MON-642 Genetic Knockout of Intestinal Hexokinase Domain-Containing Protein 1 Affects Whole-Body Glycemic Control and Triglyceride Metabolism

Abstract Hexokinase domain-containing protein 1 (HKDC1) is a recently discovered putative fifth hexokinase that is widely expressed in a variety of human and mouse tissues. Previous work indicate that HKDC1 is important for whole-body glucose homeostasis and utilization in pregnancy and aging, and suggest roles for HKDC1 in nonalcoholic fatty liver disease development and progression of hepatocellular carcinoma. Prior work in the lab further showed that global heterozygous-deleted HKDC1 mice exhibit blunted uptake of triglycerides following an olive oil bolus compared to wild-type mice, suggesting a role for intestinal HKDC1 expression in intestinal lipid metabolism (unpublished results). To specifically study the significance of intestinal HKDC1 on whole-body glucose and lipid homeostasis, we utilized Cre-mediated recombination of HKDC1 in which Cre was expressed under the control of the villin gene promoter, creating a mouse model in which HKDC1 expression is specifically deleted in the intestinal epithelium. Quantitative RT-PCR data confirmed the knockout of HKDC1 within the mouse intestine in young and aged mice, while HKDC1 expression in other tissues was comparable to wild-type mice. Next, intestinal HKDC1 knockout mice and their wild-type littermate controls were either maintained on a normal diet or were switched to a high fat diet at 6 weeks of age to simulate the state of impaired glucose tolerance, and the effects of intestinal HKDC1 on glucose and lipid homeostasis were analyzed between 28-34 weeks of age. Mice fed a normal diet did not exhibit any differences in serum glucose or triglyceride during oral/intraperitoneal glucose tolerance tests or oral olive oil bolus, respectively, regardless of intestinal HKDC1 status. Interestingly, mice lacking intestinal HKDC1 that were on a high fat diet demonstrated improved overall glycemic control compared to wild-type mice after the administration of an oral glucose load, all while there were no changes in insulin levels, gluconeogenesis or insulin tolerance related to HKDC1 status. Additionally, introduction of an intraperitoneal glucose load to mice fed a high fat diet did not alter glucose control in the presence or absence of intestinal HKDC1. However, high fat diet-fed mice lacking intestinal HKDC1 did not have a significant increase in serum triglyceride following an oral olive oil bolus, while their stool fat and triglyceride content were comparable to wild-type. Collectively, these data indicate that intestinal HKDC1 has important roles in glucose and triglyceride metabolism within the intestinal epithelium, and further suggest a role in whole-body glucose homeostasis and in the development of insulin resistance and diabetes.

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Novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway

Scientific Reports ◽

10.1038/s41598-021-90952-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Safia Akhtar ◽

Silas A. Culver ◽

Helmy M. Siragy

Keyword(s):

Protein Expression ◽

High Fat Diet ◽

Normal Diet ◽

Receptor Expression ◽

Wild Type ◽

High Fat ◽

Renal Gluconeogenesis ◽

Mrna And Protein Expression ◽

Polymerase Chain ◽

Renal Expression

AbstractRecent studies suggested that renal gluconeogenesis is substantially stimulated in the kidney in presence of obesity. However, the mechanisms responsible for such stimulation are not well understood. Recently, our laboratory demonstrated that mice fed high fat diet (HFD) exhibited increase in renal Atp6ap2 [also known as (Pro)renin receptor] expression. We hypothesized that HFD upregulates renal gluconeogenesis via Atp6ap2-PGC-1α and AKT pathway. Using real-time polymerase chain reaction, western blot analysis and immunostaining, we evaluated renal expression of the Atp6ap2 and renal gluconeogenic enzymes, PEPCK and G6Pase, in wild type and inducible nephron specific Atp6ap2 knockout mice fed normal diet (ND, 12 kcal% fat) or a high-fat diet (HFD, 45 kcal% fat) for 8 weeks. Compared with ND, HFD mice had significantly higher body weight (23%) (P < 0.05), renal mRNA and protein expression of Atp6ap2 (39 and 35%), PEPCK (44 and 125%) and G6Pase (39 and 44%) respectively. In addition, compared to ND, HFD mice had increased renal protein expression of PGC-1α by 32% (P < 0.05) and downregulated AKT by 33% (P < 0.05) respectively in renal cortex. Atp6ap2-KO abrogated these changes in the mice fed HFD. In conclusion, we identified novel regulation of renal gluconeogenesis by Atp6ap2 in response to high fat diet via PGC1-α/AKT-1 pathway.

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Abstract 657: A New Translational Model of Hypercholesterolemia and Atherosclerosis: Effect of Statins on LDLR KO Miniature Swine

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.657 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Dale E Mais ◽

Thomas Vihtelic ◽

Chidozie Amuzie ◽

Steven Denham ◽

John R Swart ◽

...

