Adipose extracellular matrix deposition is an indicator of obesity and metabolic disorders.

Obesity and metabolic disorders are threats to human health. Extracellular matrix (ECM) is an important member of adipose microenvironment. ECM remodeling contributes to obesity and insulin resistance, but the roles of every single ECM component is still not fully understood. We observed glucose and lipids metabolic disorders in high-fat diet (HFD)-fed mice and humans with obesity. Higher levels of inflammatory factors and hormones existed in serum of HFD-fed mice. Multiple collagens, laminins, fibronectin, nidogen, and Hspg2 were upregulated in obese white adipose tissue (WAT) from mice and humans. These effects were stronger in subcutaneous WAT than visceral WAT in mice, but the fat depot difference was reversed in humans. The ECM structure and the morphology of adipocytes seeded on ECM were changed in the HFD group. In human visceral WAT, ECM genes showed positive correlations with blood lipids and glucose. In vitro, collagen I/IV and LAMA4 proteins showed similar changes with C/EBPα during the differentiation of adipocytes. Macromolecular crowders (MMC) promoted partial collagen and non-collagen gene expression. Oleic acid (OA) and MMC upregulated collagen I/IV and LAMA4 proteins, and the effects of MMC were stronger than that of OA. Moreover, MMC promoted the differentiation of adipocytes, but OA increased the size of lipid droplets. Positive correlations were observed between ECM genes and adipogenesis-related genes in adipocytes. In conclusion, some obesogens (such as HFD) induce ECM remodeling, and the upregulation of ECM components is closely related to adipogenesis, suggesting that adipose ECM deposition is an indicator of obesity and metabolic disorders.

High-Fat-Diet-Induced Extracellular Matrix Deposition Regulates Integrin-FAK Signals in Adipose Tissue to Promote Obesity.

SCOPE: High-fat-diet (HFD) is an important factor in obesity. Extracellular matrix (ECM) regulates white adipose tissue (WAT), but its mechanism is unknown. METHODS AND RESULTS: This study uses three models-HFD-fed mice, human with obesity, and 3T3-L1 adipocytes with oleic acid (OA)/macromolecular crowders (MMC) treatment. Glucose and lipids metabolic disorders, increased collagen I/IV and laminin α2/4 (LAMA2/4), and upregulated integrins (ITGA1/ITGA7) - focal adhesion kinase (FAK) - c-Jun N-terminal kinase (JNK)/extracellular regulated protein kinase 1/2 (ERK1/2) signals in obese WAT from mice and human are observed. The upregulation of ECM - integrin - FAK signals is stronger in subcutaneous WAT than that in visceral WAT of mice, but these results are reversed in human. In vitro, oleic acid (OA) promotes lipid accumulation and upregulates collagen IV, LAMA4, and p-JNK. MMC is used to induce ECM deposition in adipocytes. MMC promotes adipocyte differentiation and integrins - FAK - JNK/ERK1/2 signals. When FAK phosphorylation is inhibited, downstream p-JNK is decreased. Inhibition of FAK phosphorylation reduces adipocyte differentiation, but MMC partially reverses this effect. CONCLUSION: HFD-induced ECM deposition, whose signals are transmitted into adipocytes through upregulating ITGA1/ITGA7, activates the phosphorylation of intracellular FAK - JNK/ERK1/2 signals, and promotes adipogenesis in WAT. This mechanism provides novel therapeutic targets to treat obesity.

Maternal nicotine exposure impairs brown adipose tissue via AMPK-SIRT1-PGC-1α signals in male offspring.

AIMS: Maternal nicotine exposure during pregnancy and lactation is associated with obesity in offspring. Brown adipose tissue (BAT) is correlated with energy metabolism and obesity. In this study, we explored the mechanism of maternal nicotine exposure on BAT changes in male offspring. MAIN METHODS: Pregnant rats were randomly assigned to nicotine (1.0 mg/kg twice per day, subcutaneous administration) or control groups. In vitro, C3H10T1/2 cells were induced to differentiate into mature brown adipocytes, and 0-50 µM nicotine was given to C3H10T1/2 cells during the differentiation process. KEY FINDINGS: Nicotine-exposed males had white-like adipocytes and abnormal mitochondria structure in iBAT at 26 weeks. The expression of mitochondrial genes, UCP1 and AMPK-SIRT1-PGC-1α pathway were downregulated in the nicotine group at 26 weeks rather than 4 weeks. In vitro, 50 µM nicotine decreased the expression of mitochondrial genes, UCP1 and AMPK-SIRT1-PGC-1α pathway in brown adipocytes. SIGNIFICANCE: Maternal nicotine exposure showed the "programming" effect on the decreased brown-like phenotype in BAT of adult male offspring via downregulating AMPK-SIRT1-PGC-1α pathway. This impairment of BAT may be a potential mechanism of nicotine-induced obesity in male offspring.

