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Background: White adipose tissue (WAT) has a key role in maintaining energy balance throughout the body, and their dysfunction take part in the regulation of diabetes mellitus. However, the internal regulatory mechanisms underlying are still unknown. Methods and results: We generated adipocyte‐specific FAK KO (FAK‐AKO) mice and investigated their phenotype. The cascade of adipocyte, macrophage in adipocyte tissues, and pancreatic β‐cells were proposed in FAK‐AKO mice and validated by cell line studies using 3T3‐L1, Raw264.7 and Min6. The FAK‐AKO mice exhibited glucose intolerance, reduced adipose tissue mass and increased apoptosis, lipolysis and inflammatory response in adipose tissue. We further demonstrate that adipocyte FAK deletion increases β cell apoptosis and inflammatory infiltrates into islets, which is potentiated if mice were treated with STZ. In the STZ‐induced diabetes model, FAK AKO mice exhibit less serum insulin content and pancreatic β cell area. Moreover, serum pro‐inflammatory factors increased and insulin levels decreased after glucose stimulation in FAK AKO mice. In a parallel vitro experiment, knockdown or inhibition of FAK during differentiation also increased apoptosis, lipolysis and inflammatory in 3T3‐L1 adipocytes, whereas the opposite was observed upon overexpression of FAK. Moreover, coculturing LPS‐treated RAW264.7 macrophages with knockdown FAK of 3T3‐L1 adipocytes increased macrophage pro‐inflammatory response. Furthermore, conditioned medium from above stimulated Min6 cells apoptosis (with or without STZ), whereas the opposite was observed upon overexpression of FAK. Mechanistically, FAK protein interact with TRAF6 in adipocytes and knockdown or inhibition of FAK activated TRAF6/TAK1/NF‐κB signaling, which exacerbates inflammation of adipocytes themselves. Conclusion: Adipocyte FAK deletion promotes both adipocyte apoptosis and adipose tissue inflammation. Pro‐inflammatory factors released by the FAK‐null adipose tissue further trigger apoptosis in pancreatic islets induced by the administration of STZ, thereby exacerbating the diabetes mellitus. This study reveals a link between FAK‐mediated adipose inflammation and diabetes mellitus, a mechanism that has not been previously recognized. [ABSTRACT FROM AUTHOR]

Nicotine, the main component of cigarette smoke, affects white/brown adipocytes. Few studies have concentrated on beige adipocytes. In this study, 3T3-L1 cells were differentiated in the presence of nicotine (25, 50 and 100 μmol/L) during early differentiation and maintenance stages. Cell viability and the state of lipid droplets were assessed by the MTT assay and Oil Red O, respectively, and the expression of beige-related genes and proteins was examined by RT-qPCR, Western blotting and flow cytometry. Nicotine did not alter adipocyte differentiation; however, it increased the expression of peroxisome proliferator- activated receptor gamma (PPARγ) protein during early differentiation and maintenance. Nicotine treatment during early differentiation downregulated gene and protein expression of PPARγ coactivator 1-alpha (PGC-1α), uncoupling protein 1 (UCP1) and cluster of differentiation 137 (CD137), and gene expression of Cbp/p300 interacting transactivator with Glu/ Asp rich carboxy-terminal domain 1 (Cited1), transmembrane protein 26 (Tmem26), and short stature homeobox 2 (Shox2). Nicotine treatment during the maintenance stage upregulated these beige-related genes/proteins. Nicotine treatment of immature adipocytes damaged beige function through a decrease in PGC-1α/UCP1 expression, but nicotine treatment of mature adipocytes or both immature and mature cells enhanced beige functioning. Nicotine induced beige-like phenotype dysfunction in 3T3-L1 adipocytes. This process may affect thermogenesis in adipose tissue and cause a dysfunction in fat metabolism.

This study was carried out to explore environmental compound such as nicotine can cause adverse effect on chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Rat BMSCs were capsulated in alginate beads incubated with a chondrogenic differentiation medium and while chondrogenic differentiation of rat BMSCs were cultured for 4 weeks treated with nicotine at concentrations of 25, 50 and 100 μM. The effect of nicotine on BMSCs viability was tested using MTT assay. After chondrogenic differentiation, alginate beads sections were stained for glycosaminoglycan (GAG) with alcian blue and safranin-O. The mRNA expression of chondrogenesis related genes, including collagen type 2 alpha 1 (Col2A1), aggrecan, insulin-like growth factor-1 (IGF-1) were determined by RT-PCR. Nicotine did not affect viability of BMSCs at any indicated concentration. Continuous exposure to nicotine for 4 weeks resulted in significant decrease of the area stained with alcian blue and safranin-O in a concentration-dependent manner compared with the control (P<0.05). After 4 weeks in chondrogenic medium, nicotine dose-dependently decreased the expression of aggrecan, Col2A1 and IGF-1 genes in rat BMSCs chondrogenesis compared with the control (P<0.05). It turned out that nicotine suppresses chondrogenic differentiation potential of BMSCs, leading to a poorly differentiated cartilage. [ABSTRACT FROM AUTHOR]

