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Objective: Gremlin 1 (GREM1) is a secreted BMP2/4 inhibitor which regulates commitment and differentiation of human adipose precursor cells and prevents the browning effect of BMP4. GREM1 is an insulin antagonist and serum levels are high in type 2 diabetes (T2D). We here examined in vivo effects of AAV8 (Adeno-Associated Viral vectors of serotype eight) GREM 1 targeting the liver in mature mice to increase its systemic secretion and also, in a separate study, injected recombinant GREM 1 intraperitoneally. The objective was to characterize systemic effects of GREM 1 on insulin sensitivity, glucose tolerance, body weight, adipose cell browning and other local tissue effects., Methods: Adult mice were injected with AAV8 vectors expressing GREM1 in the liver or receiving regular intra-peritoneal injections of recombinant GREM1 protein. The mice were fed with a low fat or high fat diet (HFD) and followed over time., Results: Liver-targeted AAV8-GREM1 did not alter body weight, whole-body glucose and insulin tolerance, or adipose tissue gene expression. Although GREM1 protein accumulated in liver cells, GREM1 serum levels were not increased suggesting that it may not have been normally processed for secretion. Hepatic lipid accumulation, inflammation and fibrosis were also not changed. Repeated intraperitoneal rec-GREM1 injections for 5 weeks were also without effects on body weight and insulin sensitivity. UCP1 was slightly but significantly reduced in both white and brown adipose tissue but this was not of sufficient magnitude to alter body weight. We validated that recombinant GREM1 inhibited BMP4-induced pSMAD1/5/9 in murine cells in vitro, but saw no direct inhibitory effect on insulin signalling and pAkt (ser 473 and thr 308) activation., Conclusion: GREM1 accumulates intracellularly when overexpressed in the liver cells of mature mice and is apparently not normally processed/secreted. However, also repeated intraperitoneal injections were without effects on body weight and insulin sensitivity and adipose tissue UCP1 levels were only marginally reduced. These results suggest that mature mice do not readily respond to GREMLIN 1 but treatment of murine cells with GREMLIN 1 protein in vitro validated its inhibitory effect on BMP4 signalling while insulin signalling was not altered., Competing Interests: All authors declare that they have no competing interests and that the funding of SH, CC and JB by Astra Zeneca only relates to funding these salaries. Furthermore, this funding does not alter our adherence to PLOS ONE policies on sharing data and materials.

Females are, in general, more insulin sensitive than males. To investigate whether this is a direct effect of sex-steroids (SS) in white adipose tissue (WAT), we developed a male mouse model overexpressing the aromatase enzyme, converting testosterone (T) to estradiol (E 2 ), specifically in WAT (Ap2-arom mice). Adipose tissue E 2 levels were increased while circulating SS levels were unaffected in male Ap2-arom mice. Importantly, male Ap2-arom mice were more insulin sensitive compared with WT mice and exhibited increased serum adiponectin levels and upregulated expression of Glut4 and Irs1 in WAT. The expression of markers of macrophages and immune cell infiltration was markedly decreased in WAT of male Ap2-arom mice. The adipogenesis was enhanced in male Ap2-arom mice, supported by elevated Pparg expression in WAT and enhanced differentiation of preadipocyte into mature adipocytes. In summary, increased adipose tissue aromatase activity reduces adipose tissue inflammation and improves insulin sensitivity in male mice. We propose that estrogen increases insulin sensitivity via a local effect in WAT on adiponectin expression, adipose tissue inflammation, and adipogenesis., (Copyright © 2017 the American Physiological Society.)

Background: Type 2 diabetes (T2D) is associated with substantial morbidity and mortality. Individuals with a family history of T2D are at an increased risk of developing the disease. The aim of this study was to assess metabolic differences between first-degree relatives (FDR) of T2D patients and persons with no known family history of T2D (non-FDR)., Methods: In 200 FDR and 73 non-FDR, we compared anthropometrics, glucose tolerance status, different measurements of insulin secretion, insulin resistance, as well as blood lipids and other blood analyses., Results: In the FDR group, 30 individuals had impaired glucose tolerance or T2D. Among the non-FDR, two individuals had impaired glucose tolerance. In unadjusted data, the FDR were older, had stronger heredity for coronary heart disease, lower body mass index and weight, higher OGTT plasma glucose concentrations, and impaired insulin secretion (all p < 0.05). Using propensity score, we matched the groups, resulting in significantly stronger heredity of coronary heart disease, higher OGTT plasma glucose at 60 and 90 min, larger glucose area under curve during the OGTT and higher serum creatinine among the FDR. Using least squares means, OGTT glucose at 60 and 120 min, as well as the area under curve, and OGTT insulin levels at 60 min were significantly higher. Body mass index was negatively correlated with insulin sensitivity (MI) and positively correlated with HOMA-β, a measurement of insulin secretion., Conclusions: We show that FDR are more likely to have impaired glucose tolerance and display higher OGTT plasma glucose and insulin, indicating an unfavorable metabolic profile. We conclude that OGTT is a simple and yet informative metabolic assessment in the FDR group. In both groups, we saw a negative correlation between body mass index and MI, confirming the role of body mass index in insulin resistance.

