scholarly journals The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B4axis

2020 ◽  
Vol 117 (21) ◽  
pp. 11674-11684
Author(s):  
Tetsuya Hosooka ◽  
Yusei Hosokawa ◽  
Kaku Matsugi ◽  
Masakazu Shinohara ◽  
Yoko Senga ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Pharmacological Intervention ◽  
Tissue Mass ◽  
Adipose Tissue Mass ◽  
Isolated Adipocytes ◽  
Genetic Deletion ◽  
Impaired Insulin Action ◽  
Microarray Analyses

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3′-phosphoinositide–dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B4(LTB4) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB4receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB4production through down-regulation of 5-LO expression via the PDK1−FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB4via the PDK1−FoxO1 pathway and thereby maintains systemic insulin sensitivity.

scholarly journals Chemotactic cytokines, obesity and type 2 diabetes:in vivoandin vitroevidence for a possible causal correlation?

2009 ◽  
Vol 68 (4) ◽  
pp. 378-384 ◽  
Author(s):  
Henrike Sell ◽  
Jürgen Eckel
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Obese Patients ◽  
Tissue Mass ◽  
Tissue Biology ◽  
Wide Range ◽  
Adipose Tissue Mass

A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistancein vivoandin vitro.

scholarly journals Resistin expression and plasma concentration peak at different times during pregnancy in rats

2005 ◽  
Vol 185 (3) ◽  
pp. 551-559 ◽  
Author(s):  
Sergio Caja ◽  
Izaskun Martínez ◽  
María Abelenda ◽  
Marisa Puerta
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Plasma Concentration ◽  
White Adipose Tissue ◽  
Post Partum ◽  
Time Lag ◽  
Simultaneous Increase ◽  
Tissue Mass ◽  
Pregnant Rats ◽  
Adipose Tissue Mass

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5–15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin – which peaks in early pregnancy – to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.

scholarly journals Activation of the adipocyte CREB/CRTC pathway in obesity

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Young-Sil Yoon ◽  
Weiyi Liu ◽  
Sam Van de Velde ◽  
Shigenobu Matsumura ◽  
Ezra Wiater ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Type Ii Diabetes ◽  
High Fat ◽  
Tissue Mass ◽  
Pparγ Agonist ◽  
Adipose Tissue Mass ◽  
Factor C ◽  
Pro Inflammatory Cytokines

AbstractObesity is a major risk factor for the development of type II diabetes. Increases in adipose tissue mass trigger insulin resistance via the release of pro-inflammatory cytokines from adipocytes and macrophages. CREB and the CRTC coactivators have been found to promote insulin resistance in obesity, although the mechanism is unclear. Here we show that high fat diet feeding activates the CREB/CRTC pathway in adipocytes by decreasing the expression of SIK2, a Ser/Thr kinase that phosphorylates and inhibits CRTCs. SIK2 levels are regulated by the adipogenic factor C/EBPα, whose expression is reduced in obesity. Exposure to PPARγ agonist rescues C/EBPα expression and restores SIK2 levels. CRTC2/3 promote insulin resistance via induction of the chemokines CXCL1/2. Knockout of CRTC2/3 in adipocytes reduces CXCL1/2 expression and improves insulin sensitivity. As administration of CXCL1/2 reverses salutary effects of CRTC2/3 depletion, our results demonstrate the importance of the CREB/CRTC pathway in modulating adipose tissue function.

scholarly journals Interleukin-18 in plasma and adipose tissue: effects of obesity, insulin resistance, and weight loss

2007 ◽  
Vol 157 (4) ◽  
pp. 465-471 ◽  
Author(s):  
Jens M Bruun ◽  
Bente Stallknecht ◽  
Jørn W Helge ◽  
Bjørn Richelsen
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Rt Pcr ◽  
Reduced Body ◽  
Daily Exercise ◽  
Life Style Intervention ◽  
Obese Subjects ◽  
Isolated Adipocytes

