scholarly journals Adipocyte-specific deletion of PIP5K1c reduces diet-induced obesity and insulin resistance by increasing energy expenditure

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Guan Huang ◽  
Cuishan Yang ◽  
Sheng Guo ◽  
Miaoling Huang ◽  
Liping Deng ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Adhesion Formation ◽  
Physiological Mechanism ◽  
Stromal Vascular Fraction ◽  
Conditional Knockout ◽  
Chow Diet ◽  
Type I ◽  
Phosphatidylinositol 4

Abstract Background Phosphatidylinositol 4-phosphate 5-kinase type I c (PIP5K1c) catalyses the synthesis of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) by phosphorylating phosphatidylinositol 4 phosphate, which plays multiple roles in regulating focal adhesion formation, invasion, and cell migration signal transduction cascades. Here, a new physiological mechanism of PIP5K1c in adipocytes and systemic metabolism is reported. Methods Adipose-specific conditional knockout mice were generated to delete the PIP5K1c gene in adipocytes. In addition, in vitro research investigated the effect of PIP5K1c deletion on adipogenesis. Results Deletion of PIP5K1c in adipocytes significantly alleviated high fat diet (HFD)-induced obesity, hyperlipidaemia, hepatic steatosis, and insulin resistance. PIP5K1c deficiency in adipocytes also decreased adipocyte volume in HFD-induced obese mice, whereas no significant differences were observed in body weight and adipose tissue weight under normal chow diet conditions. PIP5K1c knockout in adipocytes significantly enhanced energy expenditure, which protected mice from HFD-induced weight gain. In addition, adipogenesis was markedly impaired in mouse stromal vascular fraction (SVF) from PIP5K1c-deleted mice. Conclusion Under HFD conditions, PIP5K1c regulates adipogenesis and adipose tissue homeostasis. Together, these data indicate that PIP5K1c could be a novel potential target for regulating fat accumulation, which could provide novel insight into the treatment of obesity.

scholarly journals Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2109-2117 ◽  
Author(s):  
Elodie Riant ◽  
Aurélie Waget ◽  
Haude Cogo ◽  
Jean-François Arnal ◽  
Rémy Burcelin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Chow Diet ◽  
High Fat ◽  
Normal Chow ◽  
Visceral Adipose ◽  
Deficient Mice ◽  
Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

scholarly journals FABP4-Cre Mediated Expression of Constitutively Active ChREBP Protects Against Obesity, Fatty Liver, and Insulin Resistance

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4020-4032 ◽  
Author(s):  
Alli M. Nuotio-Antar ◽  
Naravat Poungvarin ◽  
Ming Li ◽  
Michael Schupp ◽  
Mahmoud Mohammad ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Fatty Liver ◽  
Binding Protein ◽  
Western Diet ◽  
Whole Body ◽  
Lipid Homeostasis ◽  
Chow Diet ◽  
Fatty Acid Binding ◽  
Constitutively Active

Carbohydrate response element binding protein (ChREBP) regulates cellular glucose and lipid homeostasis. Although ChREBP is highly expressed in many key metabolic tissues, the role of ChREBP in most of those tissues and the consequent effects on whole-body glucose and lipid metabolism are not well understood. Therefore, we generated a transgenic mouse that overexpresses a constitutively active ChREBP isoform under the control of the fatty acid binding protein 4-Cre-driven promoter (FaChOX). Weight gain was blunted in male, but not female, FaChOX mice when placed on either a normal chow diet or an obesogenic Western diet. Respiratory exchange ratios were increased in Western diet-fed FaChOX mice, indicating a shift in whole-body substrate use favoring carbohydrate metabolism. Western diet-fed FaChOX mice showed improved insulin sensitivity and glucose tolerance in comparison with controls. Hepatic triglyceride content was reduced in Western diet-fed FaChOX mice in comparison with controls, suggesting protection from fatty liver. Epididymal adipose tissue exhibited differential expression of genes involved in differentiation, browning, metabolism, lipid homeostasis, and inflammation between Western diet-fed FaChOX mice and controls. Our findings support a role for ChREBP in modulating adipocyte differentiation and adipose tissue metabolism and inflammation as well as consequent risks for obesity and insulin resistance.