WISP2 is a novel adipokine, most highly expressed in the adipose tissue and primarily in undifferentiated mesenchymal cells. As a secreted protein, it is an autocrine/paracrine activator of canonical WNT signaling and, as an intracellular protein, it helps to maintain precursor cells undifferentiated. To examine effects of increased WISP2 in vivo, we generated an aP2-WISP2 transgenic (Tg) mouse. These mice had increased serum levels of WISP2, increased lean body mass and whole body energy expenditure, hyperplastic brown/white adipose tissues and larger hyperplastic hearts. Obese Tg mice remained insulin sensitive, had increased glucose uptake by adipose cells and skeletal muscle in vivo and ex vivo, increased GLUT4, increased ChREBP and markers of adipose tissue lipogenesis. Serum levels of the novel fatty acid esters of hydroxy fatty acids (FAHFAs) were increased and transplantation of Tg adipose tissue improved glucose tolerance in recipient mice supporting a role of secreted FAHFAs. The growth-promoting effect of WISP2 was shown by increased BrdU incorporation in vivo and Tg serum increased mesenchymal precursor cell proliferation in vitro. In contrast to conventional canonical WNT ligands, WISP2 expression was inhibited by BMP4 thereby allowing normal induction of adipogenesis. WISP2 is a novel secreted regulator of mesenchymal tissue cellularity.

Background: We characterized in detail (oral and intravenous glucose tolerance tests (OGTT and IVGTT), euglycemic hyperinsulinemic clamp, adipose tissue biopsy), healthy first-degree relatives (FDR) of individuals with type 2 diabetes (T2D), to examine predictive factors for future development of impaired glucose tolerance (IGT) or T2D., Methods: Non-diabetic FDR (n = 138, mean age 40.5 ± 6.5 years, 57 % women) underwent an extended OGTT every 3 years to assess any deterioration in glucose tolerance status. Differences between groups were assessed by logistic fit for continuous variables and by contingency analysis for categorical variables. Multiple logistic regression analysis was applied to adjust for confounding variables., Results: At follow-up (mean 5.6 ± 2.4 years) 19 subjects had IGT and 4 had T2D. At baseline these 23 subjects had more family members with T2D, higher fasting plasma glucose, higher OGTT plasma glucose at 120 min, higher HbA1c, lower M-value and higher total cholesterol compared to subjects with normal glucose tolerance (NGT). There were significantly larger changes in weight, BMI, fasting plasma glucose, OGTT plasma glucose at 120 min and HbA1c in individuals developing IGT or T2D during the follow-up period than the subjects remaining NGT. Crude predictors of deteriorating glucose tolerance were age, family history of diabetes and of hypertension, OGTT plasma glucose levels at 60 min, 90 min, and 120 min, as well as serum bilirubin, ALP and creatinine (p-values <0.05). A multiple nominal logistic regression model revealed that male sex, low M-value and high physical exercise (p-values <0.05) predicted development of IGT/T2DM., Conclusion: In sum, genetically predisposed individuals for T2D with deteriorating glucose tolerance exhibit insulin resistance as well as beta-cell and signs of adipose tissue dysfunction, emphasizing the multifactorial pathophysiology in the development of IGT and T2D.

