• 생명과학회지
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• 제34권1호
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• pp.1-8
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• 2024

Brain-type natriuretic peptide (BNP)은 뇌나트륨이뇨펩티드로, 좌심실의 심근세포에서 분비되는 호르몬으로, 심장과 신장에 작용하여 혈관 확장과 나트륨 이뇨 작용 등을 하는 것으로 알려져 있으나, 최근에는 다양한 조직에서 대사 작용을 조절하는 것으로 보고된다. 본 연구에서는 간 조직에서 BNP의 영향을 알기 위해 BNP가 고지방식이에 의해 유도되는 인슐린 저항성을 개선하는지를 조사하였다. BNP을 주입한 쥐와 control로서 saline을 주입한 쥐들 간에는 몸무게, 체지방양(fat mass), 제지방량(lean body mass)의 변화는 없었다. 고인슐린혈증 정상혈당 글루코스 클램프(Hyperinsulinemic Euglycemic Glucose Clam) 동안, BNP를 주입한 고지방 식이 쥐들은 saline을 주입한 고지방식이 쥐에 비해 혈당(blood glucose)은 감소하였으며, 포도당 주입 속도(glucose infusion rate)는 증가하였다. 또한 BNP은 포도당 신생 및 중성지방 합성 관련 유전자들의 발현을 감소시켜, 간에서 포도당 생성과 중성지방의 양을 감소시켰다. BNP는 saline을 주입한 쥐에 비해 간 조직에서 Akt와 AMP-activated protein kinase (AMPK)의 인산화를 증가시켰는데, 이는 BNP을 처리한 AML12 간세포에서도 BNP는Akt와 AMPK 인산화를 증가시켰다. 이상의 결과는 BNP가 간에서 인슐린 저항성을 개선하여 포도당 생성과 중성 지방 생성을 억제함을 알 수 있었다.

• BMB Reports
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• 제46권12호
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• pp.567-574
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• 2013

Liver plays a major role in maintaining glucose homeostasis in mammals. Under fasting conditions, hepatic glucose production is critical as a source of fuel to maintain the basic functions in other tissues, including skeletal muscle, red blood cells, and the brain. Fasting hormones glucagon and cortisol play major roles during the process, in part by activating the transcription of key enzyme genes in the gluconeogenesis such as phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6 phosphatase catalytic subunit (G6Pase). Conversely, gluconeogenic transcription is repressed by pancreatic insulin under feeding conditions, which effectively inhibits transcriptional activator complexes by either promoting post-translational modifications or activating transcriptional inhibitors in the liver, resulting in the reduction of hepatic glucose output. The transcriptional regulatory machineries have been highlighted as targets for type 2 diabetes drugs to control glycemia, so understanding of the complex regulatory mechanisms for transcription circuits for hepatic gluconeogenesis is critical in the potential development of therapeutic tools for the treatment of this disease. In this review, the current understanding regarding the roles of two key transcriptional activators, CREB and FoxO1, in the regulation of hepatic gluconeogenic program is discussed.

• 한국발생생물학회지:발생과생식
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• 제27권2호
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• pp.77-89
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• 2023

Metformin is the most widely used anti-diabetic drug that helps maintain normal blood glucose levels primarily by suppressing hepatic gluconeogenesis in type II diabetic patients. We previously found that metformin induces apoptotic death in H4IIE rat hepatocellular carcinoma cells. Despite its anti-diabetic roles, the effect of metformin on hepatic de novo lipogenesis (DNL) remains unclear. We investigated the effect of metformin on hepatic DNL and apoptotic cell death in H4IIE cells. Metformin treatment stimulated glucose consumption, lactate production, intracellular fat accumulation, and the expressions of lipogenic proteins. It also stimulated apoptosis but reduced autophagic responses. These metformin-induced changes were clearly reversed by compound C, an inhibitor of AMP-activated protein kinase (AMPK). Interestingly, metformin massively increased the production of reactive oxygen species (ROS), which was completely blocked by compound C. Metformin also stimulated the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Finally, inhibition of p38MAPK mimicked the effects of compound C, and suppressed the metformin-induced fat accumulation and apoptosis. Taken together, metformin stimulates dysregulated glucose metabolism, intracellular fat accumulation, and apoptosis. Our findings suggest that metformin induces excessive glucose-induced DNL, oxidative stress by ROS generation, activation of AMPK and p38MAPK, suppression of autophagy, and ultimately apoptosis.