Maternal nicotine exposure during pregnancy and lactation induces brown adipose tissue whitening in female offspring.

Maternal nicotine exposure during pregnancy and lactation is associated with obesity in female offspring. Brown adipose tissue (BAT) is related to energy metabolism and obesity. In this study, we explored the mechanism of maternal nicotine exposure on BAT "whitening" in female offspring. Pregnant rats were randomly assigned to nicotine (1.0 mg/kg twice per day, subcutaneous administration) or control groups. The weight, structure, and microvascular density of interscapular BAT (iBAT) and the expression of PGC-1αUCP1 signals, mitochondrial biogenesis-related genes and angiogenesis-related genes were tested in 4- and 26-week-aged female offspring. In vitro, C3H10T1/2 cells were induced to differentiate into mature brown adipocytes, and 0-50 µM nicotine was treated on cells during the differentiation process. Nicotine-exposed females had higher iBAT weight, white-like adipocytes and abnormal mitochondrial structure in iBAT at 26 weeks rather than 4 weeks. The PGC-1αUCP1 signals and brown-like genes were down-regulated at 26 weeks, but the microvascular density and the expression of pro-angiogenic factors reduced more at 4 weeks in the nicotine group. In vitro, 50 µM nicotine significantly decreased the expression of PGC-1αUCP1 signals and angiogenesis-related genes. In conclusion, maternal nicotine exposure during pregnancy and lactation led to the "whitening" of BAT in adult female offspring: nicotine decreased BAT angiogenesis in the early development stage, and then, the impairment of blood vessels programed for the reduction of BAT phenotype through down-regulating the PGC-1αUCP1 signals in adulthood. This impairment of BAT may be a potential mechanism of nicotine-induced obesity in female offspring.

Maternal nicotine exposure enhances adipose tissue angiogenic activity in offspring: Sex and age differences.

Maternal nicotine exposure during pregnancy and lactation (NIC) is associated with dysfunction of white adipose tissue (WAT). We focused on the NIC-induced WAT angiogenesis and explored its sex and age differences. Pregnant rats were randomly assigned to NIC (1.0 mg/kg nicotine twice per day) or control groups. Distribution and density of blood vessels were observed. Angiogenesis-related genes were tested at 4, 12 and 26 weeks to estimate angiogenic activity. In vitro, nicotine concentration- and time-response experiments (0-50 µM) were conducted in 3T3-L1. Lipid accumulation and angiogenesis-related genes were tested. NIC increased the blood vessels in inguinal subcutaneous WAT (igSWAT) and gonadal WAT (gWAT) of 26-week-aged male and 4-week-aged female offspring. In males, nicotine showed higher angiogenic activity at 26 weeks than at 4 weeks in igSWAT and gWAT. In females, nicotine's angiogenic activity was higher at 4 weeks than 26 weeks in igSWAT and gWAT. In vitro, nicotine promoted adipocyte differentiation, and increased the expression of angiogenesis-related genes in concentration- and time dependent manners. In conclusion, NIC-induced enhancement of angiogenic activity in WAT presented sex and age differences: nicotine showed higher angiogenic activity in adulthood than in childhood of male offspring, but the converse results were observed in female offspring.

The association between maternal nicotine exposure and adipose angiogenesis in female rat offspring: A mechanism of adipose tissue function changes.

Maternal smoking during pregnancy and lactation is associated with increased fat mass in the offspring, but the mechanism by which this occurs is not fully understood. Our study focused on the relationships among maternal nicotine exposure, adipose angiogenesis and adipose tissue function in female offspring. Pregnant rats were randomly assigned to nicotine or control groups. Microvascular density, lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins were tested in 4-, 12- and 26-week female offspring. In vitro, nicotine concentration- and time-response experiments were conducted in 3T3-L1. Lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins were tested. The conditioned media of differentiated 3T3-L1 treated with nicotine were used to observe tube formation in human umbilical vein endothelial cells (HUVECs). Nicotine-exposed females presented higher adipose microvascular density. The gene expression of α7nAChR, Egr1 and FGF2 was significantly increased in gonadal white adipose tissue (gWAT) and inguinal subcutaneous WAT (igSWAT) of nicotine-exposed females at 4 weeks of age. The protein expression of α7nAChR, Egr1 and FGF2 was increased in gWAT and igSWAT of nicotine-exposed females at 4 weeks of age, and increased in gWAT at 26 weeks. In vitro, nicotine increased the expression of lipid metabolism and α7nAChR-Egr1-FGF2 signaling pathway genes/proteins in a concentration- and time-dependent manner. In the tube formation experiment, adipocytes affected by nicotine promoted HUVEC angiogenesis. Therefore, maternal nicotine exposure promoted the early angiogenesis of adipose tissue via the α7nAChR-Egr1-FGF2 signaling pathway, and this angiogenesis mechanism was associated with increased adipogenesis in adipose tissue of female offspring.

