Angiotensin II Increases Endoplasmic Reticulum Stress in Adipose Tissue and Adipocytes.

The Renin Angiotensin System (RAS), a key regulator of blood pressure has been linked to metabolic disorders. We have previously reported that adipose overexpression of angiotensinogen in mice (Agt-Tg) induces obesity, in part mediated by adipose tissue inflammation, through yet unidentified mechanisms. Hence, we hypothesize that adipose tissue enrichment of angiotensinogen leads to activation of inflammatory cascades and endoplasmic reticulum (ER) stress, thereby, contributing to obesity. We used wild type (Wt), Agt-Tg and Agt-knockout (KO) mice along with 3T3-L1 and human adipocytes treated with RAS, ER stress and inflammation inhibitors. ER stress and pro-inflammation markers were significantly higher in Agt-Tg compared to Wt mice and captopril significantly reduced their expression. Furthermore, in vitro treatment with Ang II significantly induced ER stress and inflammation, whereas angiotensin II receptor inhibitor, telmisartan reduced RAS effects. Moreover, miR-30 family had significantly lower expression in Agt-Tg group. MiR-708-5p and -143-3p were upregulated when RAS was overexpressed, and RAS antagonists reduced miR-143-3p and -708-5p in both mouse adipose tissue and adipocytes. Activation of RAS by Ang II treatment, increased inflammation and ER stress in adipocytes mainly via AT1 receptor, possibly mediated by miR-30 family, -708-5p and/or -143-3p. Hence, RAS and mediating microRNAs could be used as potential targets to reduce RAS induced obesity and related comorbid diseases.

Maternal and Postnatal Supplementation of Fish Oil Improves Metabolic Health of Mouse Male Offspring.

OBJECTIVE: Over half of American women of childbearing age have either obesity or overweight. Hence, maternal programming through diet is critical for prevention of diseases in the offspring. Clinical trials with fish oil (FO) report various health benefits; however, it remains unclear whether maternal and postnatal consumption of FO protects offspring from adverse effects of consuming a high-fat (HF) diet. METHODS: Female mice were fed HF diets supplemented without (HF) or with FO from 8 weeks before pregnancy through lactation. A low-fat (LF) diet was included as a control diet. After weaning, male offspring from HF or FO dams were either continued on their respective diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) and compared with LF. Phenotypic and mechanistic studies were performed. RESULTS: FO-FO offspring demonstrated significantly higher glucose clearance and insulin sensitivity compared with other pups fed the HF diet (P < 0.05). Furthermore, FO-FO pups had lower adiposity, inflammation, and fat deposition in the liver, consistent with reduced markers of hepatic lipogenesis and increased hepatic lipid oxidation. CONCLUSIONS: Supplementation of FO during pregnancy and early life is more beneficial than treating with FO either during pregnancy or in pups.

Effects of delta-tocotrienol on obesity-related adipocyte hypertrophy, inflammation and hepatic steatosis in high-fat-fed mice.

Inflammation is a major underlying cause for obesity-associated metabolic diseases. Hence, anti-inflammatory dietary components may improve obesity-related disorders. We hypothesized that delta-tocotrienol (δT3), a member of the vitamin E family, reduces adiposity, insulin resistance and hepatic triglycerides through its anti-inflammatory properties. To test this hypothesis, C57BL/6J male mice were fed a high-fat diet (HF) with or without supplementation of δT3 (HF+δT3) at 400 mg/kg and 1600 mg/kg for 14 weeks, and they were compared to mice fed a low-fat diet (LF) or HF supplemented with metformin as an antidiabetic control. Glucose tolerance tests were administered 2 weeks prior to the end of treatments. Histology, quantitative polymerase chain reaction and protein analyses were performed to assess inflammation and fatty acid metabolism in adipose and liver tissues. Significant improvements in glucose tolerance, and reduced hepatic steatosis and serum triglycerides were observed in δT3-supplemented groups compared to the HF group. Body and fat pad weights were not significantly reduced in HF+δT3 groups; however, we observed smaller fat cell size and reduced macrophage infiltration in their adipose tissues compared to other groups. These changes were at least in part mechanistically explained by a reduction of mRNA and protein expression of proinflammatory adipokines and increased expression of anti-inflammatory adipokines in HF+δT3 mice. Moreover, δT3 dose-dependently increased markers of fatty acid oxidation and reduced markers of fatty acid synthesis in adipose tissue and liver. In conclusion, our studies suggest that δT3 may promote metabolically healthy obesity by reducing fat cell hypertrophy and decreasing inflammation in both liver and adipose tissue.