Abstract 369: Naringenin Supplementation to a Chow Diet Reduces Plasma Lipids and Adiposity, and Suppresses Rer In Ldlr -/- Mice Fed a Chow Diet

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Amy C Burke ◽  
Dawn E Telford ◽  
Brian G Sutherland ◽  
Jane Y Edwards ◽  
Murray W Huff
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
White Adipose Tissue ◽  
Plasma Lipids ◽  
Metabolic Effects ◽  
Chow Diet ◽  
Light Cycle ◽  
Ambulatory Activity ◽  
Metabolic Dysregulation

Previously, we have shown that intervention by the addition of the citrus flavonoid naringenin to a chow diet enhances the reversal of diet-induced metabolic dysregulation, obesity, and atherosclerosis. However, the metabolic effects of naringenin in the absence of obesity and metabolic dysregulation are unknown. In the present study, we assessed the effect of naringenin supplementation to a chow diet on plasma lipids, adiposity, respiratory exchange ratio (RER), ambulatory activity and tissue lipolysis. For 8 weeks, Ldlr -/- mice were fed an isoflavone-free chow diet supplemented with or without 3% naringenin. Over 8 weeks, there was no difference in caloric intake between the two groups. Naringenin supplementation reduced plasma VLDL-cholesterol (C) (-46%; P <0.05), VLDL-triglycerides (-43%; P <0.05), and LDL-C (-27%; P <0.05) compared to mice consuming chow alone. Chow-fed mice maintained body weight, whereas mice fed chow with naringenin were ~1.4 g lighter ( P <0.05) with significantly reduced adiposity (-48%; P <0.05). Histological analysis of epididymal white adipose tissue showed naringenin supplementation reduced adipocyte size and number. Between 6 and 8 weeks of diet, mice were assessed in metabolic cages. Naringenin supplementation had no effect on food intake, ambulatory activity or energy expenditure during both the light and dark cycles. Consistently, naringenin-treated mice had significantly lower RER compared to mice fed chow alone (0.97 vs 0.99; P <0.05). This difference was driven by a significant suppression in RER during the light cycle (0.96 vs 1.00; P <0.05), but not the dark cycle (0.97 vs 0.98 N.S ), suggesting an enhanced starvation response. Triglyceride lipolysis was highest in white adipose tissue, followed by liver and muscle. Naringenin supplementation to chow increased the lipolytic rate in adipose, but not in muscle or liver, suggesting reduced adiposity was related to increased expression of ATGL or HSL. In conclusion, compared to chow alone, naringenin supplementation reduced plasma lipids and decreased body weight via increased adipose tissue lipolysis and suppressed RER, with no change in energy expenditure.

Abstract 12656: Phosphodiesterase 4 (PDE4) Inhibition Induces Weight Loss and Improves Insulin Resistance via cAMP-EPAC-AMPK Mediated Reprogramming of Macrophages

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Chaoneng Wu ◽  
Andrei Maiseyeu ◽  
Jeffrey A Deiuliis ◽  
Jixin Zhong ◽  
Xiaoquan Rao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Catecholamine Release ◽  
Innate Immune ◽  
Chow Diet ◽  
Intracellular Camp ◽  
Mouse Bone Marrow ◽  
Phosphodiesterase 4 ◽  
Brown Adipose

Objective: Recent evidence suggests an important role for cAMP-dependent pathways in modulation of innate immune function. Phosphodiesterase 4 (PDE4) is widely expressed in innate immune cells such as macrophages/dendritic cells with potent anti-inflammatory effects on pharmacologic inhibition of the enzyme. We investigated the importance of PDE4 in diet-induced obesity (DIO) and hypothesized that PDE4 inhibition will improve insulin sensitivity and reduce inflammation. Methods and Results: PDE4 was upregulated in both visceral and subcutaneous (SubQ) white adipose tissue (WAT) in DIO mice (12 weeks of high-fat diet, HFD, 60% fat) compared to normal-chow diet (NCD) mice (↑4∼10-folds, p<0.01). The degree of expression was correlated with macrophage infiltration in stromal vascular fraction from WAT (CD11b + F4/80 + cells, r=0.56, p<0.05). Treatment with Roflumilast (3mg/kg/day), a high affinity inhibitor of PDE4 (IC 50 0.39 nM) versus vehicle control (n=6∼10 in each group) for 21 days concomitant with HFD, resulted in rapid and substantial weight loss (↓45.8% fat content), enhanced thermogenesis [(∼20% higher oxygen consumption and heat production, 0.7∼1.1°C higher core body temperature in a cold environment (4°C)], brown adipose reprogramming, improvement in insulin resistance (HOMA-IR ↓ from 0.69±0.04 to 0.44±0.01, p<0.01) and hepatic steatosis. These changes were paralleled by increased alternative macrophage activation (Altf), reduced inflammation in WAT [↑CD206 and CD301 by flow cytometry with ↓ TNF/IL-6 gene expression] and activation of thermogenic genes in brown adipose tissue. In-vitro treatment of mouse bone marrow-derived macrophages (BMDM) promoted Altf and increased expression of tyrosine hydroxylase (↑2.5 folds) and catecholamines secretion. Additional experiments with agents that augment/reduce intracellular cAMP/EPAC/AMPK revealed an essential role for this cascade in Altf activation and catecholamine release. Conclusions: PDE4 antagonism improves obese diabetic symptoms through convergent pathways involving Altf activation and enhancing thermogenesis via cAMP dependent modulation of macrophage catecholamine release.

