linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability.

Adipose tissue remodeling and dysfunction, characterized by elevated inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2D) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here, we describe the functions of linc-ADAIN (adipose anti-inflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans. We demonstrate that linc-ADAIN knockdown (KD) increases KLF5 and interleukin-8 (IL-8) mRNA stability and translation by interacting with IGF2BP2. Upregulation of KLF5 and IL-8, via linc-ADAIN KD, leads to an enhanced adipogenic program and adipose tissue inflammation, mirroring the obese state, in vitro and in vivo. KD of linc-ADAIN in human adipose stromal cell (ASC) hTERT adipocytes implanted into mice increases adipocyte size and macrophage infiltration compared to implanted control adipocytes, mimicking hallmark features of obesity-induced adipose tissue remodeling. linc-ADAIN is an anti-inflammatory lincRNA that limits adipose tissue expansion and lipid storage.

ADAMTS7 Promotes Smooth Muscle Cell Foam Cell Expansion in Atherosclerosis.

Human genetic studies have repeatedly associated SNPs near the gene ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic, induced in response to vascular injury, and alters smooth muscle cell function. However, the mechanisms governing this function and its relationship to atherosclerosis remain unclear. Here, we report the first conditional Adamts7 transgenic mouse in which the gene can be conditionally overexpressed in smooth muscle cells, mimicking its induction in atherosclerosis. We observed that smooth muscle cell Adamts7 overexpression results in a 3.5-fold increase in peripheral atherosclerosis, coinciding with an expansion of smooth muscle foam cells. RNA sequencing of Adamts7 overexpressed primary smooth muscle cells revealed an upregulation in the expression of lipid uptake genes. Subsequent experiments in primary smooth muscle cells demonstrated that increased Spi1 and Cd36 expression leads to increased smooth muscle cell oxLDL uptake. To uncover ADAMTS7 expression in human disease, we have interrogated the largest scRNA-seq dataset of human carotid atherosclerosis. This analysis discovered that endothelial cells had the highest expression level of ADAMTS7 with lesser expression in smooth muscle cells, fibroblasts, and mast cells. Subsequent conditional knockout studies in smooth muscle cells surprisingly showed no change in atherosclerosis, suggesting redundant expression of this secreted factor in the vessel wall. Finally, mice overexpressing Adamts7 in endothelial cells also exhibit increased atherosclerosis, suggesting that multiple vascular cell types can contribute to ADAMTS7-mediated foam cell expansion. In summary, Adamts7 is expressed by multiple vascular cell types in atherosclerosis, and ADAMTS7 promotes oxLDL uptake in smooth muscle cells, increasing smooth muscle foam cell formation and peripheral atherosclerosis in mice.

Adipocyte-specific tribbles pseudokinase 1 regulates plasma adiponectin and plasma lipids in mice.

OBJECTIVE: Multiple genome-wide association studies (GWAS) have identified SNPs in the 8q24 locus near TRIB1 that are significantly associated with plasma lipids and other markers of cardiometabolic health, and prior studies have revealed the roles of hepatic and myeloid Trib1 in plasma lipid regulation and atherosclerosis. The same 8q24 SNPs are additionally associated with plasma adiponectin levels in humans, implicating TRIB1 in adipocyte biology. Here, we hypothesize that TRIB1 in adipose tissue regulates plasma adiponectin, lipids, and metabolic health. METHODS: We investigate the metabolic phenotype of adipocyte-specific Trib1 knockout mice (Trib1_ASKO) fed on chow and high-fat diet (HFD). Through secretomics of adipose tissue explants and RNA-seq of adipocytes and livers from these mice, we further investigate the mechanism of TRIB1 in adipose tissue. RESULTS: Trib1_ASKO mice have an improved metabolic phenotype with increased plasma adiponectin levels, improved glucose tolerance, and decreased plasma lipids. Trib1_ASKO adipocytes have increased adiponectin production and secretion independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice indicates that alterations in adipocyte function underlie the observed plasma lipid changes. Adipose tissue explant secretomics further reveals that Trib1_ASKO adipose tissue has decreased ANGPTL4 production, and we demonstrate an accompanying increase in the lipoprotein lipase (LPL) activity that likely underlies the triglyceride phenotype. CONCLUSIONS: This study shows that adipocyte Trib1 regulates multiple aspects of metabolic health, confirming previously observed genetic associations in humans and shedding light on the further mechanisms by which TRIB1 regulates plasma lipids and metabolic health.