Adiponectin, an adipocyte‐derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T‐cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin–T‐cadherin association protected against vascular injury. In the apolipoprotein E‐knockout (ApoE‐KO) mice, adiponectin and T‐cadherin colocalized on en‐dothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T‐cadherin/ApoE double‐knockout (Tcad/ApoE‐DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE‐DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE‐KO mice. Finally, on a high‐cholesterol diet, Tcad/ApoE‐DKO mice increased atherosclerotic plaque formation, despite a 5‐fold increase in plasma adiponectin level compared with that in ApoE‐KO mice. In vitro , knockdown of T‐cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T‐cadherin, and the adiponectin–T‐cadherin association plays a protective role against neointimal and atheroscle‐rotic plaque formations. —Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T‐cadherin protects against neointima proliferation and atherosclerosis. FASEB J . 31, 1571–1583 (2017) www.fasebj.org

The effects of high-fat (HF) feeding on gene expression in the small intestine were examined using obesity-resistant A/J mice and obesity-prone C57BL/6J (B6) mice. Both strains of mice were maintained on low-fat (LF; 5% fat) or HF (30% fat) diets for 2 wk. Quantitative reverse transcription-PCR analysis revealed that lipid metabolism-related genes, including carnitine palmitoyltransferase (CPT) I, liver fatty acid binding protein, pyruvate dehydrogenase kinase-4, and NADP⁺-dependent cytosolic malic enzyme, were upregulated by HF feeding in both strains of mice. The upregulated gene expression levels were higher in A/J mice than in B6 mice, suggesting more active lipid metabolism in the small intestine of A/J mice. The prominent upregulation of the lipid metabolism-related genes were specific to the small intestine; the expression levels were little or unchanged in the liver, muscle, and white adipose tissue. The increase by HF feeding and predominant expression of the intestinal lipid metabolism-related genes in A/J mice were reflected in the enzyme activities; malic enzyme, CPT, and β-oxidation activities were increased by HF feeding, and the upregulated malic enzyme and CPT activities were significantly higher in obesity-resistant A/J mice compared with those in obesity-prone B6 mice. These findings suggest that intestinal lipid metabolism is associated with susceptibility to obesity.

Fish oils (FO) rich in (n-3) PUFA exert hypolipidemic and antiobesity effects in association with modulated hepatic lipid metabolism. We recently demonstrated the possible involvement of intestinal lipid metabolism in the development of obesity. In this study, we examined the effect of FO ingestion on intestinal lipid metabolism in relation to obesity. When diet-induced obesity-prone C57BL/6J mice were fed an 8% FO, high-fat (30%) diet for 5 mo, body weight gain was significantly reduced compared with mice fed a 30% triacylglycerol (TG) diet without FO. In addition to modulating messenger RNA (mRNA) levels in the liver, FO ingestion for 2 wk affected the intestinal mRNA levels of lipid metabolism-related genes; those of carnitine palmitoyltransferase 1a, cytochrome P450 4A10, and malic enzyme were significantly higher in mice fed the 8% FO diet compared with mice fed the 30% TG diet. Northern blot analysis revealed that the expression levels of most lipid metabolism-related genes in the small intestine of mice fed the 8% FO diet were comparable to those in the liver. Furthermore, reflecting the difference at the mRNA level, FO ingestion affected lipid metabolism-related enzyme activity; fatty acid β-oxidation, ω-oxidation, and malic enzyme activities in the small intestine of mice fed the 8% FO diet were 1.2-, 1.6-, and 1.7-fold those in mice fed the 30% TG diet, respectively. These findings suggest that an upregulation of intestinal lipid metabolism is associated with the antiobesity effect of FO.

Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.

Significance: Infiltration of immune cells into adipose tissue has been observed in obesity, but, until now, these data were based on immunohistological microscopic analysis. Here, to our knowledge for the first time, we applied an intravital multiphoton imaging technique to adipose tissue with lysozyme M-EGFP transgenic (LysM ^EGFP ) mice whose EGFP was expressed in the myelomonocytic lineage. Mobility of LysM ^EGFP -positive macrophages was activated just 5 d after high-fat and high-sucrose (HF/HS) diet before the development of obesity. Furthermore, a significant increase of S100A8, one of the alarmins, was detected in fat tissue just 5 d after HF/HS diet. S100A8 stimulated chemotactic migration, and neutralization of S100A8 suppressed the HF/HS diet-induced activation of LysM ^EGFP -positive cells. Time-lapse intravital imaging first identified the very early event exhibiting increased mobility of adipose macrophages.