EPA/DHA Concentrate by Urea Complexation Decreases Hyperinsulinemia and Increases Plin5 in the Liver of Mice Fed a High-Fat Diet

Dietary intake of eicosapentaenoic/docosahexaenoic acid (EPA/DHA) reduces insulin resistance and hepatic manifestations through the regulation of metabolism in the liver. Obese mice present insulin resistance and lipid accumulation in intracellular lipid droplets (LDs). LD-associated proteins perilipin (Plin) have an essential role in both adipogenesis and lipolysis; Plin5 regulates lipolysis and thus contributes to fat oxidation. The purpose of this study was to compare the effects of deodorized refined salmon oil (DSO) and its polyunsaturated fatty acids concentrate (CPUFA) containing EPA and DHA, obtained by complexing with urea, on obesity-induced metabolic alteration. CPUFA maximum content was determined using the Box–Behnken experimental design based on Surface Response Methodology. The optimized CPUFA was administered to high-fat diet (HFD)-fed mice (200 mg/kg/day of EPA + DHA) for 8 weeks. No significant differences (p > 0.05) in cholesterol, glycemia, LDs or transaminase content were found. Fasting insulin and hepatic Plin5 protein level increased in the group supplemented with the EPA + DHA optimized product (38.35 g/100 g total fatty acids) compared to obese mice without fish oil supplementation. The results suggest that processing salmon oil by urea concentration can generate an EPA+DHA dose useful to prevent the increase of fasting insulin and the decrease of Plin5 in the liver of insulin-resistant mice.

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Insulin secretion after dietary supplementation with conjugated linoleic acids and n-3 polyunsaturated fatty acids in normal and insulin-resistant mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00163.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. E347-E354 ◽

Cited By ~ 32

Author(s):

Maria Sörhede Winzell ◽

Giovanni Pacini ◽

Bo Ahrén

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Secretion ◽

High Fat Diet ◽

Glucose Oxidation ◽

Dietary Supplementation ◽

Normal Diet ◽

High Fat ◽

Conjugated Linoleic Acids ◽

Insulin Resistant

Conjugated linoleic acids (CLAs) and n-3 polyunsaturated fatty acids (PUFAs) improve insulin sensitivity in insulin-resistant rodents. However, the effects of these fatty acids on insulin secretion are not known but are of importance to completely understand their influence on glucose homeostasis. We therefore examined islet function after dietary supplementation consisting of 1% CLAs in combination with 1% n-3 enriched PUFAs for 12 wk to mice on a normal diet and to insulin-resistant mice fed a high-fat diet (58% fat). In the mice fed a normal diet, CLA/PUFA supplementation resulted in insulin resistance associated with low plasma adiponectin levels and low body fat content. Intravenous and oral glucose tolerance tests revealed a marked increase in insulin secretion, which nevertheless was insufficient to counteract the insulin resistance, resulting in glucose intolerance. In freshly isolated islets from mice fed the normal diet, both basal and glucose-stimulated insulin secretion were adaptively augmented by CLA/PUFA, and at a high glucose concentration this was accompanied by elevated glucose oxidation. In contrast, in high-fat-fed mice, CLA/PUFA did not significantly affect insulin secretion, insulin resistance, or glucose tolerance. It is concluded that dietary supplementation of CLA/PUFA in mice fed the normal diet augments insulin secretion, partly because of increased islet glucose oxidation, but that this augmentation is insufficient to counterbalance the induction of insulin resistance, resulting in glucose intolerance. Furthermore, the high-fat diet partly prevents the deleterious effects of CLA/PUFA, but this dietary supplementation was not able to counteract high-fat-diet-induced insulin resistance.

