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Visceral obesity is associated with insulin resistance and higher risk of type 2 diabetes and metabolic diseases. A limited ability of adipose tissues to remodel through the recruitment and differentiation of adipose stem cells (ASCs) is associated with adipose tissue inflammation and fibrosis and the metabolic syndrome. We show that the lower adipogenesis of omental (Om) compared with abdominal subcutaneous (Abdsc) ASCs was associated with greater secretion of TGFβ ligands that acted in an autocrine/paracrine loop to activate SMAD2 and suppress adipogenesis. Inhibition of TGFβ signaling rescued Om ASC differentiation. In Abdsc ASCs, low concentrations of dexamethasone suppressed TGFβ signaling and enhanced adipogenesis, at least in part by increasing TGFBR3 protein that can sequester TGFβ ligands. Om ASCs were resistant to these dexamethasone effects; recombinant TGFBR3 increased their differentiation. Pericellular fibrosis, a hallmark of dysfunctional adipose tissue, was greater in Om and correlated with higher level of tissue TGFβ signaling activity and lower ASC differentiation. We conclude that glucocorticoids restrain cell-autonomous TGFβ signaling in ASCs to facilitate adipogenesis and healthy remodeling in Abdsc and these processes are impaired in Om. Therapies directed at overcoming glucocorticoid resistance in visceral adipose tissue may improve remodeling and help prevent metabolic complications of visceral obesity. [ABSTRACT FROM AUTHOR]

Mice null for adipocyte fatty acid binding protein (AFABP) compensate by increasing expression of keratinocyte fatty acid binding protein (KFABP) (Hotamisligil et al. Science 274:1377-1379, 1996). In the present study, AFABP knockout (KO) and wild-type (WT) mice became equally obese on a high-fat diet, as judged by fat pad weights, adipocyte size, and body composition analysis. High-fat feeding led to moderate insulin resistance in both WT and AFABP knockout mice, as indicated by an approximately 2-fold increase in plasma insulin. However, in the high fat-fed mice, plasma glucose levels were approximately 15% lower in the AFABP-KO mice. Adipocytes isolated from AFABP-KO and WT mice fed high- or low-fat diets exhibited similar rates of basal and norepinephrine-stimulated lipolysis and insulin-stimulated rates of glucose conversion to fatty acids and glyceride-glycerol. However, basal glucose conversion to fatty acids was higher in adipocytes of AFABP-KO mice. Adipocyte tumor necrosis factor-alpha release was similarly increased by high-fat diet-induced obesity in both WT and AFABP-KO mice. As assessed by Western blot analysis, the level of KFABP protein in AFABP-KOs was approximately 40% of the level of AFABP in WT controls. The binding affinities of KFABP for long-chain fatty acids were 2- to 4-fold higher than those of AFABP, but the relative affinities for different fatty acids were similar. As for AFABP, the rate of fatty acid transfer from KFABP to model phospholipid vesicles was increased with acceptor membrane concentration and by inclusion of acidic phospholipids, indicating a similar mechanism of transfer. We conclude KFABP can functionally compensate for the absence of AFABP, resulting in no major alterations in adipocyte metabolism or fat accumulation in response to short-term feeding of high-fat diets that result in moderate hyperinsulinemia. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) are powerful modulators of adipose tissue function, and GC action varies in human visceral and sc adipose tissues. To establish if alterations in GC action are secondary to alterations in its receptor, and post-receptor events, we assessed the tissue-specific expression of glucocorticoid receptor (GR) translational isoforms (A-D). Direct GR isoforms exert diverse and partially non-overlapping effects of GC on gene expression. GRA/B (94-91kDa) and GR D (54 kDa) were major translational isoforms expressed in human adipose tissue. The expression of the more transcriptionally active A/B form was higher in subcutaneous than omentum, while D form was similar (n=5). Because GC action is regulated by inflammatory cytokines in other cell types and tumor necrosis factor alpha (TNF) expression in adipose tissue is increased in human obesity, we examined whether TNF modulates glucocorticoid receptor expression and activity in human adipose tissue. TNF treatment (3 ng/ml, 2d) of subcutaneous adipose tissue fragments in organ culture increased GRα expression levels but simultaneously increased GRα phosphorylational at serine 226 (+82% in ratio to total GR p<0.05, n=4), a post-translational modification known to decrease GR activity. In addition, TNF decreased GR serine 211 phosphorylation (ligand dependent) (ratio to total, +8.9 fold without TNF vs. +4.5 fold with TNF, n=3) and attenuated the magnitude of GC effects on key target genes (glucocortieoid induced leucine zipper (GILZ) and PEPCK). TNF also decreased sensitivity and responsiveness to stimulatory effects of GC on lipoprotein lipase (LPL) activity. These effects on LPL were partially blocked by a JNK inhibitor (SP600125, 25 µM) while p38 or ERK1/2 inhibitors were ineffective. Collectively, these data indicate TNF regulates the expression and activity of the GR in human adipose tissue at translational and post-translational levels. Further, depot- and/or obesity-related differences in TNF in obesity may regulate GR activity. [ABSTRACT FROM AUTHOR]