The adipose tissue is crucial in regulating insulin sensitivity and risk for diabetes through its lipid storage capacity and thermogenic and endocrine functions. Subcutaneous adipose tissue (SAT) stores excess lipids through expansion of adipocytes (hypertrophic obesity) and/or recruitment of new precursor cells (hyperplastic obesity). Hypertrophic obesity in humans, a characteristic of genetic predisposition for diabetes, is associated with abdominal obesity, ectopic fat accumulation, and the metabolic syndrome (MS), while the ability to recruit new adipocytes prevents this. We review the regulation of adipogenesis, its relation to SAT expandability and the risks of ectopic fat accumulation, and insulin resistance. The actions of GLUT4 in SAT, including a novel family of lipids enhancing insulin sensitivity/secretion, and the function of bone morphogenetic proteins (BMPs) in white and beige/brown adipogenesis in humans are highlighted., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Hyperinsulinemia emerges as a negative modulator of the circulating high-molecular-weight adiponectin multimers., Objectives: Here we asked whether, in vivo, acute hyperinsulinemia regulates adiponectin formation and oligomeric complex distribution at the transcriptional or posttranslational level., Design: Nine lean and nine uncomplicated obese males were studied in the postabsorptive state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Subcutaneous abdominal adipose tissue biopsies and interstitial and serum samples were taken at baseline and after the hyperinsulinemia. Adiponectin complexes were characterized by nonheating/nonreducing SDS-PAGE., Results: At baseline, serum and interstitial total adiponectin levels were lower (P < 0.01) in obese than in lean subjects primarily due to a reduction of the high-molecular-weight isoforms. After hyperinsulinemia, serum and interstitial total adiponectin was reduced in both groups. The degree of adiponectin reduction was more prominent in interstitial fluid than in serum. Lean individuals showed an equal suppression of the high-, low-, and middle-molecular-weight adiponectin complexes both in serum and in situ (P < 0.01 vs. basal). In obese subjects, despite the lower interstitial adiponectin subfractions, insulin challenge reduced significantly the circulating middle-molecular-weight forms only. At the mRNA level, adiponectin and its receptors 1 and 2, as well as the abundance of the endoplasmic reticulum chaperone proteins ERp44 and Epsilonro1-Lalpha were similar within the groups, before and after the clamp., Conclusions: In human obesity, the impaired adiponectin oligomeric pattern in the circulation is mimicked at the tissue level, and hyperinsulinemia may differentially affect the compartmental distribution of the adiponectin complexes.

Type 2 diabetes is the most common metabolic disorder today and has reached epidemic proportions in many countries. Insulin resistance and inflammation play a central role in the pathogenesis of type 2 diabetes and are present long before the onset of the disease. During this time, many of the complications associated with type 2 diabetes are initiated. Of major concern is the two- to fourfold increase in cardiovascular morbidity and mortality in this group compared to a nondiabetic population. Obesity, characterized by enlarged fat cells, and insulin resistance are, like type 2 diabetes, associated with impaired adipogenesis and a low-grade chronic inflammation that to a large extent emanates from the adipose tissue. Both these processes contribute to unfavourable alterations of the circulating levels of several bioactive molecules (adipokines) that are secreted from the adipose tissue, many of which have documented inhibitory effects on insulin sensitivity in the liver and peripheral tissues and, in addition, have negative effects on the cardiovascular system.Here we review current knowledge of the adipose tissue as an endocrine organ, the local and systemic effects of a chronic state of low-grade inflammation residing in the adipose tissue, and, in particular, the effects of inflammation and circulating adipokines on the vascular wall., (Copyright 2008 John Wiley & Sons, Ltd.)

Background: Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance., Methods: We measured serum RBP4, insulin resistance, and components of the metabolic syndrome in three groups of subjects. Measurements were repeated after exercise training in one group. GLUT4 protein was measured in isolated adipocytes., Results: Serum RBP4 levels correlated with the magnitude of insulin resistance in subjects with obesity, impaired glucose tolerance, or type 2 diabetes and in nonobese, nondiabetic subjects with a strong family history of type 2 diabetes. Elevated serum RBP4 was associated with components of the metabolic syndrome, including increased body-mass index, waist-to-hip ratio, serum triglyceride levels, and systolic blood pressure and decreased high-density lipoprotein cholesterol levels. Exercise training was associated with a reduction in serum RBP4 levels only in subjects in whom insulin resistance improved. Adipocyte GLUT4 protein and serum RBP4 levels were inversely correlated., Conclusions: RBP4 is an adipocyte-secreted molecule that is elevated in the serum before the development of frank diabetes and appears to identify insulin resistance and associated cardiovascular risk factors in subjects with varied clinical presentations. These findings provide a rationale for antidiabetic therapies aimed at lowering serum RBP4 levels., (Copyright 2006 Massachusetts Medical Society.)