Objective: Interleukin (IL)-18 is associated with obesity, insulin resistance, and cardiovascular disease. The present study compared 1) IL-18 in adipocytes versus stromal vascular (SV) cells, 2) IL-18 in plasma and adipose tissue (AT) in obese versus lean subjects, and 3) IL-18 in plasma, AT, and skeletal muscle (SM) in obese subjects after weight loss. Subjects and methods: At baseline, plasma and AT IL-18 in 23 obese subjects were compared with that in 12 lean subjects. The obese subjects were submitted to a 15-week life-style intervention (hypocaloric diet and daily exercise) after which plasma samples, AT, and SM biopsies were obtained. Analyses were performed by ELISA and RT-PCR respectively. Results: IL-18 expression in isolated adipocytes was ~2% of that in SV cells. Plasma IL-18 was higher in obese subjects (P < 0.001) and associated with insulin resistance (HOMA; P < 0.001). AT expression of IL-18, CD14, and CD68 was higher in obese (P < 0.01). The intervention reduced body weight (P < 0.001), plasma IL-18 (P < 0.001), and increased insulin sensitivity (HOMA; P < 0.05). AT and SM expression of IL-18 remained unchanged after the intervention. Changes in plasma IL-18 were associated with changes in insulin sensitivity (P < 0.05) but not with BMI or AT expression of IL-18. Conclusion: Plasma IL-18 is associated with changes in insulin resistance and reduced after weight loss. AT expression of IL-18 is increased in obesity but not affected by weight loss, indicating that changes in plasma IL-18 are related to insulin resistance rather than changes in obesity per se.

scholarly journals Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction

2016 ◽  
Vol 311 (1) ◽  
pp. E56-E68 ◽  
Author(s):  
Trevor Teich ◽  
Emily C. Dunford ◽  
Deanna P. Porras ◽  
Jacklyn A. Pivovarov ◽  
Jacqueline L. Beaudry ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Receptor Antagonist ◽  
Caloric Restriction ◽  
Mass Gain ◽  
Male Rats ◽  
Tissue Mass ◽  
Adiposity Rebound ◽  
Adipose Tissue Mass

Severe caloric restriction (CR), in a setting of regular physical exercise, may be a stress that sets the stage for adiposity rebound and insulin resistance when the food restriction and exercise stop. In this study, we examined the effect of mifepristone, a glucocorticoid (GC) receptor antagonist, on limiting adipose tissue mass gain and preserving whole body insulin sensitivity following the cessation of daily running and CR. We calorically restricted male Sprague-Dawley rats and provided access to voluntary running wheels for 3 wk followed by locking of the wheels and reintroduction to ad libitum feeding with or without mifepristone (80 mg·kg−1·day−1) for 1 wk. Cessation of daily running and CR increased HOMA-IR and visceral adipose mass as well as glucose and insulin area under the curve during an oral glucose tolerance test vs. pre-wheel lock exercised rats and sedentary rats (all P < 0.05). Insulin sensitivity and glucose tolerance were preserved and adipose tissue mass gain was attenuated by daily mifepristone treatment during the post-wheel lock period. These findings suggest that following regular exercise and CR there are GC-induced mechanisms that promote adipose tissue mass gain and impaired metabolic control in healthy organisms and that this phenomenon can be inhibited by the GC receptor antagonist mifepristone.

scholarly journals Impact of increased adipose tissue mass on inflammation, insulin resistance, and dyslipidemia

2009 ◽  
Vol 9 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Dario A. Gutierrez ◽  
Michael J. Puglisi ◽  
Alyssa H. Hasty
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Tissue Mass ◽  
Adipose Tissue Mass

scholarly journals How does 6 months of active bike commuting or leisure-time exercise affect insulin sensitivity, cardiorespiratory fitness and intra-abdominal fat? A randomised controlled trial in individuals with overweight and obesity

2019 ◽  
Vol 53 (18) ◽  
pp. 1183-1192 ◽  
Author(s):  
Martin Bæk Blond ◽  
Mads Rosenkilde ◽  
Anne Sofie Gram ◽  
Marie Tindborg ◽  
Anders Nymark Christensen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Cardiorespiratory Fitness ◽  
Leisure Time ◽  
Overweight And Obesity ◽  
Moderate Intensity ◽  
Tissue Mass ◽  
Abdominal Adipose Tissue ◽  
Peripheral Insulin Sensitivity ◽  
Adipose Tissue Mass