Retinol binding protein 4 (RBP4) was overexpressed in adipose tissue of Glut4 KO mice, and elevated RBP4 has been associated with insulin resistance in mouse and human studies. To determine the relationship between RBP4 and obesity, insulin resistance, and other markers of insulin resistance in humans, RBP4 gene expression measured by real-time RT-PCR and blood levels measured by ELISA and Western blotting were studied in adipose tissue and muscle of 85 non-diabetic humans over a wide range of BMI (19-55 Kg/m²) and S[sub I] (1.02-26.77 x 10[sup -5] x min[sup -1]/pM), and RBP4 expression was also measured from visceral (VAT) and subcutaneous adipose tissue (SAT) from 16 surgical patients. RBP4 expression was 3-fold higher in SAT vs VAT (p<0.005), and RBP4 was 7-fold higher in the adipocyte (vs stromal) fraction, and undetectable in preadipocytes. Neither SAT RBP4 expression nor blood RBP4 level showed a significant relationship with BMI or S[sub I]. However, there was a strong positive correlation between RBP4 mRNA and the inflammation markers MCP1 (r=0.42, p<0.0001) and CD68 (r=0.46, p<0.0001)). Adipose GLUT4 mRNA was also highly associated with RBP4 (r=0.53, p<0.0001). These relationships remained significant after adjustment for BMI and St. Impaired glucose tolerant subjects were treated with pioglitazone, resulting in an increase in S[sub 1] along with a 60% increase in RBP4 expression, but no change in plasma RBP4. The in vitro treatment of cultured adipocytes with pioglitazone yielded a similar increase in RBP4 mRNA. Hence, RBP4 expression in humans was not significantly associated with obesity or insulin resistance, and actually increased with TZD treatment. However, RBP4 was associated with inflammatory markers and GLUT 4 expression, suggesting a complex role in metabolic syndrome. [ABSTRACT FROM AUTHOR]

Visceral obesity is associated with insulin resistance and higher risk of type 2 diabetes and metabolic diseases. A limited ability of adipose tissues to remodel through the recruitment and differentiation of adipose stem cells (ASCs) is associated with adipose tissue inflammation and fibrosis and the metabolic syndrome. We show that the lower adipogenesis of omental (Om) compared with abdominal subcutaneous (Abdsc) ASCs was associated with greater secretion of TGFβ ligands that acted in an autocrine/paracrine loop to activate SMAD2 and suppress adipogenesis. Inhibition of TGFβ signaling rescued Om ASC differentiation. In Abdsc ASCs, low concentrations of dexamethasone suppressed TGFβ signaling and enhanced adipogenesis, at least in part by increasing TGFBR3 protein that can sequester TGFβ ligands. Om ASCs were resistant to these dexamethasone effects; recombinant TGFBR3 increased their differentiation. Pericellular fibrosis, a hallmark of dysfunctional adipose tissue, was greater in Om and correlated with higher level of tissue TGFβ signaling activity and lower ASC differentiation. We conclude that glucocorticoids restrain cell-autonomous TGFβ signaling in ASCs to facilitate adipogenesis and healthy remodeling in Abdsc and these processes are impaired in Om. Therapies directed at overcoming glucocorticoid resistance in visceral adipose tissue may improve remodeling and help prevent metabolic complications of visceral obesity., (© 2018 by the American Diabetes Association.)