• Journal of Yeungnam Medical Science
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• 제36권1호
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• pp.26-35
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• 2019

Background: Dysregulation of hepatic glucose production (HGP) contributes to the development of type 2 diabetes mellitus. Telmisartan, an angiotensin II type 1 receptor blocker (ARB), has various ancillary effects in addition to common blood pressure-lowering effects. The effects and mechanism of telmisartan on HGP have not been fully elucidated and, therefore, we investigated these phenomena in hyperglycemic HepG2 cells and high-fat diet (HFD)-fed mice. Methods: Glucose production and glucose uptake were measured in HepG2 cells. Expression levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase ${\alpha}$ ($G6Pase-{\alpha}$), and phosphorylation levels of insulin receptor substrate-1 (IRS-1) and protein kinase C ${\zeta}$ ($PKC{\zeta}$) were assessed by western blot analysis. Animal studies were performed using HFD-fed mice. Results: Telmisartan dose-dependently increased HGP, and PEPCK expression was minimally increased at a $40{\mu}M$ concentration without a change in $G6Pase-{\alpha}$ expression. In contrast, telmisartan increased phosphorylation of IRS-1 at Ser302 ($p-IRS-1-Ser^{302}$) and decreased $p-IRS-1-Tyr^{632}$ dose-dependently. Telmisartan dose-dependently increased $p-PKC{\zeta}-Thr^{410}$ which is known to reduce insulin action by inducing IRS-1 serine phosphorylation. Ectopic expression of dominant-negative $PKC{\zeta}$ significantly attenuated telmisartan-induced HGP and $p-IRS-1-Ser^{302}$ and -inhibited $p-IRS-1-Tyr^{632}$. Among ARBs, including losartan and fimasartan, only telmisartan changed IRS-1 phosphorylation and pretreatment with GW9662, a specific and irreversible peroxisome proliferator-activated receptor ${\gamma}$ ($PPAR{\gamma}$) antagonist, did not alter this effect. Finally, in the livers from HFD-fed mice, telmisartan increased $p-IRS-1-Ser^{302}$ and decreased $p-IRS-1-Tyr^{632}$, which was accompanied by an increase in $p-PKC{\zeta}-Thr^{410}$. Conclusion: These results suggest that telmisartan increases HGP by inducing $p-PKC{\zeta}-Thr^{410}$ that increases $p-IRS-1-Ser^{302}$ and decreases $p-IRS-1-Tyr^{632}$ in a $PPAR{\gamma}$-independent manner

• Asian-Australasian Journal of Animal Sciences
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• 제28권2호
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• pp.207-214
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• 2015

The effects of high carbohydrate diet on growth, serum physiological response, and hepatic heat shock protein 70 expression in Wuchang bream were determined at $25^{\circ}C$ and $30^{\circ}C$. At each temperature, the fish fed the control diet (31% CHO) had significantly higher weight gain, specific growth rate, protein efficiency ratio and hepatic glucose-6-phosphatase activities, lower feed conversion ratio and hepatosomatic index (HSI), whole crude lipid, serum glucose, hepatic glucokinase (GK) activity than those fed the high-carbohydrate diet (47% CHO) (p<0.05). The fish reared at $25^{\circ}C$ had significantly higher whole body crude protein and ash, serum cholesterol and triglyceride, hepatic G-6-Pase activity, lower glycogen content and relative levels of hepatic growth hormone (GH) gene expression than those reared at $30^{\circ}C$ (p<0.05). Significant interaction between temperature and diet was found for HSI, condition factor, hepatic GK activity and the relative levels of hepatic GH gene expression (p<0.05).