Keyword(s):

High Fat Diet ◽

Clinical Chemistry ◽

Small Animal ◽

Normal Diet ◽

Large Animal Model ◽

Control Group ◽

Large Animal ◽

Wild Type ◽

High Fat ◽

Miniature Swine

Small animal models of atherosclerosis are commonly used in drug studies; however, the results often fail to translate into the clinic. A large animal model that more accurately reflects the human disease is needed. We recently developed a transgenic Yucatan pig model in which the LDL receptor (LDLR) gene is knocked out. Five groups of Yucatan pigs (N=4 per group), either wild type (LDLR+/+) or heterozygote (LDLR+/-) were fed a normal diet or a high fat diet for a six month period. One of the heterozygote/high fat diet groups in addition received a daily dose of a statin (atorvastatin) at 3 mg/kg. Every two weeks during the study a variety of clinical chemistry parameters were measured. At study termination, select arteries were collected, stained for lipid deposits and quantitated. In addition, sections of these arteries were prepared for immunohistochemistry to detect selected markers of macrophage infiltration into the atherosclerotic plaques. As expected, pigs fed a high fat diet gained significantly more weight at six months whether they were wild type or LDLR+/-. Atorvastatin appeared to attenuate this weight gain. There were significant increases in total cholesterol, HDL and LDL in pigs fed the high fat diet compared to their corresponding control group. The group receiving the atorvastatin had reduced values of these parameters compared to controls showing that a statin had a beneficial effect on lipid levels even in a high fat diet scenario. VLDL levels were not affected but there were triglyceride changes across the groups. Liver function was unchanged based on total bilirubin and AST while ALT measurements were altered in some of the groups. Immunohistochemistry and histomorphometry was performed on some arteries. Atorvastatin-induced amelioration of hypercholesterolemia in this model underscores its translational utility.

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Gallic Acid Ameliorated Impaired Glucose and Lipid Homeostasis in High Fat Diet-Induced NAFLD Mice

PLoS ONE ◽

10.1371/journal.pone.0096969 ◽

2014 ◽

Vol 9 (6) ◽

pp. e96969 ◽

Cited By ~ 88

Author(s):

Jung Chao ◽

Teh-Ia Huo ◽

Hao-Yuan Cheng ◽

Jen-Chieh Tsai ◽

Jiunn-Wang Liao ◽

...

Keyword(s):

Gallic Acid ◽

High Fat Diet ◽

Lipid Homeostasis ◽

High Fat ◽

Glucose And Lipid Homeostasis

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Regulating AMPKα and insulin level by Vinegar, Swimming and Refeeding on High-Fat Diet Rats to Rebuild Lipid Homeostasis

10.1101/2020.01.08.899419 ◽

2020 ◽

Author(s):

Yuan Yang ◽

Feng Zhang ◽

Xiao Xiao ◽

Chunlian Ma ◽

Hua Liu ◽

...

Keyword(s):

Weight Gain ◽

High Fat Diet ◽

Insulin Level ◽

Diet Group ◽

Normal Diet ◽

Lipid Homeostasis ◽

Control Group ◽

High Fat ◽

Better Regulation ◽

Rice Vinegar

AbstractOur aims were to explore the effects of dietary and behavior interventions on lipometabolism caused by unhealthy high-fat diet and the best method to rebuild lipid homeostasis of this lifestyle. Apart from normal diet rats, 34 rats were fed with high-fat emulsion for 4 weeks before being divided into 4 groups and intervened for another 4 weeks. 8 of them were classified into high-fat control group and 9 were sorted into high-fat diet with rice vinegar group. Meanwhile, 10 were put into high-fat diet with swimming group and 7 were just for refeeding normal diet group. Then the data of body weight was recorded and analyzed. Serum, pancreas, liver, cardiac tissues and epididymis adipose were sampled as required. Indexes of serum were tested by kits. AMPKα, HNF1α, CTRP6 from tissues were detected by western blot. According to our experiments, Swimming and refeeding groups reflected a better regulation on lipid homeostasis mainly by up-regulating the expression of pancreas AMPKα. To be more specific, the refeeding rats showed lower T-CHO (P<0.001) and LDL-C (P<0.05), but higher weight gain (P<0.001),insulin level (P<0.01)and pancreas AMPKα (P<0.01)than high-fat control rats. Compared with rats experimented by swimming or rice vinegar, they showed higher weight gain (P<0.001),insulin level (P<0.01)and HNF1α, but lower of CTRP6. In summary, refeeding diet functioned better in regulating the lipometabolic level after high-fat diet. Whatever approach mentioned above we adopted to intervene, the best policy to keep the balance of lipid homeostasis is to maintain a healthy diet.