Age Differences in the Relationship between Secondhand Smoke Exposure and Risk of Metabolic Syndrome: A Meta-Analysis.

Secondhand smoke (SHS), a common environmental exposure factor, has become a serious public health problem. Metabolic syndrome is another worldwide clinical challenge. Our study tried to determine the age differences in the relationship between SHS and the risk of metabolic syndrome. Studies were searched in PubMed and Web of Science from 11 November to 30 November 2018. Eighteen studies were finally included based on inclusion and exclusion criteria. The relationship between SHS and the risk indicators of metabolic syndrome was analyzed. The weighted mean difference (WMD) of fasting plasma glucose (FPG), insulin, body mass index (BMI), and waist circumference (WC), and the standard mean difference (SMD) of total cholesterol, triglycerides, and low- and high-density lipoprotein-cholesterol (LDL-C, HDL-C) were calculated in a meta-analysis. SHS was positively associated with the level of insulin and WC. According to the subgroup analysis based on age difference, SHS was positively associated with FPG in the upper age group, and positively associated with LDL-C and negatively associated with HDL-C in the lower age group. BMI showed a more obvious positive correlation in the adults group than in the children and the teenagers group. In conclusion, the association of metabolic syndrome with SHS varies with age. When exposed to SHS, older people may be more susceptible to glucose metabolic disorder, but younger people may be more susceptible to lipid metabolic disorder.

Effects of maternal omega-3 fatty acids supplementation during pregnancy/lactation on body composition of the offspring: A systematic review and meta-analysis.

BACKGROUND & AIMS: The effect of maternal omega-3 fatty acids intake on the body composition of the offspring is unclear. The aim of this study was to conduct a systematic review and meta-analysis to confirm the effects of omega-3 fatty acids supplementation during pregnancy and/or lactation on body weight, body length, body mass index (BMI), waist circumference, fat mass and sum of skinfold thicknesses of offspring. METHODS: Human intervention studies were selected by a systematic search of PubMed, Web of Science, the Cochrane Library and references of related reviews and studies. Randomized controlled trials of maternal omega-3 fatty acids intake during pregnancy or lactation for offspring's growth were included. The data were analyzed with RevMan 5.3 and Stata 12.0. Effect sizes were presented as weighted mean differences (WMD) or standardized mean difference (SMD) with 95% confidence intervals (95% CI). RESULTS: Twenty-six studies comprising 10,970 participants were included. Significant increases were found in birth weight (WMD = 42.55 g, 95% CI: 21.25, 63.85) and waist circumference (WMD = 0.35 cm, 95% CI: 0.04, 0.67) in the omega-3 fatty acids group. There were no effects on birth length (WMD = 0.09 cm, 95% CI: -0.03, 0.21), postnatal length (WMD = 0.13 cm, 95% CI: -0.11, 0.36), postnatal weight (WMD = 0.04 kg, 95% CI: -0.07, 0.14), BMI (WMD = 0.09, 95% CI: -0.05, 0.23), the sum of skinfold thicknesses (WMD = 0.45 mm, 95% CI: -0.30, 1.20), fat mass (WMD = 0.05 kg, 95% CI: -0.01, 0.11) and the percentage of body fat (WMD = 0.04%, 95% CI: -0.38, 0.46). CONCLUSIONS: This meta-analysis showed that maternal omega-3 fatty acids supplementation can increase offspring's birth weight and postnatal waist circumference. However, it did not appear to influence children's birth length, postnatal weight/length, BMI, sum of skinfold thicknesses, fat mass and the percentage of body fat during postnatal period. Larger, well-designed studies are recommended to confirm this conclusion.

Perinatal nicotine exposure increases obesity susceptibility by peripheral leptin resistance in adult female rat offspring.

Maternal nicotine (NIC) exposure causes overweight, hyperleptinemia and metabolic disorders in adult offspring. Our study aims to explore the underlying mechanism of perinatal NIC exposure increases obesity susceptibility in adult female rat offspring. In our model, we found that adult NIC-exposed females presented higher body weight and subcutaneous and visceral fat mass, as well as larger adipocytes, while no change was found in food intake. Serum profile showed a higher serum glucose, insulin and leptin levels in NIC-exposed females. In adipose tissue and liver, the leptin signaling pathway was blocked at 26 weeks, presented lower Janus tyrosine kinase 2 and signal transducer and activator of transcription 3 gene expression, higher suppressor of cytokine signaling 3 gene expression (in adipose tissue) and lower leptin receptors gene expression (in liver), indicating that peripheral leptin resistance occurred in NIC-exposed adult females. In female rats, the expression of lipolysis genes was affected dominantly in adipose tissue, but lipogenesis genes was affected in liver. Furthermore, the glucose and insulin tolerance tests showed a delayed glucose clearance and a higher area under the curve in NIC-exposed females. Therefore, perinatal NIC exposure programed female rats for adipocyte hypertrophy and obesity in adult life, through the leptin resistance in peripheral tissue.