• Nutrition Research and Practice
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• 제10권5호
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• pp.507-515
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• 2016

BACKGROUND/OBJECTIVES: This study was designed to investigate whether Gynura procumbens extract (GPE) can improve insulin sensitivity and suppress hepatic glucose production in an animal model of type 2 diabetes. MATERIALS/METHODS: C57BL/Ksj-db/db mice were divided into 3 groups, a regular diet (control), GPE, and rosiglitazone groups (0.005 g/100 g diet) and fed for 6 weeks. RESULTS: Mice supplemented with GPE showed significantly lower blood levels of glucose and glycosylated hemoglobin than diabetic control mice. Glucose and insulin tolerance test also showed the positive effect of GPE on increasing insulin sensitivity. The homeostatic index of insulin resistance was significantly lower in mice supplemented with GPE than in the diabetic control mice. In the skeletal muscle, the expression of phosphorylated AMP-activated protein kinase, pAkt substrate of 160 kDa, and PM-glucose transporter type 4 increased in mice supplemented with GPE when compared to that of the diabetic control mice. GPE also decreased the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the liver. CONCLUSIONS: These findings demonstrate that GPE might improve insulin sensitivity and inhibit gluconeogenesis in the liver.

• Animal Bioscience
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• 제35권8호
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• pp.1184-1194
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• 2022

Objective: High concentrate diets are widely used to satisfy high-yielding dairy cows; however, long-term feeding of high concentrate diets can cause subacute ruminal acidosis (SARA). The endocrine disturbance is one of the important reasons for metabolic disorders caused by SARA. However, there is no current report about thyroid hormones involved in liver metabolic disorders induced by a high concentrate diet. Methods: In this study, 12 mid-lactating dairy cows were randomly assigned to HC (high concentrate) group (60% concentrate of dry matter, n = 6) and LC (low concentrate) group (40% concentrate of dry matter, n = 6). All cows were slaughtered on the 21st day, and the samples of blood and liver were collected to analyze the blood biochemistry, histological changes, thyroid hormones, and the expression of genes and proteins. Results: Compared with LC group, HC group showed decreased serum triglyceride, free fatty acid, total cholesterol, low-density lipoprotein cholesterol, increased hepatic glycogen, and glucose. For glucose metabolism, the gene and protein expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 in the liver were significantly up-regulated in HC group. For lipid metabolism, the expression of sterol regulatory element-binding protein 1, long-chain acyl-CoA synthetase 1, and fatty acid synthase in the liver was decreased in HC group, whereas carnitine palmitoyltransferase 1α and peroxisome proliferator activated receptor α were increased. Serum triiodothyronine, thyroxin, free triiodothyronine (FT3), and hepatic FT3 increased in HC group, accompanied by increased expression of thyroid hormone receptor (THR) in the liver. Conclusion: Taken together, thyroid hormones may increase hepatic gluconeogenesis, β-oxidation and reduce fatty acid synthesis through the THR pathway to participate in the metabolic disorders caused by a high concentrate diet.

• Animal Bioscience
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• 제34권3_spc호
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• pp.405-416
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• 2021

