High-fat diet affects pregestational adiposity and glucose tolerance perturbing gestational placental macronutrient transporters culminating in an obese offspring in wild-type and glucose transporter isoform 3 heterozygous null 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.

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

Endocrinology ◽

10.1210/en.2010-0661 ◽

2011 ◽

Vol 152 (1) ◽

pp. 48-58 ◽

Cited By ~ 74

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.

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Improved glucose tolerance with restored expression of glucose transporter 4 in C57BL/6 mice after a long period of high-fat diet feeding

Animal Cells and Systems ◽

10.1080/19768354.2014.924995 ◽

2014 ◽

Vol 18 (3) ◽

pp. 197-203 ◽

Cited By ~ 3

Author(s):

Jinil Kim ◽

Ja In Jeong ◽

Kwang Min Kim ◽

Inho Choi ◽

Richard E. Pratley ◽

...

Keyword(s):

Glucose Tolerance ◽

High Fat Diet ◽

Glucose Transporter ◽

Glucose Transporter 4 ◽

High Fat ◽

Long Period

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Effects of Lactobacillus on Mice with Diabetes Induced by High-Fat Diet with Streptozotocin (STZ)

Applied Sciences ◽

10.3390/app8081249 ◽

2018 ◽

Vol 8 (8) ◽

pp. 1249 ◽

Cited By ~ 10

Author(s):

Xiaoyong Chen ◽

Fang Tan ◽

Ruokun Yi ◽

Jianfei Mu ◽

Xin Zhao ◽

...

Keyword(s):

Glucose Tolerance ◽

High Fat Diet ◽

Glucose Transporter ◽

Regulatory Element ◽

Hepatic Insulin Resistance ◽

Average Weight ◽

Oral Glucose ◽

High Fat ◽

Glut 4 ◽

Tnf Α

This study aimed to evaluate and compare the effects of heat-killed and live Lactobacillus on mice with diabetes induced by high-fat diet with streptozotocin (STZ). Results based on body weight and liver pathological changes, oral glucose tolerance test, and related serum index (AST (aspartate aminotransferase), ALT (alanine aminotransferase), MDA (malondialdehyde), TNF-α (tumor necrosis factor α), INS (insulin), and GC (glucagon) and gene expression of IL-1β (Interleukin 1β), IRS-1(Insulin receptor substrate 1), GLUT-4 (glucose transporter type 4), PPARγ (peroxisome proliferators-activated receptor γ), and SREBP-1c (sterol-regulatory element-binding protein-1c) levels indicated that Lactobacillus fermentum (LF) and Lactobacillus plantarum (LP) could increase the average weight, alleviate the degree of damage in the liver, and improve the glucose tolerance of mice with diabetes. LF and LP also participated in the downregulation of AST, ALT, MDA, TNF-α, INS, and GC in serum, as well as the inhibition of IL-1β, TNF-α, IRS-1, GLUT-4, PPARγ, and SREBP-1c expression. These regulating effects were remarkable, and the regulating effect of the live group was significantly better than that of the heat-killed group. This study suggested that LF and LP can significantly alleviate liver damage and hepatic insulin resistance in mice with diabetes and that the acting mechanisms of LF and LP were related to cellular components and their activities.

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Pyruvate dehydrogenase kinase-4 deficiency lowers blood glucose and improves glucose tolerance in diet-induced obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00536.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. E46-E54 ◽

Cited By ~ 105

Author(s):

Nam Ho Jeoung ◽

Robert A. Harris

Keyword(s):