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH. [ABSTRACT FROM AUTHOR]

The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes increase worldwide at an epidemic rate. It is expected that by the year 2030 around 500 million people will have diabetes; predominantly type 2 diabetes. The CCN family of proteins has become of interest in both metabolic and other common human diseases because of their effects on mesenchymal stem cell (MSCs) proliferation and differentiation as well as being important regulators of fibrosis. We here review current knowledge of the WNT1 inducible signaling pathway protein 2 (CCN5/WISP2). It has been shown to be an important regulator of both these processes through effects on both the canonical WNT and the TGFβ pathways. It is also under normal regulation by the adipogenic commitment factor BMP4, in contrast to conventional canonical WNT ligands, and allows MSCs to undergo normal adipose cell differentiation. CCN5/WISP2 is highly expressed in, and secreted by, MSCs and is an important regulator of MSCs growth. In a transgenic mouse model overexpressing CCN5/WISP2 in the adipose tissue, we have shown that it is secreted and circulating in the blood, the mice develop hypercellular white and brown adipose tissue, have increased lean body mass and enlarged hypercellular hearts. Obese transgenic mice had improved insulin sensitivity. Interestingly, the anti-fibrotic effect of CCN5/WISP2 is protective against heart failure by inhibition of the TGFβ pathway. Understanding how CCN5/WISP2 is regulated and signals is important and may be useful for developing new treatment strategies in obesity and metabolic diseases and it can also be a target in regenerative medicine. [ABSTRACT FROM AUTHOR]

Summary We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes in vitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from obesity on a high-fat diet and have increased whole-body energy expenditure, improved insulin sensitivity, reduced liver fat, and reduced adipose tissue inflammation. On a control diet, they show unchanged body weight but improved insulin sensitivity. In contrast, AAV-BMP4-treated mice showed beiging of BAT with reduced UCP1, increased lipids, and reduced hormone-sensitive lipase (HSL). Thus, BMP4 exerts different effects on WAT and BAT, but the overall effect is to enhance insulin sensitivity and whole-body energy expenditure by browning subcutaneous adipose tissue. [ABSTRACT FROM AUTHOR]

Background: The adipose tissue is important for development of insulin resistance and type 2 diabetes and adipose tissue dysfunction has been proposed as an underlying cause. In the present study we investigated presence of adipocyte hypertrophy, and gene expression pattern of adipose tissue dysfunction in the subcutaneous adipose tissue of healthy, non-obese subjects predisposed to type 2 diabetes compared to matched control subjects with no known genetic predisposition for type 2 diabetes. Method: Seventeen healthy and non-obese subjects with known genetic predisposition for type 2 diabetes (first-degree relatives, FDRs) and 17 control subjects were recruited. The groups were matched for gender and BMI and had similar age. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was calculated using HOMA-index. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene expression analysis and adipocyte cell size measurement. Results: Our findings show that, in spite of similar age, BMI and percent body fat, FDRs displayed adipocyte hypertrophy, as well as higher waist/hip ratio, fasting insulin levels, HOMA-IR and serum triglycerides. Adipocyte hypertrophy in the FDR group, but not among controls, was associated with measures of impaired insulin sensitivity. The adipocyte hypertrophy was accompanied by increased inflammation and Wnt-signal activation. In addition, signs of tissue remodeling and fibrosis were observed indicating presence of early alterations associated with adipose tissue dysfunction in the FDRs. Conclusion: Genetic predisposition for type 2 diabetes is associated with impaired insulin sensitivity, adipocyte hypertrophy and other markers of adipose tissue dysfunction. A dysregulated subcutaneous adipose tissue may be a major susceptibility factor for later development of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Inability to recruit new adipose cells following weight gain leads to inappropriate enlargement of existing cells (hypertrophic obesity) associated with inflammation and a dysfunctional adipose tissue. We found increased expression of WNT1 inducible signaling pathway protein 2 (WISP2) and other markers of WNT activation in human abdominal s.c. adipose tissue characterized by hypertrophic obesity combined with increased visceral fat accumulation and insulin resistance. WISP2 activation in the s.c. adipose tissue, but not in visceral fat, identified the metabolic syndrome in equally obese individuals. WISP2 is a novel adipokine, highly expressed and secreted by adipose precursor cells. Knocking down WISP2 induced spontaneous differentiation of 3T3-L1 and human preadipocytes and allowed NIH 3T3 fibroblasts to become committed to the adipose lineage by bone morphogenetic protein 4 (BMP4). WISP2 forms a cytosolic complex with the peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activator zinc finger protein 423 (Zfp423), and this complex is dissociated by BMP4 in a SMAD-dependent manner, thereby allowing Zfp423 to enter the nucleus, activate PPARγ, and commit the cells to the adipose lineage. The importance of intracellular Wisp2 protein for BMP4-induced adipogenic commitment and PPARγ activation was verified by expressing a mutant Wisp2 protein lacking the endoplasmic reticulum signal and secretion sequence. Secreted Wnt/Wisp2 also inhibits differentiation and PPARγ activation, albeit not through Zfp423 nuclear translocation. Thus adipogenic commitment and differentiation is regulated by the cross-talk between BMP4 and canonical WNT signaling and where WISP2 plays a key role. Furthermore, they link WISP2 with hypertrophic obesity and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-I and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications. [ABSTRACT FROM AUTHOR]