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Mustard Oil Based High Fat Diet is Associated with Decreased Body Weight Gain, Less Adiposity and Improved Glucose and Lipid Homeostasis in Wistar Rats

Asian Journal of Clinical Nutrition ◽

10.3923/ajcn.2011.43.52 ◽

2011 ◽

Vol 3 (2) ◽

pp. 43-52 ◽

Cited By ~ 3

Author(s):

Zafar Ahmad Mali ◽

Amit Goyal ◽

Pyare Lal Sharma

Keyword(s):

Body Weight ◽

Weight Gain ◽

High Fat Diet ◽

Wistar Rats ◽

Body Weight Gain ◽

Lipid Homeostasis ◽

Mustard Oil ◽

High Fat ◽

Glucose And Lipid Homeostasis

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Effects of Brassica oleracea extract on impaired glucose and lipid homeostasis in high-fat diet-induced obese mice

Asian Pacific Journal of Tropical Biomedicine ◽

10.4103/2221-1691.250859 ◽

2019 ◽

Vol 9 (2) ◽

pp. 80

Author(s):

Jarinyaporn Naowaboot ◽

Urarat Nanna ◽

Linda Chularojmontri ◽

Pholawat Tingpej ◽

Suvara Wattanapitayakul

Keyword(s):

Brassica Oleracea ◽

High Fat Diet ◽

Lipid Homeostasis ◽

Obese Mice ◽

High Fat ◽

Glucose And Lipid Homeostasis

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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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The effectiveness comparisons of eugenosedin-A, glibenclamide and pioglitazone on diabetes mellitus induced by STZ/NA and high-fat diet in SHR

Journal of Pharmacy and Pharmacology ◽

10.1093/jpp/rgab029 ◽

2021 ◽

Author(s):

Hui-Li Lin ◽

Pei-Wen Cheng ◽

Yi-Chen Tu ◽

Bor-Chun Yeh ◽

Bin-Nan Wu ◽

...

Keyword(s):

Diabetes Mellitus ◽

High Fat Diet ◽

Lipid Synthesis ◽

Normal Diet ◽

Lipid Homeostasis ◽

Control Group ◽

Protective Effects ◽

High Fat ◽

Effective Agent ◽

Treatment Groups

Abstract Objectives Eugenosedin-A (Eu-A), an adrenergic and serotonergic antagonist, is known to have anti-metabolic syndrome effects. In this study, we evaluated its protective effects against diabetes mellitus (DM) in spontaneous hypertensive rats (SHR) and compared it with two anti-diabetes medications, glibenclamide (Gli) and pioglitazone (Pio). Methods We divided 10-week-old SHRs into five groups: a control group fed a normal diet; an untreated DM group induced by injecting the SHRs with STZ/NA and feeding them a high-fat diet (HFD); and three treated groups (after giving STZ/NA and HFD) gavage given with Eu-A, Gli or Pio (5 mg/kg per day) for 4 weeks. Key findings The untreated DM group weighed less and had hyperglycaemia, hypoinsulinemia and hyperlipidemia. They were also found to have aberrant glucose-dependent insulin pathways, glucose metabolism and lipid synthesis proteins, while the controls did not. Eu-A, Gli and Pio ameliorated the above biochemical parameters in the treatment groups. Eu-A and Pio, but not Gli, improved hypertension and tachycardia. Conclusions Taken together, Eu-A ameliorated DM, hypertension and tachycardia by improving glucose, lipid homeostasis and anti-adrenergic, serotonergic activities. We concluded that Eu-A could be used in the development of an effective agent for controlling DM and its complications.

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Aerobic Exercise Increases Meteorin-Like Protein in Muscle and Adipose Tissue of Chronic High-Fat Diet-Induced Obese Mice

BioMed Research International ◽

10.1155/2018/6283932 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Ju Yong Bae

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Normal Diet ◽

Whole Body ◽

Peroxisome Proliferator ◽

Obese Mice ◽

High Fat ◽

Peripheral Tissues ◽

Body Tissues ◽

Exercise Induced

Upregulated meteorin-like (Metrnl) protein in peripheral tissues because of exercise-induced increases in intramuscular Metrnl may effectively alleviate obesity by improving metabolism in whole-body tissues. The objective was to analyse the effects of regular treadmill exercise on Metrnl levels in muscle and peripheral tissues of chronic high-fat diet- (HFD-) induced obese mice. Forty-eight-week-old male C57BL/6 mice were first divided equally into normal-diet (CO) and high-fat diet (HF) groups. Following 16 weeks of a HFD, each group was again split equally into control (CO, HF) and training groups (COT, HFT). The HFT group expressed significantly higher phospho-AMP-activated protein kinase (AMPK), AMPK activity, and peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α) in muscle tissue than the HF group (p<0.05). Similar to muscle energy sensing network protein levels, the HFT group also expressed significantly higher muscle, plasma, and adipose tissue Metrnl (p<0.05). Moreover, regular exercise increased acyl-CoA oxidase 1 (ACOX-1) and monoglyceride lipase (MGL) expression in adipose tissue (p<0.05) and significantly decreased abdominal fat mass (p<0.05). This study suggests that exercise-induced muscle Metrnl effectively reduces fat accumulation through the increase of Metrnl in adipose tissue, which may be a therapeutic target for chronic obesity.

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