Objective: This study evaluated the effects of feeding diets naturally contaminated with deoxynivalenol (supplemental 2 mg/kg) on health, growth, and the effects of a mycotoxin-detoxifying additive in newly-weaned pigs. Methods: Thirty-six pigs (27 day-old) were housed individually and assigned to 3 treatments for 5 weeks: CON (diet containing minimal deoxynivalenol), MT (diet with supplemental 1.9 mg/kg of deoxynivalenol), and MT+D (MT + mycotoxin-detoxifying additive, 0.2%, MegaFix, ICC, São Paulo, Brazil). The mycotoxin-detoxifying additive included bentonite, algae, enzymes, and yeast. Blood was taken at week 2 and 5. Jejunal tissue were taken at week 5. Data were analyzed using the MIXED procedure of SAS. Results: Pigs fed MT+D tended to have decreased (p = 0.056) averaged daily feed intake during week 1 than MT. At week 2, serum aspartate aminotransferase/alanine aminotransferase in MT tended to be lower (p = 0.059) than CON, whereas it was increased (p<0.05) for MT+D than MT, indicating hepatic damages in MT and recovery in MT+D. Pigs fed MT had lower (p<0.05) blood urea nitrogen/creatinine than CON, supporting hepatic damage. At week 5, pigs fed MT tended to have reduced (p = 0.079) glucose than CON, whereas it was increased (p<0.05) for MT+D than MT, indicating impaired intestinal glucose absorption in MT, which was improved in MT+D. Pigs fed CON tended to have increased (p = 0.057) total glutathione in jejunum than MT, indicating oxidative stress in MT. Pigs fed MT+D had a reduced (p<0.05) proportion of Ki-67-positive cells in jejunum than MT, indicating lower enterocyte proliferation in MT+D. Conclusion: Feeding supplemental 1.9 mg/kg of deoxynivalenol reduced growth and debilitated hepatic health of pigs, as seen in leakage of hepatic enzymes, impaired nitrogen metabolism, and increase in oxidative stress. The mycotoxin-detoxifying enhanced hepatic health and glucose levels, and attenuated gut damage in pigs fed deoxynivalenol contaminated diets.

• Asian-Australasian Journal of Animal Sciences
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• 제27권1호
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• pp.147-154
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• 2014

This review focuses on modulation of growth hormone (GH) and its downstream actions on periparturient dairy cows undergoing physiological and metabolic adaptations. During the periparturient period, cows experience a negative energy balance implicating that the feed intake does not meet the total energy demand for the onset of lactation. To regulate this metabolic condition, key hormones of somatotropic axis such as GH, IGF-I and insulin must coordinate adaptations required for the preservation of metabolic homeostasis. The hepatic GHR1A transcript and GHR protein are reduced at parturition, but recovers on postpartum. However, plasma IGF-I concentration remains low even though hepatic abundance of the GHR and IGF-I mRNA return to pre-calving value. This might be caused by alternation in IGFBPs and ALS genes, which consequently affect the plasma IGF-I stability. Plasma insulin level declines in a parallel manner with the decrease in plasma IGF-I after parturition. Increased GH stimulates the lipolytic effects and hepatic glucose synthesis to meet the energy requirement for mammary lactose synthesis, suggesting that GH antagonizes insulin-dependent glucose uptake and attenuates insulin action to decrease gluconeogenesis.

• 생약학회지
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• 제53권3호
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• pp.145-152
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• 2022

Type II diabetes mellitus (T2DM) is a chronic metabolic disease caused by insulin resistance, and abnormally elevated hepatic gluconeogenesis is characterized. Phillyrin, one of the major active constituents of Forsythia suspense, is known to possess the anti-inflammatory and anti-oxidant effects. However, the anti-diabetes mellitus effect of phillyrin and its molecular mechanisms are unclear. The aim of the current study was to investigate the role of phillyrin on gluconeogenesis in insulin resistant HepG2 cells. Phillyrin suppressed high glucose (HG)-induced glucose production. In addition, phillyrin reduced HG-induced the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), major genes in hepatic gluconeogenesis. Phillyrin treatment attenuated HG-induced nucleus protein levels of FOXO1 and HDAC5 and increased the phosphorylation of Akt, AMPK, HDAC5, and FOXO1. The block of AMPK and Akt activity did not exert the inhibitory effect of phillyrin on gluconeogenesis in insulin resistant HepG2. Taken together, these results suggest that phillyrin inhibits gluconeogenesis of hepatocytes to improve glucose metabolism, through the regulation of LKB1/AMPK/HDAC5 and PI3K/AKT/FOXO1 pathway. These results indicate that phillyrin may be useful in improving hepatic gluconeogenesis associated with insulin resistant and T2DM.