Deficiency of Angiotensinogen in Hepatocytes Markedly Decreases Blood Pressure in Lean and Obese Male Mice
Frédérique YiannikourisYu WangRobin ShoemakerNika LarianJoel ThompsonVictoria EnglishRichard CharnigoWen SuMing GongLisa A. Cassis
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We recently demonstrated that adipocyte deficiency of angiotensinogen (AGT) ablated high-fat diet–induced elevations in plasma angiotensin II (Ang II) concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic AGT. Therefore, in this study, we defined the contribution of hepatocyte-derived AGT to obesity-induced elevations in plasma AGT concentrations and hypertension. Male Agt fl/fl mice expressing albumin-driven Cre recombinase were bred to female Agt fl/fl mice to generate Agt fl/fl or hepatocyte AGT–deficient male mice ( Agt Alb ). Mice were fed a low-fat or high-fat diet for 16 weeks. Hepatocyte AGT deficiency had no significant effect on body weight. Plasma AGT concentrations were increased in obese Agt fl/fl mice. Hepatocyte AGT deficiency markedly reduced plasma AGT and Ang II concentrations in lean and obese mice. Moreover, hepatocyte AGT deficiency reduced the content and release of AGT from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mm Hg) and obese Agt Alb mice (by 54 mm Hg) compared with Agt fl/fl controls. To define mechanisms, we quantified effects of Ang II on mRNA abundance of megalin, an AGT uptake transporter, in 3T3-L1 adipocytes. Ang II stimulated adipocyte megalin mRNA abundance and decreased media AGT concentrations. These results demonstrate that hepatocytes are the predominant source of systemic AGT in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte AGT–deficient mice may have limited megalin-dependent uptake of AGT into adipocytes for the production of Ang II in the development of obesity-hypertension.Intramuscular fat
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The cellular growth of adipose tissue from Dorset Horn x Merino wethers was characterized by both hypertrophy and hyperplasia of adipose cells until the sheep were c. 11 months old, after which hypertrophy of existing adipose cells was solely responsible for increases in adipose tissue mass. Omental adipose tissue contained larger adipose cells than either the perirenal or subcutaneous sites. The weight of fat which had been deposited in the boneless carcass meat and the internal adipose tissue depots were linearly and positively correlated with the volume of the adipose cells. Decreases in the mass of adipose tissue, which accompanied nutritional restriction, were due to decreased adipose cell size, since no change was observed in the number of adipose cells per carcass after loss in weight. The cellularity characteristics of rehabilitated sheep were similar to those of sheep which had undergone continuous growth.
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Recent studies have shown that heterogeneity among adipocytes exists even within a single white adipose tissue (WAT) depot. Our lab has uncovered developmentally distinct subpopulations of WAT adipocytes that are distinguished by the expression of these genes: Wilms’ Tumor 1 (Wt1) (Type 1), Transgelin (Tagln) (Type 2), and Myxovirus 1 (Mx1) (Type 3). Utilizing Cre transgenic mice, transcription of which is directed by the promoters of these marker genes, lineage tracing analysis showed that these three preadipocyte subpopulations independently gave rise to adipocytes in vivo, and differentially contribute to the adipose tissue depots. In high-fat diet induced obesity, Type 1 and Type 2 adipocytes are found roughly the same abundance in perigonadal adipose tissue, with only low numbers of Type 3 adipocytes observed. Macrophages, organized into crown like structures (CLS) around dead and dying adipocytes, are detected in the vicinity of Type 1 adipocytes derived from Wt1 positive lineage. The distributions of Type 1 adipocytes and of CLS were determined by Kernel density estimation, and found to be significantly overlapped. On the other hand, over 80% of CLS are found in direct contact with Type 2 adipocytes in the perigonadal adipose tissue. This finding indicates that diet-induced obesity preferentially causes increased death of Type 2 adipocytes compared to other adipocyte subtypes. Taken together, these data indicate that adipocyte subpopulations, at least in part, mediate the inflammatory response in adipose tissue.
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Insulin-like growth factor-1 (IGF1) regulates differentiation and growth of tissues and reduces stress and injury. IGF1 also in a tissue-specific manner modulates the differentiation and lipid storage capacity of adipocytes in vitro, but its roles in adipose tissue development and response to stress are not known.To study IGF1 in vivo, the cellular sources of adipose tissue Igf1 expression were identified and mice were generated with targeted deletion in adipocytes and macrophages. The effects of adipocyte and macrophage deficiency of IGF1 on adipose tissue development and the response to chronic (high-fat feeding) and acute (cold challenge) stress were studied.The expression of Igf1 by adipose tissue was derived from multiple cell types including adipocytes and macrophages. In lean animals, adipocytes were the primary source of IGF1, but in obesity expression by adipocytes was reduced and by macrophages increased, so as to maintain overall adipose tissue Igf1 expression. Genetic deletion studies revealed that adipocyte-derived IGF1 regulated perigonadal but not subcutaneous adipose tissue mass during high-fat feeding and the development of obesity. Conversely, macrophage-derived IGF1 acutely modulated perigonadal adipose tissue mass during thermogenic challenges.Local IGF1 is not required in lean adipose tissue development but is required to maintain homeostasis during both chronic and acute metabolic stresses.
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Adipose tissue precursor cells (pre-adipocytes) are part of a stromal vascular fraction that can be easily isolated from fat tissue. Adipose tissue can be harvested by 2 methods: aspiration and excision. We analyzed whether the pre-adipocyte yield, growth characteristics and ability to differentiate into mature adipose tissue are influenced by the type of harvesting procedure. Adipose tissue was simultaneously harvested from the abdomen by surgical excision or aspiration according to the Coleman procedure in 10 individuals. This permitted inter- and intra-individual comparisons. Cell viability and yield were determined directly after isolation of pre-adipocytes. The growth kinetics were investigated in culture. Furthermore, pre-adipocytes were cultured under adipogenic conditions to compare their differentiation potential. The number of viable pre-adipocytes was significantly higher after excision of adipose tissue compared to aspiration. The proliferation kinetic was not influenced by the type of harvesting. No differences were observed in the differentiation potential of the pre-adipocytes between both groups. Compared to excision, aspiration of adipose tissue negatively affects the yield of pre-adipocytes. However, growth characteristics and differentiation potential of viable cultured cells are not influenced by the type of surgical harvesting. Due to its reduced donor site morbidity, we conclude that aspiration of adipose tissue is a valid harvesting method for isolation of pre-adipocytes.
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Besides liver, IGF-I is expressed in adipose tissue. However, the effects of this local IGF-I on adipose tissue and metabolism are unclear. We generated adipocyte-specific knock-out mice on the background of the Berlin Fat Mouse Inbred (BFMI) line to evaluate the contribution of adipocyte-IGF-I on glucose metabolism and adipose tissue development. BFMI mice are obese, non-diabetic with elevated plasma insulin and IGF-I concentration. The knock-out in adipocytes led to a total white adipose tissue expression of 50–60% due to unaltered Igf-1 expression in stromavascular cells. The lack of IGF-I from adipocytes did not alter plasma IGF-I concentration. BFMIChr3-Igf-I-KOQ-AT mice had reduced adipose tissue mass in most depots. During oral glucose tolerance tests, BFMIChr3-Igf-I-KOQ-AT mice showed an impaired glucose clearance (p = .03). Interestingly, insulin action was enhanced during insulin tolerance tests (p = .05). In conclusion, adipocyte-specific IGF-I ablation in obese BFMI mice results in reduced adipose tissue mass and thereby alters glucose metabolism.
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