Abstract: Objective:: Low adipocyte IRS-1 protein expression is a biomarker for insulin resistance and early atherosclerosis. However, whether IRS-1 protein expression is related to systemic arterial stiffness, is unknown. Methods and results:: Ten non-diabetic male subjects with low adipocyte IRS-1 protein expression (LIRS) were matched with 10 non-diabetic males with normal IRS-1 protein expression (NIRS). Augmentation index (AIx) and time for reflection of pulse wave (Tr) were studied with pulse wave analysis, both in the fasting state and during a euglycemic hyperinsulinemic clamp. The LIRS-group showed an increased fasting insulin concentration (fP-insulin 71±4pmol/L versus 58±5pmol/L; p =0.02 (mean±S.E.)), whereas glucose disposal rate during the clamp (8.7±0.8mg/kg LBM/min versus 10.3±1.3mg/kg LBM/min; n.s.) did not differ significantly. Blood pressure, lipid parameters, adiponectin, endothelin-1 and CRP concentrations were similar. However, in the basal state, AIx was increased (129±4% versus 116±2%; p &#60;0.02) and Tr was decreased (150±3ms versus 171±5ms; p &#60;0.01), suggesting stiffer vessels in the LIRS-group. The LIRS-group exhibited an attenuated AIx response to hyperinsulinemia compared to the NIRS-group. Conclusions:: The data suggest that non-obese non-diabetic men with a low adipocyte IRS-1 protein expression have an increased systemic arterial stiffness. [Copyright &y& Elsevier]

Summary Increased adipose tissue lipogenesis is associated with enhanced insulin sensitivity. Mice overexpressing the Glut4 glucose transporter in adipocytes have elevated lipogenesis and increased glucose tolerance despite being obese with elevated circulating fatty acids. Lipidomic analysis of adipose tissue revealed the existence of branched f atty a cid esters of h ydroxy f atty a cids (FAHFAs) that were elevated 16- to 18-fold in these mice. FAHFA isomers differ by the branched ester position on the hydroxy fatty acid (e.g., p almitic- a cid-9- h ydroxy- s tearic- a cid, 9-PAHSA). PAHSAs are synthesized in vivo and regulated by fasting and high-fat feeding. PAHSA levels correlate highly with insulin sensitivity and are reduced in adipose tissue and serum of insulin-resistant humans. PAHSA administration in mice lowers ambient glycemia and improves glucose tolerance while stimulating GLP-1 and insulin secretion. PAHSAs also reduce adipose tissue inflammation. In adipocytes, PAHSAs signal through GPR120 to enhance insulin-stimulated glucose uptake. Thus, FAHFAs are endogenous lipids with the potential to treat type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Obesity and its complications are characterized by elevated circulating levels of inflammation markers like CRP, IL-6 and serum amyloid A. Although several cells secrete these markers, the adipose tissue seems to play a pivotal role for the proinflammatory state. Obesity with enlarged adipose cells leads to a marked increase in the expression of pro-inflammatory cytokines in the adipose tissue while expression of the anti-inflammatory adipokine, adiponectin, is reduced. The mechanisms for this are currently unknown but a consequence is the recruitment of inflammatory cells into the adipose tissue which, thus, becomes inflamed. Animal experiments have shown that this is associated with a clear accentuation of degree of insulin resistance. Invasion of inflammatory cells leads to the release of TNFa, which normally is not secreted by the adipose cells. The increased levels of cytokines in the adipose tissue have marked consequences for the normal differentiation of the preadipocytes. These cells become proinflammatory and the normal phenotype, i.e., lipid-accumulating and insulin-sensitive cells, is suppressed. Although inflammation in the adipose tissue also leads to a reduced insulin sensitivity, recent data have shown that induction of insulin resistance by itself in the adipose tissue also is proinflammatory since insulin can exert an anti-inflammatory effect through its cross-talk with the IL-6 signaling cascade. [Copyright &y& Elsevier]