Abstract: GGA (geranylgeranylacetone) may induce Hsp70 synthesis, thus contributing to the protective effects of GGA in several disease states. This study evaluated the protective effects of GGA against heat injury to rat and striatum neurons in terms of mechanisms. Rats were exposed to 41.5°C for 35min to induce heatstroke; the protective effects of GGA were then evaluated by change in rectal temperature (Tre) during heat exposure and survival time after heatstroke. Primary cultured striatum neurons were incubated with GGA for 24h, and then heat-treated at 43°C for a further 1h. The viability, membrane surface ultrastructure and Hsp70 expression of striatum neurons were all observed. Furthermore, the effects of quercetin an inhibitor of Hsp70 synthesis were also investigated. Compared to the heatstroke group, GGA delayed Tre in reaching 42.1°C (P <0.05) and prolonged the survival time after heatstroke (P <0.01). The LDH releasing percentage decreased in GGA groups (P <0.05, P <0.01) compared to the heat-treatment group and increased in quercetin groups (P <0.05) compared to GGA group. Results from AFM showed that GGA protected membrane surface ultrastructure against heat injury. In addition, results from Western blot showed that GGA-induced Hsp70 expression of neurons both in normal and heat-treatment conditions (P <0.01, P <0.05) and quercetin inhibited GGA-induced Hsp70 expression (P <0.05). Therefore, GGA had protective effects against heat injury in striatum neurons and rat heatstroke. Quercetin inhibited GGA-induced Hsp70 expression and prevented GGA-protective effects, which indicated that this protection was dependent on the Hsp70 synthesis. [Copyright &y& Elsevier]

Our previous studies have demonstrated that prenatal caffeine exposure (PCE) induced an intrauterine programming of hypothalamic–pituitary–adrenal axis (HPAA)-associated neuroendocrine metabolism in 3-month-old offspring rats. In this study, we aimed to confirm this programming disorder and high susceptibility to metabolic syndrome (MS) in 10-month-old female PCE offspring with postnatal catch-up growth. We found that PCE female offspring rats showed decreased bodyweight but a higher rate of weight gain after birth. Moreover, in the offspring, basal hyperinsulinemia and insulin resistance were observed before unpredictable chronic stress (UCS), but serum total cholesterol (TCH) levels and triglyceride/high-density lipoprotein–cholesterol (TG/HDL-C), TCH/HDL-C and low-density lipoprotein–cholesterol/HDL-C (LDL-C/HDL-C) ratio changes were increased after UCS, accompanied by morphological damage of the related tissues. These results suggested that PCE adult female offspring rats were highly susceptible to MS, which is related to HPAA-associated neuroendocrine-metabolic programming disorder. [ABSTRACT FROM AUTHOR]

To elucidate the possible metabolic mechanism of intrauterine growth retardation induced by nicotine, this study determines the effects of prenatal nicotine exposure on fetal development and cytochrome P4501A1 (CYP1A1), CYP2E1, and P-glycoprotein (Pgp) expression in maternal liver and placenta. Pregnant rats were given 1.0 mg/kg nicotine subcutaneously twice a day from gestational day (GD) 8 to GD 15, 18, or 21. In nicotine-treated groups, fetal developmental parameters including body weight were significantly lower. The activities of CYP1A1 and CYP2E1 in maternal liver microsomes in nicotine-treated groups increased significantly with progressing gestation when compared with the corresponding control, but returned to the level similar to the control in late pregnancy. Nicotine-treated groups induced pathological changes and increased malondialdehyde (MDA) content in the placenta when compared with the control. The gene expressions of CYP1A1 and CYP2E1 in the placenta increased significantly in nicotine-treated groups on GD 15 and GD 18, but returned to the level similar to the corresponding control on GD 21. In nicotine group, there was a decrease of mdr1a expression on GD 15, GD 18, and GD 21, with the most significant decrease on GD 15. In contrast, no significant difference was found in mdr1b mRNA expression between the nicotine-treated animals and the corresponding control. In comparison with the corresponding control, the placental Pgp protein significantly decreased on GD 15 and GD 18. Our results showed that prenatal nicotine exposure resulted in inhibition of fetal growth significantly. The induction of CYP2E1 and CYP1A1 gene expression by nicotine in the maternal liver and placenta may be involved with the observed increase in oxidative stress and lipid peroxidation. The inhibition of the placental Pgp expression by nicotine may also contribute to an increased susceptibility of the fetus to environmental toxins.

Neurodegenerative diseases are characterized by the accumulation of intracellular or extracellular protein aggregates that result from conformational changes in proteins. These diseases may result from an imbalance between the production of misfolded proteins and normal chaperone capacity. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are, therefore, promising therapeutic targets for neurodegenerative diseases.