Skeletal Muscle ◽

Blood Glucose ◽

Glucose Tolerance ◽

Pyruvate Dehydrogenase ◽

High Fat Diet ◽

Pyruvate Dehydrogenase Kinase ◽

Wild Type ◽

High Fat ◽

Pyruvate Dehydrogenase Kinase 4 ◽

Liver And Kidney

The effect of pyruvate dehydrogenase kinase-4 (PDK4) deficiency on glucose homeostasis was studied in mice fed a high-fat diet. Expression of PDK4 was greatly increased in skeletal muscle and diaphragm but not liver and kidney of wild-type mice fed the high-fat diet. Wild-type and PDK4−/− mice consumed similar amounts of the diet and became equally obese. Insulin resistance developed in both groups. Nevertheless, fasting blood glucose levels were lower, glucose tolerance was slightly improved, and insulin sensitivity was slightly greater in the PDK4−/− mice compared with wild-type mice. When the mice were killed in the fed state, the actual activity of the pyruvate dehydrogenase complex (PDC) was higher in the skeletal muscle and diaphragm but not in the liver and kidney of PDK4−/− mice compared with wild-type mice. When the mice were killed after overnight fasting, the actual PDC activity was higher only in the kidney of PDK4−/− mice compared with wild-type mice. The concentrations of gluconeogenic substrates were lower in the blood of PDK4−/− mice compared with wild-type mice, consistent with reduced formation in peripheral tissues. Diaphragms isolated from PDK4−/− mice oxidized glucose faster and fatty acids slower than diaphragms from wild-type mice. Fatty acid oxidation inhibited glucose oxidation by diaphragms from wild-type but not PDK4−/− mice. NEFA, ketone bodies, and branched-chain amino acids were elevated more in PDK4−/− mice, consistent with slower rates of oxidation. These findings show that PDK4 deficiency lowers blood glucose and slightly improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity.

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Metabolic Burden of Erythropoietin Stimulated Erythropoiesis in Mice

Blood ◽

10.1182/blood.v128.22.2421.2421 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2421-2421

Author(s):

Constance Tom Noguchi ◽

Heather Marie Rogers

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Male Mice ◽

Wild Type ◽

Hematopoietic Tissue ◽

High Fat ◽

Epor Expression

Erythropoietin (EPO) promotes erythroid differentiation and increases glucose uptake in erythroid progenitor cells in culture. The metabolic burden associated with EPO treatment in adult mice is suggested by a decrease in body weight concomitant with increased hematocrit. Wild type male mice (C57Bl/6, age 8 months) treated with EPO showed the expected increase in hematocrit accompanied by a fall in blood glucose level and a decrease in body weight and fat mass. However, the decrease in body weight is even more evident in obese mice on a high fat diet and has also been linked to non-hematopoietic response, particularly with EPO receptor (EpoR) expression in white adipose tissue. We examined the metabolic burden of EPO treatment (3000U/kg for 3 weeks) in young, lean male mice (3 months) placed on high fat diet at the time of EPO administration. The increase in hematocrit was accompanied by decreased blood glucose level and improved glucose tolerance. However, no difference in body weight was observed between mice treated with EPO and the saline treated group, suggesting that the EPO stimulated decrease in body weight is evident primarily in older animals with greater fat mass. To determine the contribution of EpoR expression in non-hematopoietic tissue to the metabolic EPO response, young male mice with EpoR restricted to erythroid tissue (TgEpoR) were placed on high fat diet and treated with EPO. The expected increased hematocrit was also accompanied by decreased blood glucose level and improved glucose tolerance, and no change in body weight between EPO and saline treatment. The similar responses observed in young wild type and TgEpoR mice suggest that the EPO stimulated increase in glucose metabolism is associated with increased erythropoiesis rather than a direct EPO response in non-hematopoietic tissue. TgEpoR mice exhibit an age dependent increase in fat mass even greater than that observed in wild type mice, and by 8 months TgEpoR mice are obese, glucose intolerant and insulin resistant compared with wild type mice. At 8 months, TgEpoR mice treated with EPO show the increase in hematocrit and, despite the increase in fat mass, there is only a minimal decrease in body weight compared with wild type mice. These data provide evidence that in addition to the age dependent association of EPO stimulated decrease in body weight and fat mass, this decrease in body weight is due largely to EPO response related to EpoR expression in non-hematopoietic tissue. Interestingly, young male mice with targeted deletion of EpoR in adipose tissue placed on a high fat diet and treated with EPO show the increase in hematocrit and improvement in glucose tolerance, and at 8 months, the increase in hematocrit with EPO treatment is accompanied by minimal change in body weight. The similar metabolic response of these mice with targeted deletion of EpoR in adipose tissue to TgEpoR mice indicate the contribution of EpoR expression in adipose tissue to the loss of body weight and fat mass. Therefore, the metabolic burden associated with EPO stimulated erythropoiesis appears to be reflected in improved glucose metabolism and glucose tolerance with minimal or no effect on body weight, is evident in young, lean mice, and is independent of EpoR expression in non-hematopoietic tissue. In older mice, non-hematopoietic metabolic EPO response is more readily apparent as reflected in loss of body weight/fat mass, which overshadows the erythropoietic metabolic response. In combination, the metabolic response to EPO treatment results from EPO stimulated increased erythropoiesis, improved glucose metabolism and glucose tolerance, and an age dependent decrease in body weight and fat mass associated with EpoR expression in non-hematopoietic tissue, particularly in white adipose tissue. Disclosures No relevant conflicts of interest to declare.

