scholarly journals Adipose Triglyceride Lipase-Null Mice Are Resistant to High-Fat Diet–Induced Insulin Resistance Despite Reduced Energy Expenditure and Ectopic Lipid Accumulation

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 48-58 ◽  
Author(s):  
Andrew J. Hoy ◽  
Clinton R. Bruce ◽  
Sarah M. Turpin ◽  
Alexander J. Morris ◽  
Mark A. Febbraio ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Adipose Triglyceride Lipase ◽  
Wild Type ◽  
High Fat

Abstract Adipose triglyceride lipase (ATGL) null (−/−) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL−/− mice persist when challenged with a high-fat diet. ATGL−/− mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL−/− mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre–high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet–induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet–induced insulin resistance in ATGL−/− mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL−/− mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.

scholarly journals Hypoglycemic effects and mechanisms of electroacupuncture on insulin resistance

2014 ◽  
Vol 307 (3) ◽  
pp. R332-R339 ◽  
Author(s):  
Jieyun Yin ◽  
Jian Kuang ◽  
Manisha Chandalia ◽  
Demidmaa Tuvdendorj ◽  
Batbayar Tumurbaatar ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Free Fatty Acid ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Postprandial Glucose ◽  
Tolerance Test ◽  
High Fat

The aim of this study was to investigate effects and mechanisms of electroacupuncture (EA) on blood glucose and insulin sensitivity in mice fed a high-fat diet. Both wild-type (WT) and adipose ectonucleotide pyrophosphate phosphodiesterase (ENPP1) transgenic (TG) mice were fed a high-fat diet for 12 wk; for each mouse, an intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed with or without EA at abdomen or auricular areas. A high-fat diet-induced insulin resistance in both WT and TG mice. In the WT mice, EA at 3 Hz and 15 Hz, but not at 1 Hz or 100 Hz, via CV4+CV12 significantly reduced postprandial glucose levels; EA at 3 Hz was most potent. The glucose level was reduced by 61.7% at 60 min and 74.5% at 120 min with EA at 3 Hz (all P < 0.001 vs. control). Similar hypoglycemic effect was noted in the TG mice. On the contrary, EA at auricular points increased postprandial glucose level ( P < 0.03). 4). EA at 3 Hz via CV4+CV12 significantly enhanced the decrease of blood glucose after insulin injection, suggesting improvement of insulin sensitivity. Plasma free fatty acid was significantly suppressed by 42.5% at 15 min and 50.8% at 30 min with EA ( P < 0.01) in both WT and TG mice. EA improves glucose tolerance in both WT and TG mice fed a high-fat diet, and the effect is associated with stimulation parameters and acupoints and is probably attributed to the reduction of free fatty acid.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals Germline or inducible knockout of p300 or CBP in skeletal muscle does not alter insulin sensitivity

2019 ◽  
Vol 316 (6) ◽  
pp. E1024-E1035 ◽  
Author(s):  
Vitor F. Martins ◽  
Jessica R. Dent ◽  
Kristoffer Svensson ◽  
Shahriar Tahvilian ◽  
Maedha Begur ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Binding Protein ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
High Fat ◽  
Skeletal Muscle Insulin Sensitivity

Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. We used Cre-LoxP methodology to generate mice with germline [muscle creatine kinase promoter (P-MCK and C-MCK)] or inducible [tamoxifen-activated, human skeletal actin promoter (P-iHSA and C-iHSA)] knockout of p300 or CBP. A subset of P-MCK and C-MCK mice were switched to a calorie-restriction diet (60% of ad libitum intake) or high-fat diet at 10 wk of age. For P-iHSA and C-iHSA mice, knockout was induced at 10 wk of age. At 13–15 wk of age, we measured whole-body energy expenditure, oral glucose tolerance, and/or ex vivo skeletal muscle insulin sensitivity. Although p300 and CBP protein abundance and mRNA expression were reduced 55%–90% in p300 and CBP knockout mice, there were no genotype differences in energy expenditure or fasting glucose and insulin concentrations. Moreover, neither loss of p300 or CBP impacted oral glucose tolerance or skeletal muscle insulin sensitivity, nor did their loss impact alterations in these parameters in response to a calorie restriction or high-fat diet. Muscle-specific loss of either p300 or CBP, be it germline or in adulthood, does not impact energy expenditure, glucose tolerance, or skeletal muscle insulin action.

scholarly journals Lemon Balm Extract ALS-L1023 Regulates Obesity and Improves Insulin Sensitivity via Activation of Hepatic PPARα in High-Fat Diet-Fed Obese C57BL/6J Mice

