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OBJECTIVE--To examine in obese young adults the influence of ethnicity and subcutaneous adipose tissue (SAT) inflammation on hepatic fat fraction (HFF), visceral adipose tissue (VAT) deposition, insulin sensitivity (SI), β-cell function, and SAT gene expression. RESEARCH DESIGN AND METHODS--SAT biopsies were obtained from 36 obese young adults (20 Hispanics, 16 African Americans) to measure crown-like structures (CLS), reflecting SAT inflammation. SAT, VAT, and HFF were measured by magnetic resonance imaging, and SI and β-cell function (disposition index [DI]) were measured by intravenous glucose tolerance test. SAT gene expression was assessed using Illumina microarrays. RESULTS--Participants with CLS in SAT (n = 16) were similar to those without CLS in terms of ethnicity, sex, and total body fat. Individuals with CLS had greater VAT (3.7 ± 1.3 vs. 2.6 ± 1.6 L; P = 0.04), HFF (9.9 ± 7.3 vs. 5.8 ± 4.4%; P = 0.03), minor necrosis factor-α (20.8 ± 4.8 vs. 16.2 ± 5.8 pg/mL; P = 0.01), fasting insulin (20.9 ± 10.6 vs. 9.7 ± 6.6 mU/mL; P < 0.001) and glucose (94.4 ± 9.3 vs. 86.8 ± 5.3 mg/dL; P = 0.005), and lower DI (1,559 ± 984 vs. 2,024 ± 829 x [10.sup.-4] [min.sup.-1]; p = 0.03). Individuals with CLS in SAT exhibited upregulation of matrix metalloproteinase-9 and monocyte antigen CD14 genes, as well as several other genes belonging to the nuclear factor-κB (NF-κB) stress pathway. CONCLUSIONS--Adipose tissue inflammation was equally distributed between sexes and ethnicities. It was associated with partitioning of fat toward VAT and the liver and altered β-cell function, independent of total adiposity. Several genes belonging to the NF-κB stress pathway were upregulated, suggesting stimulation of proinflammatory mediators. Diabetes 60:2802-2809, 2011, Adipose tissue inflammation is now recognized as an important mediating link that may help explain the relationship between obesity and several metabolic abnormalities, including insulin resistance (1,2), liver fat accumulation [...]

OBJECTIVE--Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS--Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS--We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyper-insulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS--Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity. Diabetes 60:1168-1176, 2011, Obesity is an independent risk factor for type 2 diabetes, cardiovascular disease, nonalcoholic steatohepatitis, stroke, and certain cancers (1,2). Obesity is now recognized as a state of chronic low-grade systemic [...]

OBJECTIVE--To identify, localize, and determine M1/M2 polarization of epidydimal adipose tissue (eAT) macrophages (Φs) during high-fat diet (HFD)-induced obesity. RESEARCH DESIGN AND METHODS--Male C57BL/6 mice were fed an HFD (60% fat kcal) or low-fat diet (LFD) (10% fat kcal) for 8 or 12 weeks, eATMΦs (F4/[80.sup.+] cells) were characterized by in vivo fluorescent labeling, immunohistochemistry, fluorescence-activated cell sorting, and quantitative PCR. RESULTS--Recruited interstitial macrophage galactose-type C-type lectin (MGL)[1.sup.+]/[CD11c.sup.-] and crown-like structure-associated [MGL1.sup.-]/[CD11c.sup.+] and [MGL1.sup.med]/[CD11c.sup.+] eATMΦs were identified after 8 weeks of HFD. [MGL1.sup.med]/[CD11c.sup.+] cells comprised ~65% of [CD11c.sup.+] eATMΦs. [CD11c.sup.+] eATΦs expressed a mixed M1/M2 profile, with some M1 transcripts upregulated (IL-12p40 and IL-1β), others downregulated (iNOS, caspase-1, MCP-1, and CD86), and multiple M2 and matrix remodeling transcripts upregulated (arginase-1, IL-1Ra, MMP-12, ADAM8, VEGF, and Clec-7a). At HFD week 12, each eATMΦ subtype displayed an enhanced M2 phenotype as compared with HFD week 8. [CD11c.sup.+] subtypes downregulated IL-1β and genes mediating antigen presentation (I-a, CD80) and upregulated the M2 hallmark Ym-1 and genes promoting oxidative metabolism (PGC-1α) and adipogenesis (MMP-2). [MGL1.sup.med]/[CD11c.sup.+] eATMΦs upregulated additional M2 genes (IL-13, SPHK1, CD163, LYVE-1, and PPAR-α). [MGL1.sup.med]/[CD11c.sup.+] ATM(Ps expressing elevated PGC-1α, PPAR-α, and Ym-1 transcripts were selectively enriched in eAT of obese mice fed pioglitazone for 6 days, confirming the M2 features of the [MGL1.sup.med]/[CD11c.sup.+] eATMΦ transcriptional profile and implicating PPAR activation in its elicitation. CONCLUSIONS--These results 1) redefine the phenotypic potential of [CD11c.sup.+] eATMΦs and 2) suggest previously unappreciated phenotypic and functional commonality between murine and human ATMΦs in the development of obesity and its complications. Diabetes 59:1171-1181, 2010, Chronic inflammation is a pathogenic factor in obesity complications, in particular insulin resistance (1,2). A significant advance in our understanding of obesity-associated inflammation and insulin resistance has been recognition of [...]

OBJECTIVE--We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. RESEARCH DESIGN AND METHODS--Male C57BL/6 mice were fed a high-fat diet for [...]

Nonalcoholic fatty liver disease (NAFLD) occurs in 20-30% of Americans and is the most prevalent form of liver disease (1,2). NAFLD is commonly linked to hepatic and whole-body insulin resistance [...]

Tumor necrosis factor-α (TNF-α) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF-α increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF-α activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF-α treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). Coincubation with TNF-α and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF-α induces perilipin hyperphosphorylation by activating PKA, TNF-α increased intracellular cAMP ~1.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF-α--induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF-α--induced lipolysis. Finally, TNF-α decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by ~50%, delineating a mechanism by which TNF-α could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF-α stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP., Obesity and type 2 diabetes are associated with increased concentrations of circulating free fatty acids (FFAs) that are thought to elicit systemic insulin resistance (1). The flux of FFA is [...]

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in [...]

Lifestyle changes, in particular reducing energy intake, are the cornerstone of current approaches to weight loss and prevention of type 2 diabetes. However, there is currently no consensus that one [...]

Obesity and increased free fatty acid flux from adipocytes are risk factors for the development of insulin resistance and diabetes. In adipocytes, the perilipins are localized at the surface of [...]