scholarly journals Effects of food pattern change and physical exercise on cafeteria diet-induced obesity in female rats

2012 ◽  
Vol 108 (8) ◽  
pp. 1511-1518 ◽  
Author(s):  
Jéferson F. Goularte ◽  
Maria B. C. Ferreira ◽  
Gilberto L. Sanvitto
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Physical Exercise ◽  
Energy Intake ◽  
Liver Weight ◽  
Cafeteria Diet ◽  
Chow Diet ◽  
Diet Induced Obesity ◽  
Visceral Adipose

Obesity affects a large number of people around the world and appears to be the result of changes in food intake, eating habits and physical activity levels. Changes in dietary patterns and physical exercise are therefore strongly recommended to treat obesity and its complications. The present study tested the hypothesis that obesity and metabolic changes produced by a cafeteria diet can be prevented with dietary changes and/or physical exercise. A total of fifty-six female Wistar rats underwent one of five treatments: chow diet; cafeteria diet; cafeteria diet followed by a chow diet; cafeteria diet plus exercise; cafeteria diet followed by a chow diet plus exercise. The duration of the experiment was 34 weeks. The cafeteria diet resulted in higher energy intake, weight gain, increased visceral adipose tissue and liver weight, and insulin resistance. The cafeteria diet followed by the chow diet resulted in energy intake, body weight, visceral adipose tissue and liver weight and insulin sensitivity equal to that of the controls. Exercise increased total energy intake at week 34, but produced no changes in the animals' body weight or adipose tissue mass. However, insulin sensitivity in animals subjected to exercise and the diet was similar to that of the controls. The present study found that exposure to palatable food caused obesity and insulin resistance and a diet change was sufficient to prevent cafeteria diet-induced obesity and to maintain insulin sensitivity at normal levels. In addition, exercise resulted in normal insulin sensitivity in obese rats. These results may help to develop new approaches for the treatment of obesity and type 2 diabetes mellitus.

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats

1986 ◽  
Vol 251 (5) ◽  
pp. E576-E583 ◽  
Author(s):  
L. H. Storlien ◽  
D. E. James ◽  
K. M. Burleigh ◽  
D. J. Chisholm ◽  
E. W. Kraegen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Brown Adipose Tissue ◽  
Whole Body ◽  
Brown Adipose ◽  
Glucose Output ◽  
Fat Feeding

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Decaffeinated Green Coffee Bean Extract Attenuates Diet-Induced Obesity and Insulin Resistance in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Su Jin Song ◽  
Sena Choi ◽  
Taesun Park
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Plasma Lipids ◽  
Body Weight Gain ◽  
Chow Diet ◽  
Coffee Bean ◽  
Green Coffee ◽  
Visceral Adipose ◽  
Green Coffee Bean Extract ◽  
Green Coffee Bean

This study investigated whether decaffeinated green coffee bean extract prevents obesity and improves insulin resistance and elucidated its mechanism of action. Male C57BL/6N mice(N=48)were divided into six dietary groups: chow diet, HFD, HFD-supplemented with 0.1%, 0.3%, and 0.9% decaffeinated green coffee bean extract, and 0.15% 5-caffeoylquinic acid. Based on the reduction in HFD-induced body weight gain and increments in plasma lipids, glucose, and insulin levels, the minimum effective dose of green coffee bean extract appears to be 0.3%. Green coffee bean extract resulted in downregulation of genes involved in WNT10b- and galanin-mediated adipogenesis and TLR4-mediated proinflammatory pathway and stimulation of GLUT4 translocation to the plasma membrane in white adipose tissue. Taken together, decaffeinated green coffee bean extract appeared to reverse HFD-induced fat accumulation and insulin resistance by downregulating the genes involved in adipogenesis and inflammation in visceral adipose tissue.

scholarly journals Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance

2020 ◽  
Vol 245 (1) ◽  
pp. 165-178 ◽  
Author(s):  
Terese M Zidon ◽  
Jaume Padilla ◽  
Kevin L Fritsche ◽  
Rebecca J Welly ◽  
Leighton T McCabe ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
Estrogen Receptor Alpha ◽  
Metabolic Diseases ◽  
Metabolic Effects ◽  
Metabolic Dysfunction ◽  
Gene And Protein Expression ◽  
Induced Changes

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7–12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.

scholarly journals TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Junling Yang ◽  
Ken-Ichiro Fukuchi
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Epididymal Adipose Tissue ◽  
Chow Diet ◽  
Low Grade ◽  
Interferon Β ◽  
Tlr Signaling ◽  
Normal Chow ◽  
Low Grade Inflammation

Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

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