2020 ◽  
Vol 21 (12) ◽  
pp. 4256
Author(s):  
Dongju Lee ◽  
Yujin Shin ◽  
Jong Seong Roh ◽  
Jiwon Ahn ◽  
Sunhyo Jeoong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Lipid Accumulation ◽  
High Fat Diet ◽  
Obese Mice ◽  
High Fat ◽  
Lemon Balm ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Our previous studies demonstrated that peroxisome proliferator-activated receptor α (PPARα) activation reduces weight gain and improves insulin sensitivity in obese mice. Since excess lipid accumulation in non-adipose tissues is suggested to be responsible for the development of insulin resistance, this study was undertaken to examine whether the lemon balm extract ALS-L1023 regulates hepatic lipid accumulation, obesity, and insulin resistance and to determine whether its mechanism of action involves PPARα. Administration of ALS-L1023 to high-fat-diet-induced obese mice caused reductions in body weight gain, visceral fat mass, and visceral adipocyte size without changes of food consumption profiles. ALS-L1023 improved hyperglycemia, hyperinsulinemia, glucose and insulin tolerance, and normalized insulin-positive β-cell area in obese mice. ALS-L1023 decreased hepatic lipid accumulation and concomitantly increased the expression of PPARα target genes responsible for fatty acid β-oxidation in livers. In accordance with the in vivo data, ALS-L1023 reduced lipid accumulation and stimulated PPARα reporter gene expression in HepG2 cells. These effects of ALS-L1023 were comparable to those of the PPARα ligand fenofibrate, while the PPARα antagonist GW6471 inhibited the actions of ALS-L1023 on lipid accumulation and PPARα luciferase activity in HepG2 cells. Higher phosphorylated protein kinase B (pAkt)/Akt ratios and lower expression of gluconeogenesis genes were observed in the livers of ALS-L1023-treated mice. These results indicate that ALS-L1023 may inhibit obesity and improve insulin sensitivity in part through inhibition of hepatic lipid accumulation via hepatic PPARα activation.

scholarly journals Inactivation of SPAK kinase reduces body weight gain in mice fed a high-fat diet by improving energy expenditure and insulin sensitivity

2018 ◽  
Vol 314 (1) ◽  
pp. E53-E65 ◽  
Author(s):  
Ivan Torre-Villalvazo ◽  
Luz Graciela Cervantes-Pérez ◽  
Lilia G. Noriega ◽  
Jose V. Jiménez ◽  
Norma Uribe ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat ◽  
The Metabolic Syndrome ◽  
Brown Adipose

The STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) controls the activity of the electroneutral cation-chloride cotransporters (SLC12 family) and thus physiological processes such as modulation of cell volume, intracellular chloride concentration [Cl−]i, and transepithelial salt transport. Modulation of SPAK kinase activity may have an impact on hypertension and obesity, as STK39, the gene encoding SPAK, has been suggested as a hypertension and obesity susceptibility gene. In fact, the absence of SPAK activity in mice in which the activating threonine in the T loop was substituted by alanine (SPAK-KI mice) is associated with decreased blood pressure; however its consequences in metabolism have not been explored. Here, we fed wild-type and homozygous SPAK-KI mice a high-fat diet for 17 wk to evaluate weight gain, circulating substrates and hormones, energy expenditure, glucose tolerance, and insulin sensitivity. SPAK-KI mice exhibit resistance to HFD-induced obesity and hepatic steatosis associated with increased energy expenditure, higher thermogenic activity in brown adipose tissue, increased mitochondrial activity in skeletal muscle, and reduced white adipose tissue hypertrophy mediated by augmented whole body insulin sensitivity and glucose tolerance. Our data reveal a previously unrecognized role for the SPAK kinase in the regulation of energy balance, thermogenesis, and insulin sensitivity, suggesting that this kinase could be a new drug target for the treatment of obesity and the metabolic syndrome.

A modified high-fat diet induces insulin resistance in rat skeletal muscle but not adipocytes

1998 ◽  
Vol 275 (4) ◽  
pp. E679-E686 ◽  
Author(s):  
Jason J. Wilkes ◽  
Arend Bonen ◽  
Rhonda C. Bell
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Glucose Tolerance ◽  
Polyunsaturated Fatty Acids ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Control Diet ◽  
Mixed Diet ◽  
High Fat

