like endoplasmic reticulum kinase(p-PERK), and NF-κB protein in adipose tissue. Serum levels of TNF-α, IL-6, serum 25-hydroxyvitamin D, fasting plasma glucose, HbA1C, triacylglyceride, and fasting insulin were measured and the insulin resistance index was calculated. Results Vitamin D3 down-regulated the expressions of endoplasmic reticulum stress key genes including Bip, p-IRE1, and p-PERK; and decreased the protein expression of NF-κB and the serum levels of TNF-α and IL-6(P<0.05). Vitamin D3 also significantly reduced the levels of fasting blood glucose, HbA1C, triacylglyceride, and fasting insulin in obese mice(P<0.05), while alleviated the insluin resistance in obese mice. Conclusion Vitamin D3 may significantly improve inflammatory response and insulin resistance via inhibiting endoplasmic reticulum stress in adipose tissue of obese mice. (Chin J Endocrinol Metab, 2017, 33: 861-864) Key words: Obesity; Vitamin D3; Endoplasmic reticulum stress; Insulin resistance

Curcumin inhibits lipolysis via suppression of ER stress in adipose tissue and prevents hepatic insulin resistance

Curcumin is natural polyphenol with beneficial effects on lipid and glucose metabolism and this study aimed to investigate the effects of curcumin on lipolysis and hepatic insulin resistance. Endoplasmic reticulum (ER) stress and lipolysis signaling in adipose and FFA influx, lipid deposits, and glucose production in liver were examined. Palmitate challenge and high-fat diet feeding evoked ER stress-associated lipolysis with cAMP accumulation in adipose tissue. Curcumin treatment inhibited adipose tissue ER stress by dephosphorylation of inositol-requiring enzyme 1α and eukaryotic initiation factor 2α and reduced cAMP accumulation by preserving phosphodiesterase 3B induction. Knockdown of mitogen-activated protein kinase α1/2α with siRNAs diminished such effects of curcumin. As a result from downregulation of cAMP, curcumin blocked protein kinase (PK)A/hormone-sensitive lipase lipolysis signaling, and thereby reduced glycerol and FFA release from adipose tissue. Curcumin reduced FFA influx into the liver by blocking FFA trafficking, and then prevented diacylglycerol deposits and PKCε translocation in the liver, resultantly improving insulin action in the suppression of hepatic gluconeogenesis. Curcumin decreased adipose lipolysis by attenuating ER stress through the cAMP/PKA pathway, reduced FFA influx into the liver by blocking FFA trafficking, and thereby improved insulin sensitivity to inhibit hepatic glucose production. These findings suggested a novel pathway of curcumin to prevent lipid deposits and insulin resistance in liver by beneficial regulation of adipose function.

Fatty acid-mediated endoplasmic reticulum stress in vivo: Differential response to the infusion of Soybean and Lard Oil in rats

BackgroundIn cell systems, saturated fatty acids, compared to unsaturated fatty acids, induce a greater degree of ER stress and inflammatory signaling in a number of cell types, including hepatocytes and adipocytes. The aim of the present study was to determine the effects of infusions of lard oil (enriched in saturated fatty acids) and soybean oil (enriched in unsaturated fatty acids) on liver and adipose tissue ER stress and inflammatory signaling in vivo. MethodsLipid emulsions containing glycerol, phosphatidylcholine, antibiotics (Control, n=7) and either soybean oil (Soybean, n=7) or lard oil (Lard, n=7) were infused intravenously into rats over a 4 h period. ResultsPlasma free fatty acid levels were 0.5±0.1mmol/L (mean±SD) in Control and were increased to 1.0±0.3mmol/L and 1.1±0.3mmol/L in Soybean and Lard, respectively. Glucose and insulin levels were not different among groups. Markers of endoplasmic reticulum (ER) stress and activation of inflammatory pathway signaling were increased in liver and adipose tissue from Soybean and Lard compared to Control, but were increased to a greater extent in Lard compared to Soybean. ConclusionsThese data suggest that elevated plasma free fatty acids can induce hepatic and adipose tissue ER stress and inflammation in vivo. In addition, saturated fatty acids appear to be more cytotoxic than unsaturated fatty acids in vivo.