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Anti‐inflammatory and metabolic mechanisms by which omega‐3 fatty acids improve insulin resistance in high fat diet‐induced obese mice

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.551.2 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Nishan Sudheera Kalupahana ◽

Kate Claycombe ◽

Taryn Stewart ◽

Rachael Hadidsaz ◽

Suzanne Booker ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

High Fat Diet ◽

Omega 3 Fatty Acids ◽

Obese Mice ◽

Omega 3 ◽

High Fat ◽

Improve Insulin Resistance ◽

Anti Inflammatory

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The Impact of OMEGA-3 Fatty Acids Supplementation on Insulin Resistance and Content of Adipocytokines and Biologically Active Lipids in Adipose Tissue of High-Fat Diet Fed Rats

Nutrients ◽

10.3390/nu11040835 ◽

2019 ◽

Vol 11 (4) ◽

pp. 835 ◽

Cited By ~ 8

Author(s):

Chacińska ◽

Zabielski ◽

Książek ◽

Szałaj ◽

Jarząbek ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Adipose Tissue ◽

Fish Oil ◽

High Fat Diet ◽

Biologically Active ◽

Omega 3 Fatty Acids ◽

Omega 3 ◽

High Fat ◽

Fish Oil Supplementation

It has been established that OMEGA-3 polyunsaturated fatty acids (PUFAs) may improve lipid and glucose homeostasis and prevent the “low-grade” state of inflammation in animals. Little is known about the effect of PUFAs on adipocytokines expression and biologically active lipids accumulation under the influence of high-fat diet-induced obesity. The aim of the study was to examine the effect of fish oil supplementation on adipocytokines expression and ceramide (Cer) and diacylglycerols (DAG) content in visceral and subcutaneous adipose tissue of high-fat fed animals. The experiments were carried out on Wistar rats divided into three groups: standard diet–control (SD), high-fat diet (HFD), and high-fat diet + fish oil (HFD+FO). The fasting plasma glucose and insulin concentrations were examined. Expression of carnitine palmitoyltransferase 1 (CPT1) protein was determined using the Western blot method. Plasma adipocytokines concentration was measured using ELISA kits and mRNA expression was determined by qRT-PCR reaction. Cer, DAG, and acyl-carnitine (A-CAR) content was analyzed by UHPLC/MS/MS. The fish oil supplementation significantly decreased plasma insulin concentration and Homeostatic Model Assesment for Insulin Resistance (HOMA-IR) index and reduced content of adipose tissue biologically active lipids in comparison with HFD-fed subjects. The expression of CPT1 protein in HFD+FO in both adipose tissues was elevated, whereas the content of A-CAR was lower in both HFD groups. There was an increase of adiponectin concentration and expression in HFD+FO as compared to HFD group. OMEGA-3 fatty acids supplementation improved insulin sensitivity and decreased content of Cer and DAG in both fat depots. Our results also demonstrate that PUFAs may prevent the development of insulin resistance in response to high-fat feeding and may regulate the expression and secretion of adipocytokines in this animal model.

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Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

Food & Function ◽

10.1039/d1fo01394g ◽

2021 ◽

Author(s):

Haizhao Song ◽

Xinchun Shen ◽

Yang Zhou ◽

Xiaodong Zheng

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Liver Steatosis ◽

Obese Mice ◽

Black Rice ◽

High Fat ◽

Diet Induced Obesity

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

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CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice

Journal of Endocrinology ◽

10.1530/joe-19-0251 ◽

2020 ◽

Vol 244 (2) ◽

pp. 353-367 ◽

Cited By ~ 2

Author(s):

Jiali Liu ◽

Yue Li ◽

Xiaoyan Zhou ◽

Xi Zhang ◽

Hao Meng ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Inflammatory Response ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Insulin Action ◽

Hepatic Insulin Resistance ◽

Obese Mice ◽

High Fat ◽

Impaired Insulin

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

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BCAA Supplementation in Mice with Diet-Induced Obesity Alters the Metabolome Without Impairing Glucose Homeostasis

Endocrinology ◽

10.1210/endocr/bqab062 ◽

2021 ◽

Author(s):