ObjectivesTo evaluate effects of active bike commuting or leisure-time exercise of two intensities on peripheral insulin sensitivity (primary outcome), cardiorespiratory fitness and intra-abdominal adipose tissue mass (secondary outcomes).Methods188 physically inactive, healthy women and men (20-45 years) with overweight or class 1 obesity were recruited. In the 6-month trial, 130 participants were randomised to either: no intervention (CON), active commuting (BIKE) or leisure-time exercise of moderate (MOD, 50% VO2peak) or vigorous (VIG, 70% VO2peak) intensity. 100 completed follow-up testing. Exercise prescription was 5 days/week with a weekly exercise energy expenditure of 1600 kcal for women and 2100 kcal for men. Testing was performed at baseline, 3 months and 6 months.ResultsPeripheral insulin sensitivity (ml/min/pmol insulin/L) increased (improved) by 24% (95% CI 6% to 46%, p=0.01) in VIG compared with CON at 3 months. Peripheral insulin sensitivity increased (improved) by 20% in BIKE (95% CI 1% to 43%, p=0.04) and 26% in VIG (95% CI 7% to 47%, p<0.01) compared with CON at 6 months. Cardiorespiratory fitness increased in all exercise groups compared with CON at 6 months; but the increase was higher in those that undertook vigorous exercise than those who did moderate exercise. Intra-abdominal adipose tissue mass diminished across all exercise groups in comparison to CON at 6 months.ConclusionsActive bike commuting improved cardiometabolic health; as did leisure-time exercise. Leisure-time exercise of vigorous intensity conferred more rapid effects on peripheral insulin sensitivity as well as additional effects on cardiorespiratory fitness than did moderate intensity exercise.Trial registrationNCT01962259

scholarly journals Associations of Haplotypes Upstream ofIRS1with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal MuscleLOC646736mRNA Levels

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Selma M. Soyal ◽  
Thomas Felder ◽  
Simon Auer ◽  
Hannes Oberkofler ◽  
Bernhard Iglseder ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Lipid Profile ◽  
Mrna Levels ◽  
Tissue Mass ◽  
Cross Sectional ◽  
Adipose Tissue Mass

The genomic region ~500 kb upstream ofIRS1has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.01 were observed. We identified one haplotype that was protective against insulin resistance (determined by HOMA-IR and fasting plasma insulin levels), type 2 diabetes, an adverse lipid profile, increased C-reactive protein, and asymptomatic atherosclerotic disease (assessed by intima media thickness of the common carotid arteries). BMI and total adipose tissue mass as well as visceral and subcutaneous adipose tissue mass did not differ between the reference and protective haplotypes. In 92 subjects, we observed an association of the protective haplotype with higher skeletal muscle mRNA levels ofLOC646736, which is located in the same haplotype block as the informative SNPs and is mainly expressed in skeletal muscle, but only at very low levels in liver or adipose tissues. These data suggest a role forLOC646736in human insulin resistance and warrant further studies on the functional effects of this locus.

scholarly journals Regulation of adipose tissue lipolysis revisited

2009 ◽  
Vol 68 (4) ◽  
pp. 350-360 ◽  
Author(s):  
Véronic Bézaire ◽  
Dominique Langin
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Regulatory Control ◽  
Tissue Mass ◽  
Underdeveloped Countries ◽  
Metabolic States ◽  
Tremendous Progress ◽  
Adipose Tissue Mass ◽  
Adipose Tissue Lipolysis ◽  
Made In

Human obesity and its complications are an increasing burden in developed and underdeveloped countries. Adipose tissue mass and the mechanisms that control it are central to elucidating the aetiology of obesity and insulin resistance. Over the past 15 years tremendous progress has been made in several avenues relating to adipose tissue. Knowledge of the lipolytic machinery has grown with the identification of new lipases, cofactors and interactions between proteins and lipids that are central to the regulation of basal and stimulated lipolysis. The dated idea of an inert lipid droplet has been appropriately revamped to that of a dynamic and highly-structured organelle that in itself offers regulatory control over lipolysis. The present review provides an overview of the numerous partners and pathways involved in adipose tissue lipolysis and their interaction under various metabolic states. Integration of these findings into whole adipose tissue metabolism and its systemic effects is also presented in the context of inflammation and insulin resistance.

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