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Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00010.2021 ◽

2021 ◽

Author(s):

Cody D. Smith ◽

Chein-Te Lin ◽

Shawna L. McMillin ◽

Luke A. Weyrauch ◽

Cameron Alan Schmidt ◽

...

Keyword(s):

Skeletal Muscle ◽

Fatty Acid ◽

Glucose Tolerance ◽

Glucose Intolerance ◽

High Fat Diet ◽

Whole Body ◽

Acid Oxidation ◽

Wild Type ◽

High Fat ◽

Redox Environment

Elevated mitochondrial H2O2 emission and an oxidative shift in cytosolic redox environment have been linked to high fat diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle β-oxidation flux were studied. In mice overexpressing peroxisome proliferator activated receptor-α in muscle (MCK-PPARα), lipid supported mitochondrial respiration, membrane potential (ΔΨm) and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole-body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1 deficient, fatty-liver dystrophic mice, another model characterized by increased β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondrial-targeted catalase) with MCK-PPARα mice normalized JH2O2 production, redox environment and glucose tolerance, but surprisingly both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high fat diet MCK-PPARα mice were characterized by much lower whole body, fat and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in attempt to restore bioenergetic homeostasis.

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Comparison between pre-exercise casein peptide and intact casein supplementation on glucose tolerance in mice fed a high-fat diet

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2017-0485 ◽

2018 ◽

Vol 43 (4) ◽

pp. 355-362 ◽

Cited By ~ 1

Author(s):

Yutaka Matsunaga ◽

Yuki Tamura ◽

Yasuyuki Sakata ◽

Yudai Nonaka ◽

Noriko Saito ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Tolerance ◽

Endurance Training ◽

Soleus Muscle ◽

High Fat Diet ◽

Glucose Transporter ◽

Area Under The Curve ◽

Abdominal Fat ◽

Oral Glucose ◽

High Fat

We hypothesized that along with exercise, casein peptide supplementation would have a higher impact on improving glucose tolerance than intact casein. Male 6-week-old ICR mice were provided a high-fat diet to induce obesity and glucose intolerance. The mice were randomly divided into 4 treatment groups: control (Con), endurance training (Tr), endurance training with intact casein supplementation (Cas+Tr), and endurance training with casein peptide supplementation (CP+Tr). The mice in each group were orally administrated water, intact casein, or casein peptide (1.0 mg/g body weight, every day), and then subjected to endurance training (15–25 m/min, 60 min, 5 times/week for 4 weeks) on a motor-driven treadmill 30 min after ingestion. Our results revealed that total intra-abdominal fat was significantly lower in CP+Tr than in Con (p < 0.05). Following an oral glucose tolerance test, the blood glucose area under the curve (AUC) was found to be significantly smaller for CP+Tr than for Con (p < 0.05). Moreover, in the soleus muscle, glucose transporter 4 (GLUT4) protein levels were significantly higher in CP+Tr than in Con (p < 0.01). However, intra-abdominal fat, blood glucose AUC, and GLUT4 protein content in the soleus muscle did not alter in Tr and Cas+Tr when compared with Con. These observations suggest that pre-exercise casein peptide supplementation has a higher effect on improving glucose tolerance than intact casein does in mice fed a high-fat diet.

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High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain

PeerJ ◽

10.7717/peerj.9811 ◽

2020 ◽

Vol 8 ◽

pp. e9811

Author(s):

Edward T. Wargent ◽

Malgorzata Kepczynska ◽

Mohamed Sghaier Zaibi ◽

David C. Hislop ◽

Jonathan R.S. Arch ◽

...

Keyword(s):

Body Composition ◽

Body Weight ◽

Weight Gain ◽

Energy Balance ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Insulin Tolerance

Background The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied. Methods In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg−1 po) and rimonabant (10 mg kg−1 po) were compared in the two genotypes. Results There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice. Conclusions Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.

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