Repin1 deficiency improves insulin sensitivity and glucose metabolism in db/db mice by reducing adipose tissue mass and inflammation

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1921015117 ◽

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00490.2015 ◽

2016 ◽

Vol 311 (1) ◽

pp. E56-E68 ◽

Cited By ~ 7

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.

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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

British Journal of Sports Medicine ◽

10.1136/bjsports-2018-100036 ◽

2019 ◽

Vol 53 (18) ◽

pp. 1183-1192 ◽

Cited By ~ 12

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

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Interleukin-7 Regulates Adipose Tissue Mass and Insulin Sensitivity in High-Fat Diet-Fed Mice through Lymphocyte-Dependent and Independent Mechanisms

PLoS ONE ◽

10.1371/journal.pone.0040351 ◽

2012 ◽

Vol 7 (6) ◽

pp. e40351 ◽

Cited By ~ 15

Author(s):

Stéphanie Lucas ◽

Solenne Taront ◽

Christophe Magnan ◽

Laurence Fauconnier ◽

Myriam Delacre ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

High Fat Diet ◽

High Fat ◽

Tissue Mass ◽

Interleukin 7 ◽

Adipose Tissue Mass

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MED19 Regulates Adipogenesis and Maintenance of White Adipose Tissue Mass by Mediating PPARγ-Dependent Gene Expression

Cell Reports ◽

10.1016/j.celrep.2020.108228 ◽

2020 ◽

Vol 33 (1) ◽

pp. 108228 ◽

Cited By ~ 1

Author(s):

John M. Dean ◽

Anyuan He ◽

Min Tan ◽

Jun Wang ◽

Dongliang Lu ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

White Adipose Tissue ◽

Tissue Mass ◽

Adipose Tissue Mass

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

Proceedings of The Nutrition Society ◽

10.1017/s0029665109990218 ◽

2009 ◽

Vol 68 (4) ◽

pp. 378-384 ◽

Cited By ~ 41

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.

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