We hypothesized that variation in dietary fatty acid composition in rats fed a high-fat diet had tissue-specific effects on glucose uptake sufficient to maintain normal glucose tolerance. Rats were fed one of three diets for 3 wk. The isocaloric high-fat-mixed oil (HF-mixed) diet and the high-fat-safflower oil (HF-saff) diet both provided 60% kcal fat, but fat composition differed [HF-mixed = saturated, polyunsaturated (n-3 and n-6), and monounsaturated fatty acids; HF-saff = polyunsaturated fatty acids (mainly n-6)]. The control diet was high carbohydrate (HCHO, 10% kcal fat). Insulin-stimulated 3- O-methylglucose uptake into perfused hindlimb muscles was reduced in rats fed HF-saff and HF-mixed diets compared with those fed HCHO diet ( P< 0.02). Basal uptake increased in HF-saff- and HF-mixed-fed rats vs. HCHO-fed rats ( P < 0.04). In adipocytes, HF-saff feeding decreased 2-deoxyglucose uptake vs. HF-mixed feeding and HCHO feeding ( P< 0.05), but 2-deoxyglucose uptake in HF-mixed-fed rats did not differ from that in HCHO-fed rats ( P> 0.05). Glucose tolerance was significantly reduced in HF-saff-fed rats but was unaffected by the HF-mixed diet. Therefore, in skeletal muscle of rats, 1) feeding a diet high in fat induces a reduction in insulin-stimulated glucose uptake but 2) provides an increase in basal glucose uptake. In contrast, 3) in adipocytes, insulin-stimulated glucose transport is reduced only when the high-fat diet is high in n-6 polyunsaturated fatty acids but not when fat comes from these mixed sources. Glucose intolerance becomes evident when insulin resistance is seen in multiple tissues.

scholarly journals High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression

2014 ◽  
Vol 307 (9) ◽  
pp. E764-E772 ◽  
Author(s):  
Amanda T. White ◽  
Andrew Philp ◽  
Heidi N. Fridolfsson ◽  
Jan M. Schilling ◽  
Anne N. Murphy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Sirtuin 1 ◽  
Whole Body ◽  
Oral Glucose ◽  
High Fat

Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

2013 ◽  
Vol 305 (3) ◽  
pp. E388-E395 ◽  
Author(s):  
Michael S. F. Wiedemann ◽  
Stephan Wueest ◽  
Flurin Item ◽  
Eugen J. Schoenle ◽  
Daniel Konrad
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Hepatic Insulin Sensitivity ◽  
Tissue Inflammation

High-fat feeding for 3–4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

scholarly journals Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5173 ◽  
Author(s):  
Shibin Ding ◽  
Jinjin Jiang ◽  
Zhe Wang ◽  
Guofu Zhang ◽  
Jianli Yin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Inflammatory Response ◽  
Glucose Tolerance ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Density Lipoprotein ◽  
High Fat

Background Obesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice. Methods A total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT. Results HFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT. Conclusion Our results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity.

scholarly journals Expressing the Human Cholesteryl Ester Transfer Protein Minigene Improves Diet-Induced Fatty Liver and Insulin Resistance in Female Mice

2022 ◽  
Vol 12 ◽  
Author(s):  
Lin Zhu ◽  
Julia An ◽  
Sivaprakasam Chinnarasu ◽  
Thao Luu ◽  
Yasminye D. Pettway ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Target Genes ◽  
Metabolic Adaptation ◽  
Liver Cholesterol ◽  
Wild Type ◽  
High Fat

Mounting evidence has shown that CETP has important physiological roles in adapting to chronic nutrient excess, specifically, to protect against diet-induced insulin resistance. However, the underlying mechanisms for the protective roles of CETP in metabolism are not yet clear. Mice naturally lack CETP expression. We used transgenic mice with a human CETP minigene (huCETP) controlled by its natural flanking region to further understand CETP-related physiology in response to obesity. Female huCETP mice and their wild-type littermates were fed a high-fat diet for 6 months. Blood lipid profile and liver lipid metabolism were studied. Insulin sensitivity was analyzed with euglycemic-hyperinsulinemic clamp studies combined with 3H-glucose tracer techniques. While high-fat diet feeding induced obesity for huCETP mice and their wild-type littermates lacking CETP expression, insulin sensitivity was higher for female huCETP mice than for their wild-type littermates. There was no difference in insulin sensitivity for male huCETP mice vs. littermates. The increased insulin sensitivity in females was largely caused by the better insulin-mediated suppression of hepatic glucose production. In huCETP females, CETP in the circulation decreased HDL-cholesterol content and increased liver cholesterol uptake and liver cholesterol and oxysterol contents, which was associated with the upregulation of LXR target genes in long-chain polyunsaturated fatty acid biosynthesis and PPARα target genes in fatty acid β-oxidation in the liver. The upregulated fatty acid β-oxidation may account for the improved fatty liver and liver insulin action in female huCETP mice. This study provides further evidence that CETP has beneficial physiological roles in the metabolic adaptation to nutrient excess by promoting liver fatty acid oxidation and hepatic insulin sensitivity, particularly for females.

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