In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of sc-WAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56؉/CD68؉; 22.6 ؎ 4.3 vs. 1.4 ؎ 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (؊11.63 ؎ 2.3%, P < 0.

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-α-positive (PDGFRα) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFRα cells with high CD9 expression (CD9) originates pro-fibrotic cells whereas their CD9 counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRα pathway activation promotes a phenotypic shift toward PDGFRαCD9 fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9 progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFRα cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.

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Peroxisome proliferator-activated receptor (PPAR)-␣ controls the expression of genes involved in lipid metabolism. PPAR-␣ furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-␣-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-␣ in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-␣-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-␣-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-␣-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wildtype mice, whereas it remained unchanged in PPAR-␣-null mice. In contrast, PPAR-␣ deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-␣ dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-␣ deficiency on glucose homeostasis seem not to occur via the pancreas, because glucosestimulated insulin secretion of islets was not influenced by the PPAR-␣ genotype. These data suggest that PPAR-␣ plays a role for the development of IR in response to a Western-type high-fat diet. Diabetes 50: 2809 -2814, 2001 M itochondrial ␤-oxidation is the major metabolic process by which fatty acids are utilized intracellularly, thus providing energy primarily for the heart and skeletal muscles. In the liver, ␤-oxidation also provides the substrates required for the synthesis of ketone bodies and supplies ATP and reducing equivalents to sustain gluconeogenesis. The physiological impact of enzymatic defects in these pathways is evidenced by the phenotype of patients with inherited ␤-oxidation deficiency. The clinical presentation includes cardiomyopathy, liver and muscle dysfunction, and episodes of nonketotic hypoglycemia (rev. in Eaton et al. [1]). Recently, a mouse model of ␤-oxidation deficiency was produced by targeted disruption of long-chain acylCoA dehydrogenase, an enzyme that catalyzes the initial step of this pathway. These mice display several features that resemble those of patients with ␤-oxidation defects, including reduced tolerance to fasting as a result of hypoglycemia and hepatic and cardiac disturbances (2).The peroxisome proliferator-activated receptor (PPAR)-␣ plays a central role in the control of mitochondrial ␤-oxidation of fatty acids. PPAR-␣-null mice (3) exhibit a reduced capacity to metabolize long-chain fatty acids (4,5), which likely contributes to dyslipidemia (6) and larger adipose stores observed in th...

White adipose tissue (WAT) in obese humans is characterized by macrophage accumulation the effects of which on WAT biology are not fully understood. We previously demonstrated that macrophage-secreted factors impair preadipocyte differentiation and induce inflammation, and we described the excessive fibrotic deposition in WAT from obese individuals. Microarray analysis revealed significant overexpression of extracellular matrix (ECM) genes in inflammatory preadipocytes. We show here an organized deposition of fibronectin, collagen I, and tenascin-C and clustering of the ECM receptor alpha5 integrin, characterizing inflammatory preadipocytes. Anti-alpha5 integrin-neutralizing antibody decreased proliferation of these cells, underlining the importance of the fibronectin/integrin partnership. Fibronectin-cultured preadipocytes exhibited increased proliferation and expression of both nuclear factor-kappaB and cyclin D1. Small interfering RNA deletion of nuclear factor-kappaB and cyclin D1 showed that these factors link preadipocyte proliferation with inflammation and ECM remodeling. Macrophage-secreted molecules increased preadipocyte migration through an increase in active/phosphorylated focal adhesion kinase. Gene expression and neutralizing antibody experiments suggest that inhibin beta A, a TGF-beta family member, is a major fibrotic factor. Interactions between preadipocytes and macrophages were favored in a three-dimensional collagen I matrix mimicking the fibrotic context of WAT. Cell-rich regions were immunostained for preadipocytes, proliferation, and macrophages in the vicinity of fibrotic WAT from obese individuals. In conclusion, an inflammatory environment leads to profound modifications of the human preadipocyte phenotype, producing fibrotic components with increased migration and proliferation. This phenomenon might play a role in facilitating the constitution of quiescent preadipocyte pools and eventually in the maintenance and aggravation of increased fat mass in obesity.

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD (n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.

Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three-dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1b as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders.During obesity, hypertrophy of white adipose tissue (WAT) is associated with fibro-inflammation and cell dysfunction. However, visceral depot (visceral adipose tissue [VAT]) differs from subcutaneous adipose tissue (SAT) by its inflammatory status because of its high infiltration with immune cells such as macrophages, T lymphocytes, and mast cells (1,2). Hence, VAT hypertrophy is considered an important contributor to obesityrelated metabolic and cardiovascular diseases (3). In obese subjects, hypertrophied adipocytes display abnormal secretion of leptin and adiponectin and increased production of numerous inflammatory cytokines and chemokines, leading to a disrupted interorgan communication between VAT and important metabolic peripheral tissues such as liver and skeletal muscle (4). These organs are particularly exposed to free fatty acids and cytokines, mostly interleukin (IL)-6, which are increasingly released by the visceral fat of obese subjects (5,6). Skeletal muscles are one of the major metabolic tissues of the body, playing a pivotal role in glucose and lipid metabolism. There is a growing body of evidence showing the effects of obesity on skeletal muscle dysfunction, such as the development of insulin resistance, as attested to by numerous studies performed

Objectives-To examine the role of adipose-produced chemokine, chemokine ligand (CCL) 5, on the recruitment and survival of macrophages in human white adipose tissue (WAT). Methods and Results-CCL5 levels measured by enzyme immunoassay in serum and by real-time polymerase chain reaction in WAT were higher in obese compared to lean subjects. CCL5, but not CCL2, secretion was higher in visceral compared to subcutaneous WAT. CCL5 mRNA expression was positively correlated with the inflammatory macrophage markers as CD11b, tumor necrosis factor-␣, and IL-6 in visceral WAT (nϭ24 obese subjects), and was higher in macrophages than other WAT cells. We found that CCL5 triggered adhesion and transmigration of blood monocytes to/through endothelial cells of human WAT. Whereas in obese WAT apoptotic macrophages were located around necrotic adipocytes, we demonstrated that CCL5, but not CCL2, protected macrophages from free cholesterol-induced apoptosis via activation of the Akt/Erk pathways. Conclusions-CCL5