Betatrophin expression is promoted in obese hyperinsulinemic type 2 but not type 1 diabetic mice

Li, EnXu; Nakata, Masao; Shinozaki, Atsumi; Yang, Yifei; Zhang, Boyang; Yada, Toshihiko

doi:10.1507/endocrj.ej16-0164

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…Our data indicated that elevation of plasma insulin is an important factor that induces the upregulation of hepatic Angptl8 expression. Consistent with this result, a previous study showed that the expression of Angptl8 was only upregulated in the liver, white adipose tissue and brown adipose tissue of obesity-induced hyperinsulinemic type 2 diabetes mice, but it was decreased in white adipose tissue of streptozotocin-induced hypoinsulinemic type 1 diabetes mice [37]. Together, our data and the results from other studies show that insulin-mediated PI3K/Akt signaling pathway is a major upstream regulator for HFD-induced Angptl8 expression, but not blood glucose.…”

Section: Discussionsupporting

confidence: 78%

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice

Huang

Chen

Yen

et al. 2019

IJMS

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Imbalance of lipid metabolism is a main cause of metabolic syndrome leading to life-threatening metabolic diseases. Angiopoietin-like protein 8 (Angptl8) was recently identified as a liver and adipose tissue-released hormone that is one of the molecules involved in triglyceride metabolism. However, the regulatory mechanism of Angptl8 is largely unknown. A high fat diet (HFD)-fed mouse model, which showed high cholesterol, high triglyceride, and high insulin in the blood, revealed the upregulation of hepatic and plasma Angptl8 and the downregulation of hepatic glycine N-methyltransferase (GNMT). The inverse correlation of hepatic Angptl8 and GNMT expression in the livers of HFD-fed mice was also confirmed in a publicly available microarray dataset. The mechanistic study using primary hepatocytes showed that the Angptl8 expression could be induced by insulin treatment in a dose- and time-dependent manner. Inhibition of PI3K/Akt pathway by the specific inhibitors or the dominant-negative Akt blocked the insulin-induced Angptl8 expression. Moreover, knockout of GNMT promoted the Akt activation as well as the Angptl8 expression. These results suggested that GNMT might be involved in insulin-induced Angptl8 expression in HFD-mediated metabolic syndrome.

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Section: Discussionsupporting

confidence: 78%

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice

Huang

Chen

Yen

et al. 2019

IJMS

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“…To confirm the influence of Angptl8 KO on body weight, we measured weights when the rats were on a high-fat diet (5.24 kcal/g, with 60% of calories from fat, D12492; Research Diets Inc., New Brunswick, NJ), which increases the expression of ANGPTL8 in liver and adipose tissue (7,26,27). Rats were fed a high-fat diet from the age of 8 weeks, and they all gained weight gradually, but from the age of 13 weeks on, Angptl8 KO rats gained significantly less weight than WT rats (Fig.…”

Section: Angptl8 Ko Rats Were Resistant To Diet-induced Obesitymentioning

confidence: 99%

CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats

Izumi

Kusakabe

Noguchi

et al. 2018

Journal of Lipid Research

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Angiopoietin-like protein (ANGPTL)8 is a liver- and adipocyte-derived protein that controls plasma triglyceride (TG) levels. Most animal studies have used mouse models. Here, we generated an KO rat model using a clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system to clarify the roles of ANGPTL8 in glucose and lipid metabolism. Compared with WT rats, KO rats had lower body weight and fat content, associated with impaired lipogenesis in adipocytes; no differences existed between the groups in food intake or rectal temperature. Plasma TG levels in both the fasted and refed states were significantly lower in KO than in WT rats, and an oral fat tolerance test showed decreased plasma TG excursion in KO rats. Higher levels of lipase activity in the heart and greater expression of genes related to β-oxidation in heart and skeletal muscle were observed in KO rats. However, there were no significant differences between KO and WT rats in glucose metabolism or the histology of pancreatic β-cells on both standard and high-fat diets. In conclusion, we demonstrated that KO in rats resulted in lower body weight and plasma TG levels without affecting glucose metabolism. ANGPTL8 might be an important therapeutic target for obesity and dyslipidemia.

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“…It would be beneficial to increase the sample size of DIO-C57BL/6J mice to obtain more precise data of plasma podocan levels in DIO-C57BL/6J mice. Plasma insulin levels have been reported to increase to a greater extent in obese-diabetic mice such as the db/db mice than in obese DIO-C57BL/6J mice without diabetes [ 18 ]. In adipose tissues, TNF- α mRNA levels are elevated, which correlates highly with plasma insulin levels [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Podocan Is Expressed in Blood and Adipose Tissue and Correlates Negatively With the Induction of Diabetic Nephropathy

Nio¹,

Okawara²,

Okuda

et al. 2017

Journal of the Endocrine Society

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Podocan, a member of the small leucine-rich repeat proteoglycans (SLRPs), is expressed in vascular endothelial cells with high levels of expression in the sclerotic glomerular lesions of experimental HIV-associated nephropathy. It is also found in vascular smooth muscle cells and is involved in atherosclerosis. Decorin, a protein similar to podocan, also belongs to the SLRP family and is highly expressed in adipose tissues. It is a secreted protein associated with obesity, type 2 diabetes, and diabetic nephropathy. Based on the similarity of podocan to decorin and its functions reported in the renal and cardiovascular systems, we hypothesized that podocan levels might correlate with the occurrence of metabolic syndromes such as obesity, diabetes, and diabetic nephropathy. We found that podocan was highly expressed in the adipose tissue of mice and humans and its expression was regulated by tumor necrosis factor-α in mouse 3T3-L1 adipocytes. In addition, podocan was detected in the plasma, and its levels tended to increase in diet-induced obese C57BL/6J mice and decrease in obese-diabetic KKAy and db/db mice. Podocan messenger RNA (mRNA) levels in the renal cortex correlated negatively with the urinary albumin-to-creatinine ratio, a surrogate marker of glomerular injury in uninephrectomized db/db mice used as a model of diabetic nephropathy. Our results suggest that podocan is involved in kidney function and could be a unique therapeutic target for diabetic nephropathy.

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Betatrophin expression is promoted in obese hyperinsulinemic type 2 but not type 1 diabetic mice

Cited by 10 publications

References 22 publications

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice

Loss of Glycine N-Methyltransferase Associates with Angiopoietin-Like Protein 8 Expression in High Fat-Diet-Fed Mice

CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats

Podocan Is Expressed in Blood and Adipose Tissue and Correlates Negatively With the Induction of Diabetic Nephropathy

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