Jennifer Lee ◽

Archana Vijayakumar ◽

Phillip J White ◽

Yuping Xu ◽

Olga Ilkayeva ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Homeostasis ◽

Obese Mice ◽

High Fat ◽

Leucine Oxidation ◽

Insulin Resistant ◽

Diet Induced Obesity ◽

Chain Acyl ◽

Branched Chain ◽

Relationship Of

Abstract Circulating branched chain amino acid (BCAA) levels are elevated in obese humans and genetically obese rodents. However, the relationship of BCAAs to insulin resistance in diet-induced obese mice, a commonly used model to study glucose homeostasis, is still ill-defined. Here we examined how high-fat high-sucrose (HFHS) or high-fat diet (HFD) feeding, with or without BCAA supplementation in water, alters the metabolome in serum/plasma and tissues in mice and whether raising circulating BCAA levels worsens insulin resistance and glucose intolerance. Neither HFHS nor HFD-feeding raised circulating BCAA levels in insulin-resistant diet-induced obese mice. BCAA supplementation raised circulating BCAA and BCKA levels and C5-OH/C3-DC acylcarnitines (AC) in muscle from HFHS or HFD-fed mice, but did not worsen insulin resistance. A set of short and long-chain acyl CoAs were elevated by diet alone in muscle, liver and WAT, but not increased further by BCAA supplementation. HFD feeding reduced valine and leucine oxidation in WAT but not in muscle. BCAA supplementation markedly increased valine oxidation in muscle from HFD-fed mice while leucine oxidation was unaffected by diet or BCAA treatment. Here we establish an extensive metabolome database showing tissue-specific changes in mice on two different HFDs, with or without BCAA supplementation. We conclude that mildly elevating circulating BCAAs and a subset of ACs by BCAA supplementation does not worsen insulin resistance or glucose tolerance in mice. This work highlights major differences in the effects of BCAAs on glucose homeostasis in diet-induced obese mice versus data reported in obese rats and in humans.

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CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E973-E983 ◽

Cited By ~ 3

Author(s):

Annie Hasib ◽

Chandani K. Hennayake ◽

Deanna P. Bracy ◽

Aimée R. Bugler-Lamb ◽

Louise Lantier ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

High Fat Diet ◽

Critical Role ◽

Chow Diet ◽

Wild Type ◽

High Fat ◽

Insulin Resistant ◽

Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

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Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2019-000783 ◽

2019 ◽

Vol 7 (1) ◽

pp. e000783 ◽

Cited By ~ 7

Author(s):

Liang Xu ◽

Naoto Nagata ◽

Guanliang Chen ◽

Mayumi Nagashimada ◽

Fen Zhuge ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Energy Expenditure ◽

Chronic Inflammation ◽

Plasma Levels ◽

High Fat Diet ◽

Macrophage Activation ◽

Low Grade ◽

Obese Mice ◽

High Fat

ObjectiveWe reported previously that empagliflozin—a sodium-glucose cotransporter (SGLT) 2 inhibitor—exhibited preventive effects against obesity. However, it was difficult to extrapolate these results to human subjects. Here, we performed a therapeutic study, which is more relevant to clinical situations in humans, to investigate antiobesity effects of empagliflozin and illustrate the mechanism underlying empagliflozin-mediated enhanced fat browning in obese mice.Research design and methodsAfter 8 weeks on a high-fat diet (HFD), C57BL/6J mice exhibited obesity, accompanied by insulin resistance and low-grade chronic inflammation. Cohorts of obese mice were continued on the HFD for an additional 8-week treatment period with or without empagliflozin.ResultsTreatment with empagliflozin for 8 weeks markedly increased glucose excretion in urine, and suppressed HFD-induced weight gain, insulin resistance and hepatic steatosis. Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to increased energy expenditure. Consistently, the level of uncoupling protein 1 expression was increased in both brown and white (WAT) adipose tissues of empagliflozin-treated mice. Furthermore, empagliflozin decreased plasma levels of interleukin (IL)-6 and monocyte chemoattractant protein-1, but increased plasma levels of IL-33 and adiponectin in obese mice. Finally, we found that empagliflozin reduced M1-polarized macrophage accumulation, while inducing the anti-inflammatory M2 phenotype of macrophages in the WAT and liver, thereby attenuating obesity-related chronic inflammation.ConclusionsTreatment with empagliflozin attenuated weight gain by increasing energy expenditure and adipose tissue browning, and alleviated obesity-associated inflammation and insulin resistance by alternative macrophage activation in the WAT and liver of obese mice.

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Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice

AJP Cell Physiology ◽

10.1152/ajpcell.00064.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1172-C1182 ◽

Cited By ~ 3

Author(s):

Min-Gyeong Shin ◽

Hye-Na Cha ◽

Soyoung Park ◽

Yong-Woon Kim ◽

Jong-Yeon Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Control Diet ◽

In Vivo Studies ◽

Selenoprotein W ◽

Obese Mice ◽

High Fat

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.

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